bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene editing of non-coding regulatory DNA and its application in crop improvement
Authors: Chen Yu-Hao , Lu Jun , Yang Xia , Huang Li-Chun , Zhang Chang-Quan , Liu Qiao-Quan , Li Qian-Feng
Published: August 2023

The development of the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) system has provided precise and efficient strategies to edit target genes and generate transgene-free crops. Significant progress has been made in the editing of protein-coding genes; however, studies on the editing of non-coding DNA with regulatory roles lags far behind. Non-coding regulatory DNAs, including those which can be transcribed into long non-coding RNAs (lncRNAs), and miRNAs, together with cis-regulatory elements (CREs), play crucial roles in regulating plant growth and development. Therefore, the combination of CRISPR/Cas technology and non-coding regulatory DNA has great potential to generate novel alleles that affect various agronomic traits of crops, thus providing valuable genetic resources for crop breeding. Herein, we review recent advances in the roles of non-coding regulatory DNA, attempts to edit non-coding regulatory DNA for crop improvement, and potential application of novel editing tools in modulating non-coding regulatory DNA. Finally, the existing problems, possible solutions, and future applications of gene editing of non-coding regulatory DNA in modern crop breeding practice are also discussed.
Inferring the Direction of Introgression Using Genomic Sequence Data
Authors: Thawornwattana Yuttapong , Huang Jun , Flouri Tomáš , Mallet James , Yang Ziheng
Published: August 2023

Genomic data are informative about the history of species divergence and interspecific gene flow, including the direction, timing, and strength of gene flow. However, gene flow in opposite directions generates similar patterns in multilocus sequence data, such as reduced sequence divergence between the hybridizing species. As a result, inference of the direction of gene flow is challenging. Here, we investigate the information about the direction of gene flow present in genomic sequence data using likelihood-based methods under the multispecies-coalescent-with-introgression model. We analyze the case of two species, and use simulation to examine cases with three or four species. We find that it is easier to infer gene flow from a small population to a large one than in the opposite direction, and easier to infer inflow (gene flow from outgroup species to an ingroup species) than outflow (gene flow from an ingroup species to an outgroup species). It is also easier to infer gene flow if there is a longer time of separate evolution between the initial divergence and subsequent introgression. When introgression is assumed to occur in the wrong direction, the time of introgression tends to be correctly estimated and the Bayesian test of gene flow is often significant, while estimates of introgression probability can be even greater than the true probability. We analyze genomic sequences from Heliconius butterflies to demonstrate that typical genomic datasets are informative about the direction of interspecific gene flow, as well as its timing and strength.
Historic Sampling of a Vanishing Beast: Population Structure and Diversity in the Black Rhinoceros
Authors: Sánchez-Barreiro Fátima , De Cahsan Binia , Westbury Michael V , Sun Xin , Margaryan Ashot , Fontsere Claudia , Bruford Michael W , Russo Isa-Rita M , Kalthoff Daniela C , Sicheritz-Pontén Thomas , Petersen Bent , Dalén Love , Zhang Guojie , Marquès-Bonet Tomás , Gilbert M Thomas P , Moodley Yoshan
Published: August 2023

