bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepatitis delta virus RNA decline post inoculation in human NTCP transgenic mice is biphasic
Authors: Maya Stephanie , Hershkovich Leeor , Cardozo-Ojeda E Fabian , Shirvani-Dastgerdi Elham , Srinivas Jay , Shekhtman Louis , Uprichard Susan L , Berneshawi Andrew R , Cafiero Thomas R , Dahari Harel , Ploss Alexander
Published: February 2023

Background and Aims

Chronic infection with hepatitis B and hepatitis delta viruses (HDV) is considered the most serious form of viral hepatitis due to more severe manifestations of and accelerated progression to liver fibrosis, cirrhosis, and hepatocellular carcinoma. There is no FDA-approved treatment for HDV and current interferon-alpha treatment is suboptimal. We characterized early HDV kinetics post inoculation and incorporated mathematical modeling to provide insights into host-HDV dynamics.

Methods

We analyzed HDV RNA serum viremia in 192 immunocompetent (C57BL/6) and immunodeficient (NRG) mice that did or did not transgenically express the HDV receptor - human sodium taurocholate co-transporting peptide (hNTCP).

Results

Kinetic analysis indicates an unanticipated biphasic decline consisting of a sharp first-phase and slower second-phase decline regardless of immunocompetence. HDV decline after re-inoculation again followed a biphasic decline; however, a steeper second-phase HDV decline was observed in NRG-hNTCP mice compared to NRG mice. HDV-entry inhibitor bulevirtide administration and HDV re-inoculation indicated that viral entry and receptor saturation are not major contributors to clearance, respectively. The biphasic kinetics can be mathematically modeled by assuming the existence of a non-specific binding compartment with a constant on/off-rate and the steeper second-phase decline by a loss of bound virus that cannot be returned as free virus to circulation. The model predicts that free HDV is cleared with a half-life of 18 minutes (standard error, SE: 2.4), binds to non-specific cells with a rate of 0.06 hour-1(SE: 0.03), and returns as free virus with a rate of 0.23 hour-1(SE: 0.03).

Conclusions

Understanding early HDV-host kinetics will inform pre-clinical therapeutic kinetic studies on how the efficacy of anti-HDV therapeutics can be affected by early kinetics of viral decline.

LAY SUMMARY

The persistence phase of HDV infection has been studied in some animal models, however, the early kinetics of HDV in vivo is incompletely understood. In this study, we characterize an unexpectedly HDV biphasic decline post inoculation in immunocompetent and immunodeficient mouse models and use mathematical modeling to provide insights into HDV-host dynamics. Understanding the kinetics of viral clearance in the blood can aid pre-clinical development and testing models for anti-HDV therapeutics.
Vimentin supports cell polarization by enhancing centrosome function and microtubule acetylation
Authors: Saldanha Renita , Ho Thanh Minh Tri , Krishnan Nikhila , Hehnly Heidi , Patteson Alison
Published: February 2023

Cell polarity is important for controlling cell shape, motility, and cell division processes. Vimentin intermediate filaments are necessary for proper polarization of migrating fibroblasts and assembly of vimentin and microtubule networks is dynamically coordinated, but the precise details of how vimentin mediates cell polarity remain unclear. Here, we characterize the effects of vimentin on the structure and function of the centrosome and the stability of microtubule filaments in wild-type and vimentin-null mouse embryonic fibroblasts (mEFs). We find that vimentin mediates the structure of the pericentrosomal material, promotes centrosome-mediated microtubule regrowth, and increases the level of stable acetylated microtubules in the cell. Loss of vimentin also impairs centrosome repositioning during cell polarization and migration processes that occur during wound closure. Our results suggest that vimentin modulates centrosome structure and function as well as microtubule network stability, which has important implications for how cells establish proper cell polarization and persistent migration.
HECTD1 is both a positive regulator and substrate of caspase-3 activity during apoptotic cell death
Authors: Scholz Nico , Siebzehnrubl Florian , Licchesi Julien D. F
Published: February 2023

Programmed cell death is a complex and tightly regulated sequence of events that determines cell fate during tissue homeostasis, development, and pathogenesis. The small protein modifier ubiquitin mediates important regulatory functions during cell death by regulating the stability and activity of checkpoint proteins and the assembly of cell death signalling complexes. The caspase family of cysteine aspartases are essential effectors of apoptotic cell death. Components of the ubiquitin system including RING ubiquitin ligases XIAP, MDM2, RBX1; RBR E3 ubiquitin ligases Parkin and LUBAC; and HECT E3 ubiquitin ligases NEDD4 and Itch are also substrates of caspase-mediated cleavage. In the case of NEDD4 and Itch, the single cleavage event occurs outside of the catalytic HECT domain and it remains unclear whether such cleavage events impact on ubiquitin ligase activity and/or function. Here, we identified the E3 ubiquitin ligase HECTD1 as the third HECT E3 cleaved by caspase-mediated cleavage during apoptotic cell death, in a manner which does not affect the integrity of the catalytic C-ter HECT domain. We mapped the single cleavage event to DFLD1664↓S and showed that the cleaved C-ter product, which contains the HECT ligase domain, is as stable as the endogenous full length protein. We also found that HECTD1 transient depletion led to reduced caspase-3 activity, but not caspase 8 nor 9. Furthermore, we also identified caspase-3 as the protease responsible for HECTD1 cleavage at Asp1664 suggesting that HECTD1 and caspase-3 might be part of a novel feedback loop mechanism during apoptotic cell death. This study highlight novel crosstalk between cell death mechanisms and the ubiquitin system and raises important questions on whether proteolytic cleavage of E3 ubiquitin ligases might represent an underappreciated mode of regulation during cell death mechanisms.
Age-related changes in network controllability are mitigated by redundancy in large-scale brain networks
Authors: Stanford William , Mucha Peter J. , Dayan Eran
Published: February 2023

The aging brain undergoes major changes in its topology. The mechanisms by which the brain mitigates age-associated changes in topology to maintain robust control of brain networks are unknown. Here we used diffusion MRI data from cognitively intact participants (n=480, ages 40-90) to study age-associated changes in the controllability of structural brain networks, features that could mitigate these changes, and the overall effect on cognitive function. We found age-associated declines in controllability in control hubs and large-scale networks, particularly within the and frontoparietal control and default mode networks. Redundancy, quantified via the assessment of multi-step paths within networks, mitigated the effects of changes in topology on network controllability. Lastly, network controllability, redundancy, and grey matter volume each played important complementary roles in cognitive function. In sum, our results highlight the importance of redundancy for robust control of brain networks and in cognitive function in healthy-aging.
Astrocytic TIMP-1 regulates production of Anastellin, a novel inhibitor of oligodendrocyte differentiation and FTY720 responses
Authors: Sutter Pearl A. , Willis Cory M. , Menoret Antoine , Nicaise Alexandra M. , Sacino Anthony , Sikkema Arend. H. , Jellison Evan , Win Kyaw K. , Han David K. , Church William , Baron Wia , Vella Anthony T. , Crocker Stephen J.
Published: February 2023

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. We have previously demonstrated that murine astrocytes that lack expression ofTimp1do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult globalTimp1knockout (Timp1KO) mice do not efficiently remyelinate following a demyelinating injury. To better understand the basis of this, we performed unbiased proteomic analyses and identified a fibronectin-derived peptide called anastellin that is unique to the murineTimp1KOastrocyte secretome. Anastellin was found to block rOPC differentiationin vitroand enhanced the inhibitory influence of fibronectin on rOPC differentiation. Anastellin is known to act upon the sphingosine-1-phosphate receptor 1 (S1PR1), and we determined that anastellin also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiationin vitro. Further, administration of FTY720 to wild-type C57BL/6 mice during MOG35-55-EAE ameliorated clinical disability while FTY720 administered to mice lacking expression ofTimp1in astrocytes (Timp1cKO) had no effect. Analysis of humanTIMP1and fibronectin (FN1) transcripts from healthy and multiple sclerosis (MS) patient brain samples revealed an inverse relationship where lowerTIMP1expression was coincident with elevatedFN1in MS astrocytes. Lastly, we analyzed proteomic databases of MS samples and identified anastellin peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high versus low disease activity. The prospective role for anastellin generation in association with myelin lesions as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and the innate remyelination potential of the the MS brain.

Significance Statement

Astrocytic production of TIMP-1 prevents the protein catabolism of fibronectin. In the absence of TIMP-1, fibronectin is further digested leading to a higher abundance of anastellin peptides that can bind to sphingosine-1-phosphate receptor 1. The binding of anastellin with the sphingosine-1-phosphate receptor 1 impairs the differentiation of oligodendrocytes progenitor cells into myelinating oligodendrocytesin vitro, and negates the astrocyte-mediated therapeutic effects of FTY720 in the EAE model of chronic CNS inflammation. These data indicate that TIMP-1 production by astrocytes is important in coordinating astrocytic functions during inflammation. In the absence of astrocyte produced TIMP-1, elevated expression of anastellin may represent a prospective biomarker for FTY720 therapeutic responsiveness.
Differentiation of white matter histopathology using b-tensor encoding and machine learning
Authors: Rios-Carrillo Ricardo , Ramírez-Manzanares Alonso , Luna-Munguía Hiram , Regalado Mirelta , Concha Luis
Published: February 2023

Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) is a non-invasive technique that is sensitive to microstructural geometry in neural tissue and is useful for the detection of neuropathology in research and clinical settings. Tensor valued diffusion encoding schemes (b-tensor) have been developed to enrich the microstructural data that can be obtained through DW-MRI. These advanced methods have proven to be more specific to microstructural properties than conventional DW-MRI acquisitions. Additionally, machine learning methods are particularly useful for the study of multidimensional data sets. In this work, we have tested the reach of b-tensor encoding data analyses with machine learning in different histopathological scenarios. We achieved this in three steps: 1) We induced different forms of white matter damage in rodent optic nerves. 2) We obtainedex-vivoDW-MRI with b-tensor encoding schemes and calculated quantitative metrics using Q-space Trajectory Imaging. 3) We used a machine learning model to identify the main contributing features and built a voxel-wise probabilistic classification map of histological damage. Our results show that this model is sensitive to characteristics of microstructural damage. In conclusion, b-tensor encoded DW-MRI analyzed with machine learning methods, have the potential to be further developed for the detection of histopathology and neurodegeneration.
Visuomotor activity associated with conditioned hand movements in premotor cortex of blindsight macaques
Authors: Yamamoto Yusuke , Kitazume Saya , Takahashi Jun , Onoe Hirotaka , Yamaguchi Reona , Isa Tadashi
Published: February 2023