The black rhinoceros (Diceros bicornis L.) is a critically endangered species historically distributed across sub-Saharan Africa. Hunting and habitat disturbance have diminished both its numbers and distribution since the 19th century, but a poaching crisis in the late 20th century drove them to the brink of extinction. Genetic and genomic assessments can greatly increase our knowledge of the species and inform management strategies. However, when a species has been severely reduced, with the extirpation and artificial admixture of several populations, it is extremely challenging to obtain an accurate understanding of historic population structure and evolutionary history from extant samples. Therefore, we generated and analyzed whole genomes from 63 black rhinoceros museum specimens collected between 1775 and 1981. Results showed that the black rhinoceros could be genetically structured into six major historic populations (Central Africa, East Africa, Northwestern Africa, Northeastern Africa, Ruvuma, and Southern Africa) within which were nested four further subpopulations (Maasailand, southwestern, eastern rift, and northern rift), largely mirroring geography, with a punctuated north–south cline. However, we detected varying degrees of admixture among groups and found that several geographical barriers, most prominently the Zambezi River, drove population discontinuities. Genomic diversity was high in the middle of the range and decayed toward the periphery. This comprehensive historic portrait also allowed us to ascertain the ancestry of 20 resequenced genomes from extant populations. Lastly, using insights gained from this unique temporal data set, we suggest management strategies, some of which require urgent implementation, for the conservation of the remaining black rhinoceros diversity.
CDK7 and CDK9 inhibition interferes with transcription, translation, and stemness, and induces cytotoxicity in GBM irrespective of temozolomide sensitivity
Authors: Bhutada Isha , Khambati Fatema , Cheng Shi-Yuan , Tiek Deanna M , Duckett Derek , Lawrence Harshani , Vogelbaum Michael A , Mo Qianxing , Chellappan Srikumar P , Padmanabhan Jaya
Published: August 2023

Background

Glioblastoma (GBM) is refractory to current treatment modalities while side effects of treatments result in neurotoxicity and cognitive impairment. Here we test the hypothesis that inhibiting CDK7 or CDK9 would effectively combat GBM with reduced neurotoxicity.

Methods

We examined the effect of a CDK7 inhibitor, THZ1, and multiple CDK9 inhibitors (SNS032, AZD4573, NVP2, and JSH150) on GBM cell lines, patient-derived temozolomide (TMZ)-resistant and responsive primary tumor cells and glioma stem cells (GSCs). Biochemical changes were assessed by western blotting, immunofluorescence, multispectral imaging, and RT-PCR. In vivo, efficacy was assessed in orthotopic and subcutaneous xenograft models.

Results

CDK7 and CDK9 inhibitors suppressed the viability of TMZ-responsive and resistant GBM cells and GSCs at low nanomolar concentrations, with limited cytotoxic effects in vivo. The inhibitors abrogated RNA Pol II and p70S6K phosphorylation and nascent protein synthesis. Furthermore, the self-renewal of GSCs was significantly reduced with a corresponding reduction in Sox2 and Sox9 levels. Analysis of TCGA data showed increased expression of CDK7, CDK9, SOX2, SOX9, and RPS6KB1 in GBM; supporting this, multispectral imaging of a TMA revealed increased levels of CDK9, Sox2, Sox9, phospho-S6, and phospho-p70S6K in GBM compared to normal brains. RNA-Seq results suggested that inhibitors suppressed tumor-promoting genes while inducing tumor-suppressive genes. Furthermore, the studies conducted on subcutaneous and orthotopic GBM tumor xenograft models showed that administration of CDK9 inhibitors markedly suppressed tumor growth in vivo.

Conclusions

Our results suggest that CDK7 and CDK9 targeted therapies may be effective against TMZ-sensitive and resistant GBM.
Reply to Letter to the editor regarding “The effect of pistachio supplementation on metabolic syndrome and its components in adults: a systematic review and meta-analysis of randomized controlled trials”
Authors: Baghery Fatemeh , Mohammadifard Noushin , Khanamani Falahati-Pour Soudeh
Published: August 2023

Two researchers (F.B and S.K.F.-P.) reviewed the abstracts and titles of all of the acknowledged research to determine whether it was eligible for inclusion in the present meta-analysis according to the inclusion criteria. The authors included all of the relevant available data from 17 articles on interventional studies. Regarding the objection raised about the effect size calculation, the inclusion of the various effect sizes from 1 study is a routine approach used in numerous meta-analyses, and their inclusion in the study did not impair the accuracy of the findings. The included studies were homogeneous in terms of intervention, outcomes, and participants, and the high rate of heterogeneity between the included studies for the majority of the study outcomes may have derived from the different characteristics of the participant populations, especially differences in their health status. As no study included in the review reported the correlation coefficient between the placebo conditions and the experimental conditions, the authors reanalyzed the data by inputting a moderate correlation coefficient of 0.5. Our study showed that pistachio consumption has a positive effect in terms of reducing the components of metabolic syndrome. In conclusion, this study reanalyzed the data and justified the methods used for showing the positive effect of pistachio consumption on metabolic syndrome components, and the potential for further research to identify the underlying mechanisms and the effects on various populations. The study’s protocol was registered, and Comprehensive Meta-Analysis software was used in the statistical analyses. The authors recommend further research to investigate the potential effect of the consumption of pistachios.