Some patients with damage to the primary visual cortex (V1) can respond to visual stimuli in their affected visual field, even though they report loss of visual awareness. This phenomenon is termed blindsight. To clarify the visuomotor transformation for hand movement control in the blindsight condition, we conducted multichannel electrocorticographical recordings from the ipsilesional frontal cortex including the frontal eye field, premotor, primary motor, and somatosensory areas during a delayed conditioned two-alternative forced choice manual response task with arbitrary assignment of push-pull manual responses in relation to the visual target cue locations before and after unilateral V1 lesioning in macaque monkeys. Before lesioning, the activity in the dorsal premotor cortex (PMd) showed short latency task-related θ ~ α band responses that were significantly higher in the successful trials than in the error/miss trials at approximately 200 ms after target cue onset. At 2–3 months after lesioning, the monkeys regained a >80% success rate in response to appearance of the target cue in the lesion-affected visual field. At this stage, similar task-related θ ~ α band target cue responses were observed in the PMd. Further, Granger causality from the PMd to the primary motor cortex was enhanced in the θ ~ α, γ, and high-γ bands during the delay period of the task. These results suggested that the PMd plays a crucial role in mediating the visual signals for execution of hand movements in blindsight monkeys.

Significant Statement

Blindsight is a curious phenomenon in which the patients with damage to the primary visual cortex can still respond to visual stimulus in their blinded visual field despite loss of awareness. Previously we clarified the critical circuits for visually guided saccadic eye movements in blindsight macaques, however, those for the control of hand movements are still unclear. Here, we have recorded the multichannel electrocorticography in the frontal cortices during the conditioned manual response task and found that the dorsal premotor cortex exhibits task-related θ ~ α band target cue responses at approximately 200 ms after the visual cue onset, similarly to the intact state. This is the first report of electrophysiological recordings in the frontal lobe of the blindsight subjects.
Seasonal plasticity and energy efficiency in migratory buntings is an assemblage of alterations in metabolic and gut microbe adaptations
Authors: Gupta Neelu Jain , Das Samya , Das Mrinal , Arya Rakesh , Kumar Anit , Nanda Ranjan Kumar
Published: February 2023

Circulatory system is the source of useful metabolites to enable organismal energy demands of muscle during different life states of birds including migration. In this study, we profiled the serum metabolites and fecal microbiome of redheaded buntings (Emberiza bruniceps) exhibiting diurnal non-migratory (nonM) pre-migratory (preM), migratory (M) and post-migratory (posM) states, when exposed to long days (14L:10D). Using gas chromatography, out of the identified 124 serum analytes, 38 showed significant variations (Fold change, VIP) between states. Out of these, 11 metabolites (short chain fatty acids, SCFAs-butanoate and hexanoate, lactate, pyruvate, ethylene and acetate oxime, pyridoxal phosphate (PLP), niacin, L-valine and carboximidic acids viz. phosphatidyl ethanolamine (PE) and diethyl carbamate) involved in energy pathways and enhanced immunity showed higher abundance inMstate. While, upsurge of L-valine suggested energy contribution of glucogenic branched chain amino acids (BCAAs) inMstate, that of leucine metabolite, was related to higher temperature inposMbirds. Gut microbiota was analysed using faeces of buntings (n=6 each) during nonM and M states and alteration in bacterial compositions was observed; faeces of nonM birds were enriched in proteobacteria, while those of M were rich in firmicutes. This study reports the migratory state specific changes in the serum metabolome and faecal microbiome of the buntings and highlights the role of short chain fatty acids, SCFAs and branched chain amino acids, BCAAs during hypermetabolic state of migration.
Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands
Authors: Greenspon Charles M. , Valle Giacomo , Hobbs Taylor G. , Verbaarschot Ceci , Callier Thierri , Okorokova Elizaveta V. , Shelchkova Natalya D. , Sobinov Anton R. , Jordan Patrick M. , Weiss Jeffrey M. , Fitzgerald Emily E. , Prasad Dillan , van Driesche Ashley , Lee Ray C. , Satzer David , Gonzalez-Martinez Jorge , Warnke Peter C. , Miller Lee E. , Boninger Michael L. , Collinger Jennifer L. , Gaunt Robert A. , Downey John E. , Hatsopoulos Nicholas G. , Bensmaia Sliman J.
Published: February 2023

Abstract

Manual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participant’s ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing “biomimetic” ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.
Optogenetic inhibition of the caudal substantia nigra inflates behavioral responding to uncertain threat and safety
Authors: Wright Kristina M , Cieslewski Shannon , Chu Amanda , McDannald Michael A
Published: February 2023

Defensive responding is adaptive when it approximates current threat, but maladaptive when it exceeds current threat. Here we asked if the substantia nigra, a region consistently implicated in reward, is necessary to show appropriate levels of defensive responding in Pavlovian fear discrimination. Rats received bilateral transduction of the caudal substantia nigra with halorhodopsin or a control fluorophore, and bilateral ferrule implants. Rats then behaviorally discriminated cues predicting unique foot shock probabilities (danger,p=1; uncertainty,p=0.25; and safety,p=0). Green-light illumination (532 nm) during cue presentation inflated defensive responding of halorhodopsin rats – measured by suppression of reward seeking – to uncertainty and safety beyond control levels. Green-light illumination outside of cue presentation had no impact on halorhodopsin or control rat responding. The results reveal caudal substantia nigra cue activity is necessary to inhibit defensive responding to non-threatening and uncertain threat cues.
Defective mechanosensory transduction of the new inner hair cells prevents hearing recover in the damaged cochlea
Authors: Li Xiang , Ren Minhui , Gu Yunpeng , Zhu Tong , Zhang Yu , Li Jie , Li Chao , Wang Guangqin , Song Lei , Bi Zhenghong , Liu Zhiyong
Published: February 2023

ABSTRACT

Hearing loss is a major health problem worldwide. Numerous attempts at regenerating functional hair cells (HCs) have been unsuccessful, but little is known about the main barrier that prevents us from achieving it and improving the hearing ability after damage. Here, we developed anin vivogenetic mouse model, by which the inner HCs (IHCs), the primary sound receptors innervated by the auditory neurons, were specifically damaged and the neighboring nonsensory supporting cells (SCs) were transformed into IHCs by ectopic expression of transient Atoh1 and permanent Tbx2. Despite ∼477 new IHCs were regenerated per cochlea and their differentiation status was more advanced than reported previously, no significant hearing improvement was achieved. By taking advantage of this unique model, we further found that the new IHCs expressed the functional marker vGlut3, harbored the similar transcriptomic profiles and electrophysiological properties as the endogenous IHCs. However, the mechanosensory transduction (MET) current could not be recorded in the new IHCs. Thus, our study indicated that the defective MET should be the main barrier that stops us from restoring the hearing capacity in the damaged cochlea and would pave the way for regenerating IHCsin vivo.
Larger and denser: an optimal design for surface grids of EMG electrodes to identify greater and more representative samples of motor units
Authors: Caillet Arnault H. , Avrillon Simon , Kundu Aritra , Yu Tianyi , Phillips Andrew T.M. , Modenese Luca , Farina Dario
Published: February 2023

The spinal motor neurons are the only neural cells whose individual activity can be non-invasively identified. This is usually done using grids of surface electromyographic (EMG) electrodes and source separation algorithms; an approach called EMG decomposition. In this study, we combined computational and experimental analyses to assess how the design parameters of grids of electrodes influence the number and the properties of the identified motor units. We first computed the percentage of motor units that could be theoretically discriminated within a pool of 200 simulated motor units when decomposing EMG signals recorded with grids of various sizes and interelectrode distances (IED). Increasing the density, the number of electrodes, and the size of the grids, increased the number of motor units that our decomposition algorithm could theoretically discriminate, i.e., up to 83.5% of the simulated pool (range across conditions: 30.5-83.5%). We then identified motor units from experimental EMG signals recorded in six participants with grids of various sizes (range: 2-36 cm2) and IED (range: 4-16 mm). The configuration with the largest number of electrodes and the shortest IED maximized the number of identified motor units (56±14; range: 39-79) and the percentage of early recruited motor units within these samples (29±14%). Finally, the number of identified motor units further increased with a prototyped grid of 256 electrodes and an IED of 2 mm. Taken together, our results showed that larger and denser surface grids of electrodes allow to identify a more representative pool of motor units than currently reported in experimental studies.

Significance statement

The application of source separation methods to multi-channel EMG signals recorded with grids of electrodes enables users to accurately identify the activity of individual motor units. However, the design parameters of these grids have never been discussed. They are usually arbitrarily fixed, often based on commercial availability. Here, we showed that using larger and denser grids of electrodes than conventionally proposed drastically increases the number of identified motor units. The samples of identified units are more balanced between early- and late-recruited motor units. Thus, these grids provide a more representative sampling of the active motor unit population. Gathering large datasets of motor units using large and dense grids will impact the study of motor control, neuromuscular modelling, and human-machine interfacing.
Genetically distinct parallel projection populations from ventral hippocampus to prefrontal cortex
Authors: Sánchez-Bellot Candela , MacAskill Andrew F.
Published: February 2023

The ventral hippocampus is proposed to perform its multitude of roles via segregated populations of neurons identified by either genetic makeup, downstream projection, or their combination. Recently we described two parallel projections from ventral hippocampus to prefrontal cortex, segregated across the radial axis of the CA1 and subicular areas. These two populations had distinct afferent and efferent connectivity and distinct influence of approach avoidance behaviour. In this study, we extend these data by performing RNA sequencing of each population of neurons. We find that these two populations have multiple genes that are differentially expressed. These genes correspond both to genes classically thought to be distributed across the radial axis such asCalbindin 1andPcp4, but also to more unexpected genes including postsynaptic scaffolds and GABA receptor subunits. Notably, a number of genes differentially expressed across the two populations were associated with the development of mental illness, suggesting an imbalance in the function of these two pathways in disease may be an interesting area for future research. Together, these data reinforce the dissociation of function of projections to prefrontal cortex across the radial axis of the ventral hippocampus, and provide multiple targets for both the genetic and functional dissociation of these roles.
Intravenous haloperidol and cocaine alter the distribution of T CD3+CD4+, non‐T/NK and NKT cells in rats
Authors: Jankowski Maciej M. , Ignatowska‐Jankowska Bogna M. , Glac Wojciech , Wiergowski Marek , Kazmierska‐Grebowska Paulina , Swiergiel Artur H.
Published: February 2023

The modulation of dopamine transmission evokes strong behavioural effects that can be achieved by commonly used psychoactive drugs such as haloperidol or cocaine. Cocaine non‐specifically increases dopamine transmission by blocking dopamine active transporter (DAT) and evokes behavioural arousal, whereas haloperidol is a non‐specific D2‐like dopamine receptor antagonist with sedative effects. Interestingly, dopamine has been found to affect immune cells in addition to its action in the central nervous system. Here, we address the possible interactions between haloperidol and cocaine and their effects on both immune cells and behaviour in freely moving rats. We use an intravenous model of haloperidol and binge cocaine administration to evaluate the drugs' impact on the distribution of lymphocyte subsets in both the peripheral blood and the spleen. We assess the drugs' behavioural effects by measuring locomotor activity. Cocaine evoked a pronounced locomotor response and stereotypic behaviours, both of which were completely blocked after pretreatment with haloperidol. The results suggest that blood lymphopenia, which was induced by haloperidol and cocaine (except for natural killer T cells), is independent of D2‐like dopaminergic activity and most likely results from the massive secretion of corticosterone. Haloperidol pretreatment prevented the cocaine‐induced decrease in NKT cell numbers. Moreover, the increased systemic D2‐like dopaminergic activity after cocaine administration is a significant factor in retaining T CD3+CD4+ lymphocytes and non‐T/NK CD45RA+ cells in the spleen.
Recurrence of hypertensive disorders of pregnancy: results from a nationwide prospective cohort study (CONCEPTION)
Authors: Lailler G. , Grave C. , Gabet A. , Regnault N. , Deneux‐Tharaux C. , Kretz S. , Tsatsaris V. , Plu‐Bureau G. , Blacher J. , Olié V.
Published: February 2023

Objective

To assess the risk of gestational hypertension (GH) and pre‐eclampsia (PE) during a second pregnancy after occurrence during a first pregnancy.

Design

Prospective cohort study.

Setting

CONCEPTION is a French nationwide cohort study that used data from the National Health Data System (SNDS) database.

Methods

We included all women who gave birth for the first time in France in 2010–2018 and who subsequently gave birth. We identified GH and PE through hospital diagnoses and the dispensing of anti‐hypertensive drugs. The incidence rate ratios (IRR) of all hypertensive disorder of pregnancy (HDP) during the second pregnancy were estimated using Poisson models adjusted for confounding.

Main outcome measures

Incidence rate ratios of HDP during the second pregnancy.

Results

Of the 2 829 274 women included, 238 506 (8.4%) were diagnosed with HDP during their first pregnancy. In women with GH during their first pregnancy, 11.3% (IRR 4.5, 95% confidence interval [CI] 4.4–4.7) and 3.4% (IRR 5.0, 95% CI 4.8–5.3) developed GH and PE during their second pregnancy, respectively. In women with PE during their first pregnancy, 7.4% (IRR 2.6, 95% CI 2.5–2.7) and 14.7% (IRR 14.3, 95% CI 13.6–15.0) developed GH and PE during their second pregnancy, respectively. The more severe and earlier the PE during the first pregnancy, the stronger the likelihood of having PE during the second pregnancy. Maternal age, social deprivation, obesity, diabetes and chronic hypertension were all associated with PE recurrence.

Conclusion

These results can guide policymaking that focuses on improving counselling for women who wish to become pregnant more than once, by identifying those who would benefit more from tailored management of modifiable risk factors, and heightened surveillance during post‐first pregnancies.
Information about fetal movements and stillbirth trends: Analysis of time series data
Authors: Heazell Alexander E. P. , Holland Fiona , Wilkinson Jack
Published: February 2023

Objective

To investigate the implementation of the Count the Kicks campaign in Iowa to increase maternal awareness of fetal movements and its association with stillbirth rates.

Design

Time series analysis.

Setting

Iowa, Illinois, Minnesota and Missouri, USA.

Sample

Women giving birth between 2005 and 2018.

Methods

Data regarding campaign activity, including uptake of the app and the distribution of information materials, and population‐level data on stillbirth rates and potential confounding risk factors were obtained from publicly available data for 2005–2018. Data were plotted over time and examined in relation to key implementation phases.

Main outcome measure

Stillbirth.

Results

App users were largely centred on Iowa, and increased over time, although the numbers were modest relative to the number of births. Only Iowa demonstrated a reduction in stillbirth (OR 0.96, 95% CI 0.96–1.00 per year; interaction between state and time, p < 0.001); there was a decline from 2008 to 2013 (before the launch of the app), an increase from 2014 to 2016 and a decrease from 2017 to 2018, which coincided with increased app use (interaction between period and time, p = 0.06). With the exception of smoking (which fell from approx. 20% in 2005 to approx. 15% in 2018 in Iowa), all risk factors increased in prevalence, so are unlikely to account for a reduction in stillbirth.

Conclusions

There was a reduction in the stillbirth rate in Iowa, where an information campaign about fetal movements was active; this reduction was not present in neighbouring states. Large‐scale intervention studies are needed to determine whether the temporal associations between app use and stillbirth rate are causally related.
Successful Eisenmenger syndrome‐targeted drug therapy in pregnant women: a case series and literature review
Authors: Chen W. , Chen J. , Peng M. , Luo J. , Chen Y. , Qiu H. , Li J.
Published: February 2023

Objective

To clarify the real‐world outcomes in pregnant women with Eisenmenger syndrome (ES) in the new therapeutic era and provide a literature review.

Design

Retrospective case and literature review.

Setting

Tertiary referral hospital (The Second Xiangya Hospital of Central South University).

Sample

Thirteen women with ES delivered between 2011 and 2021.

Methods

Respective study and literature reviews.

Main outcomes measures

Maternal and neonatal mortality and morbidity.

Results

12/13 (92%) pregnant women were treated with targeted drugs. 9/13 (69%) of patients had heart failure, but no maternal deaths occurred. 12/13 (92%) of women chose caesarean delivery. One pregnant woman gave birth at 37+1 weeks, and the remaining 12 (92%) patients had preterm birth. 10/13 (77%) women gave birth to live infants, of which 9/10 (90%) were low birthweight infants with a mean birthweight of 1575 g. The infant mortality rate was 1/10 (10%). Cardiac functional class improved during pregnancy, probably due to therapy; 11/13 (85%) of the pregnant women were in cardiac functional level III/IV at admission and 12 (92%) were in cardiac functional class II/III at discharge. Our literature review identified 72 cases of pregnancy with ES from 11 studies, which were characterised by a low rate of targeted drug use (28%) and a high maternal mortality rate of 24% in the perinatal period.

Conclusion

Our case series and literature review suggest that targeted drugs may be key to improving maternal mortality in ES.
Emotional and psychosexual well‐being is influenced by ethnicity and birthplace in women and individuals with polycystic ovary syndrome in the UK and India
Authors: Sheikh Jameela , Khalil Halimah , Shaikh Salomi , Hebbar Meghnaa , Zia Nawal , Wicks Saskia , Jayaprakash Sindoora , Narendran Alisha , Subramanian Anuradhaa , Malhotra Kashish , Chapman Rachel , Gillett Caroline , Gleeson Helena K. , Robinson Lynne , Chu Justin J. , Lathia Tejal , Selvan Chitra , O'Reilly Michael W. , Manolopoulos Konstantinos N. , Arlt Wiebke , Kempegowda Punith ,   the PCOS SEva team
Published: February 2023

Objective

To assess the association of ethnicity and birthplace on emotional and psychosexual well‐being in women with polycystic ovary syndrome (PCOS).

Design

Cross‐sectional study.

Setting

Community recruitment via social media campaigns.

Population

Women with PCOS completing an online questionnaire in September–October 2020 (UK) and May–June 2021 (India).

Methods

The survey has five components, with a baseline information and sociodemographic section followed by four validated questionnaires: Hospital Anxiety and Depression Scale (HADS); Body Image Concern Inventory (BICI); Beliefs About Obese Persons Scale (BAOP); and Female Sexual Function Index (FSFI).

Main outcome measures

We used adjusted linear and logistic regression models, adjusting for age, education, marital status and parity, to evaluate the impact of ethnicity and birthplace on questionnaire scores and outcomes (anxiety and/or depression, HADS ≥ 11; body dysmorphic disorder (BDD), BICI ≥ 72).

Results

A total of 1008 women with PCOS were included. Women of non‐white ethnicity (613/1008) reported higher rates of depression (OR 1.96, 95% CI 1.41–2.73) and lower BDD (OR 0.57, 95% CI 0.41–0.79) than white women (395/1008). Women born in India (453/1008) had higher anxiety (OR 1.57, 95% CI 1.00–2.46) and depression (OR 2.20, 95% CI 1.52–3.18) but lower BDD rates (OR 0.42, 95% CI 0.29–0.61) than women born in the UK (437/1008). All sexual domains, excluding desire, scored lower for non‐white women and women born in India.

Conclusions

Non‐white women and women born in India reported higher emotional and sexual dysfunction, whereas white women and women born in the UK reported higher body image concerns and weight stigma. Ethnicity and birthplace need to be considered for tailored, multidisciplinary care.
Type 1 diabetes management: Room for improvement
Authors: Varkevisser Rita D. M. , Birnie Erwin , Mul Dick , van Dijk Peter R. , Aanstoot Henk‐Jan , Wolffenbuttel Bruce H. R. , van der Klauw Melanie M.
Published: February 2023

Aims/Hypothesis

Optimal diabetes care and risk factor management are important to delay micro‐ and macrovascular complications in individuals with type 1 diabetes (T1D). Ongoing improvement of management strategies requires the evaluation of target achievement and identification of risk factors in individuals who do (or do not) achieve these targets.

Methods

Cross‐sectional data were collected from adults with T1D visiting six diabetes centers in the Netherlands in 2018. Targets were defined as glycated hemoglobin (HbA1c) <53 mmol/mol, low‐density lipoprotein‐cholesterol (LDL‐c) <2.6 mmoL/L (no cardiovascular disease [CVD] present) or <1.8 mmoL/L (CVD present), or blood pressure (BP) <140/90 mm Hg. Target achievement was compared for individuals with and without CVD.

Results

Data from 1737 individuals were included. Mean HbA1c was 63 mmol/mol (7.9%), LDL‐c was 2.67 mmoL/L, and BP 131/76 mm Hg. In individuals with CVD, 24%, 33%, and 46% achieved HbA1c, LDL‐c, and BP targets respectively. In individuals without CVD these percentages were 29%, 54%, and 77%, respectively. Individuals with CVD did not have any significant risk factors for HbA1c, LDL‐c, and BP target achievement. In comparison, individuals without CVD were more likely to achieve glycemic targets if they were men and insulin pump users. Smoking, microvascular complications, and the prescription of lipid‐lowering and antihypertensive medication were negatively associated with glycemic target achievement. No characteristics were associated with LDL‐c target achievement. Microvascular complications and antihypertensive medication prescription were negatively associated with BP target attainment.

Conclusion

Opportunities for improvement of diabetes management exist for the achievement of glycemic, lipid, and BP targets but may differ between individuals with and without CVD.
Paradigm guiding to tapering or discontinuation of biologic and targeted synthetic disease‐modifying antirheumatic drugs in the treatment of patients with rheumatoid arthritis: Results from a local prospective study
Authors: Kaban Nedim , Harman Halil
Published: February 2023

Objective

We prospectively conduct the current study to figure out predicting factors whether biologic and targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs) can be discontinued or tapered in patients with rheumatoid arthritis (RA).

Materials and Methods

The study population encompassed 126 consecutive RA patients on b/tsDMARDs for at least 1 year. Remission was defined as a Disease Activity Score of 28 joints (DAS28) ‐ erythrocyte sedimentation rate <2.6. The b/tsDMARD dosing interval was increased in patients in remission for at least 6 months. In patients in whom the b/tsDMARD dosing interval could be increased by 100% for at least 6 months, the b/tsDMARD was stopped at the end of this period. Disease relapse was defined as deterioration from remission to moderate or high disease activity.

Results

The mean duration of b/tsDMARD treatment for all patients was 2.54 ± 1.55 years. Logistic regression analysis did not identify any independent predictor of treatment discontinuation. Independent predictors for tapering in b/tsDMARD treatment are no switch to another therapy and lower baseline DAS28 scores (respectively, P = .029, .024). Time to relapse after tapering was shorter in patients requiring corticosteroids when the 2 groups were compared with the log‐rank test (2.83 vs 10.8 months; P = .05).

Conclusion

It seems a reasonable approach to consider b/tsDMARD tapering in patients with remission period of >3.5 months, lower baseline DAS28 scores and without requiring corticosteroid use. Unfortunately, no predictor has been found to predict b/tsDMARD discontinuation.
Inhibitory control in young adult women with fetal alcohol syndrome: Findings from a pilot functional magnetic resonance imaging study
Authors: Rau Johanna M. H. , Sundermann Benedikt , Pfleiderer Bettina , Dehghan‐Nayyeri Mahboobeh , Garde Stefan , Weglage Josef , Feldmann Reinhold
Published: February 2023

Background

Executive dysfunction, especially impaired inhibitory control, is a common finding in individuals with fetal alcohol syndrome (FAS). Previous research has mostly focused on neural correlates of inhibitory deficits in children and adolescents. We investigated inhibitory functions and underlying cerebral activation patterns in young adult women with FAS.

Methods

Task performance and functional magnetic resonance imaging (fMRI) data were acquired during a Go/NoGo (GNG) inhibition task in 19 young adult women with FAS and 19 healthy female control subjects. Whole‐brain activation and task performance analyses were supplemented by region of interest (ROI) analyses of fMRI data within a predefined cognitive control network (CCN).

Results

Task performance did not differ significantly between groups on errors of commission, associated with inhibitory control. Similarly, overall activation within the preselected ROIs did not differ significantly between groups for the main inhibitory contrast NoGo > Go. However, whole‐brain analyses revealed activation differences in the FAS group when compared to controls under inhibitory conditions. This included hyperactivations in the left inferior frontal, superior temporal, and supramarginal gyri in the FAS group. Likewise, lateralization tendencies toward right‐hemispheric ROIs were weaker in FAS subjects. In contrast to comparable inhibitory performance, attention‐related errors of omission were significantly higher in the FAS group. Correspondingly, FAS subjects had lower activity in attention‐related temporal and parietal areas.

Conclusions

The known alterations of inhibitory functions associated with prenatal alcohol exposure in children and adolescents were not seen in this adult sample. However, differential brain activity was observed, reflecting potential compensatory mechanisms. Secondary results suggest that there is impaired attentional control in young adult women with FAS.
Transient apical breakdown of a discoloured maxillary central incisor during orthodontic treatment: A case report
Authors: Zhu Zufeng
Published: February 2023

Transient apical breakdown (TAB) appears to be a repair process taking place in the pulp and periapical area of traumatised teeth which may display crown discoloration and have no responses to pulp sensitivity tests. Few TAB cases induced by orthodontic forces have been reported so far. Presented is a case report in which TAB occurred on the maxillary right central incisor during orthodontic treatment. The affected tooth suddenly displayed crown discoloration and had no response to pulp testing at 6 weeks after the placement Invisalign Clear Aligner appliances. Condition of the discoloured tooth was monitored by periodic recall examinations without any active treatment. Six months after the occurrence of discoloration, the affected tooth recovered to its original shade and responded normally to pulp sensitivity tests.
Bag‐in‐the‐lens intraocular lens implantation before 12 weeks of age in congenital cataract
Authors: Sand Mari Kathrine , Cholidis Symira , Kristianslund Olav , Drolsum Liv
Published: February 2023

Purpose

The aim of this study was to evaluate the intra‐ and postoperative complications, especially the risk of visual axis opacification (VAO), following the implantation of the bag‐in‐the‐lens (BIL) intraocular lens (IOL) in infants with congenital cataract operated on before 12 weeks of age.

Methods

Infants operated on before 12 weeks of age between June 2020 and June 2021 with a follow‐up longer than 1 year were included in the present retrospective study. This was a first‐experience cohort of an experienced paediatric cataract surgeon with this type of lens.

Results

Nine infants (13 eyes) with a median age at surgery of 28 days (range, 21–49 days) were included. The median follow‐up time was 21.6 months (range, 12.2–23.4 months). The lens was correctly implanted with the anterior and posterior capsulorhexis edges placed into the interhaptic groove of the BIL IOL in seven of 13 eyes; none of these eyes developed VAO. In the remaining six eyes, the IOL was only fixated to the anterior capsulorhexis edge, and in these cases, an anatomical anomaly of the posterior capsule and/or anterior vitreolenticular interface dysgenesis were observed. These six eyes developed VAO. One eye had a partial iris capture in the early postoperative phase. Otherwise, the IOL remained well centred and stable in all eyes. Anterior vitrectomy was necessary in seven eyes due to vitreous prolapse. One patient with unilateral cataract was diagnosed with bilateral primary congenital glaucoma at 4 months of age.

Conclusion

Implantation of the BIL IOL is safe even in the youngest age group less than 12 weeks of age. Although being a first‐experience cohort, the BIL technique is shown to reduce the risk of VAO and the number of surgical procedures.
Patient‐targeted interventions for opioid deprescribing: An overview of systematic reviews
Authors: Langford Aili V. , Schneider Carl R. , Lin Chung‐Wei Christine , Bero Lisa , Collins Jack C. , Suckling Benita , Gnjidic Danijela
Published: February 2023

Background

Deprescribing (reduction or cessation) of prescribed opioids can be challenging for both patients and healthcare professionals.

Objective

To synthesize and evaluate evidence from systematic reviews examining the effectiveness and outcomes of patient‐targeted opioid deprescribing interventions for all types of pain.

Methods

Systematic searches were conducted in five databases with results screened against predetermined inclusion/exclusion criteria. Primary outcomes were (i) reduction in opioid dose, reported as change in oral Morphine Equivalent Daily Dose (oMEDD) and (ii) success of opioid deprescribing, reported as the proportion of the sample for which opioid use declined. Secondary outcomes included pain severity, physical function, quality of life and adverse events. The certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.

Findings

Twelve reviews were eligible for inclusion. Interventions were heterogeneous in nature and included pharmacological (n = 4), physical (n = 3), procedural (n = 3), psychological or behavioural (n = 3) and mixed (n = 5) interventions. Multidisciplinary care programmes appeared to be the most effective intervention for opioid deprescribing; however, the certainty of evidence was low, with significant variability in opioid reduction across interventions.

Conclusions

Evidence is too uncertain to draw firm conclusions about specific populations who may derive the greatest benefit from opioid deprescribing, warranting further investigation.
Medication incidents and medication errors in Danish healthcare: A descriptive study based on medication incident reports from the Danish Patient Safety Database, 2014–2018
Authors: Tchijevitch Olga , Hallas Jesper , Bogh Søren B. , Birkeland Søren F.
Published: February 2023

In Denmark, reporting of safety incidents to the nationwide Danish Patient Safety Database (DPSD) is mandatory. Medication incident reports constitute the largest category of safety reports. We aimed to provide numbers and characteristics of medication incidents and MEs reported to DPSD focusing on medication, their severity and the trends therein. This is a cross‐sectional study of medication incident reports for individuals ≥18, submitted to DPSD in 2014–2018. We performed analyses on the (1) medication incident and (2) ME levels. Out of 479 814 incident reports, 61.18% (n = 293 536) were related to individuals ≥70 and 44.6% (n = 213 974) to nursing homes. Most of the events were harmless (70.87%, n = 340 047) and 0.8% (n = 3859) had caused severe harm or death. ME‐analysis (n = 444 555) revealed that paracetamol and furosemide were the most frequently reported drugs. The most common drugs for severe and fatal MEs were warfarin, methotrexate, potassium chloride, paracetamol and morphine. When the reporting ratio for all MEs and harmful MEs was considered, other drugs than the most frequently reported ones were found to be associated with harm. We found a large proportion of harmless medication incident reports and reports from community healthcare services and identified high‐risk medicines associated with harm.