Systematic Review Registration: PROSPERO registration no. CRD42021285424.
Police Effectiveness and Procedural Justice as Competing Public Values: Moving Beyond the Instrumental-Versus-Normative Model of Police Legitimacy
Authors: Na Chongmin , Lee Seulki , Kang Inkyu
Published: August 2023

This study argues that the dichotomy of instrumental-versus-normative motives in mainstream policing literature can mislead the ways in which police effectiveness and procedural justice shape people’s judgments about the police. Effective policing may be important even for individuals who do not directly benefit from it, while procedurally just policing can bring instrumental benefits, particularly for underprivileged social groups. We propose an alternative framework that characterizes police effectiveness and procedural justice as competing public values, of which the salience depends on political dynamics that vary across time and space. We explored the South Korean case where advocates for effective crime control and procedural justice are vying without one side decisively outweighing the other. Analysis of a representative cross-sectional survey shows that people’s perceptions of police effectiveness and procedural justice are both positively associated with trust in the police which, in turn, is positively associated with willingness for voluntary compliance and cooperation. Broader implications for theory and policy are discussed.
One-loop expressions for h → l l̅γ in Higgs extensions of the Standard Model
Authors: Hue L T , Tran Dzung Tri , Nguyen Thanh Huy , Phan Khiem Hong
Published: August 2023

A systematic study of one-loop contributions to the decay channels $h\rightarrow l\bar{l}\gamma$ with l = νe, μ, τ, e, μ, performed in Higgs extended versions of the Standard Model (SM), is presented in the ’t Hooft–Veltman gauge. Analytic formulas for one-loop form factors are expressed in terms of the logarithm and di-logarithmic functions. As a result, these form factors can be reduced to those relating to the loop-induced decay processes h → γγ, Zγ, confirming not only previous results using different approaches but also close relations between the three kinds of loop-induced Higgs decay rates. For phenomenological study, we focus on the two observables, namely the enhancement factors defined as ratios of the decay rates calculated between the Higgs extended versions and the SM, and the forward-backward asymmetries of fermions, which can be used to search for Higgs extensions of the SM. We show that direct effects of mixing between neutral Higgs bosons and indirect contributions of charged Higgs boson exchanges can be probed at future colliders.
Effectiveness of self-management interventions for long-term conditions in people experiencing socio-economic deprivation in high-income countries: a systematic review and meta-analysis
Authors: Okpako Tosan , Woodward Abi , Walters Kate , Davies Nathan , Stevenson Fiona , Nimmons Danielle , Chew-Graham Carolyn A , Protheroe Joanne , Armstrong Megan
Published: August 2023

Background

Long-term conditions (LTCs) are prevalent in socio-economically deprived populations. Self-management interventions can improve health outcomes, but socio-economically deprived groups have lower participation in them, with potentially lower effectiveness. This review explored whether self-management interventions delivered to people experiencing socio-economic deprivation improve outcomes.

Methods

We searched databases up to November 2022 for randomized trials. We screened, extracted data and assessed the quality of these studies using Cochrane Risk of Bias 2 (RoB2). We narratively synthesized all studies and performed a meta-analysis on eligible articles. We assessed the certainty of evidence using GRADE for articles included in the meta-analysis.

Results

The 51 studies included in this review had mixed findings. For the diabetes meta-analysis, there was a statistically significant pooled reduction in haemoglobin A1c (−0.29%). We had moderate certainty in the evidence. Thirty-eight of the study interventions had specific tailoring for socio-economically deprived populations, including adaptions for low literacy and financial incentives. Each intervention had an average of four self-management components.

Conclusions

Self-management interventions for socio-economically deprived populations show promise, though more evidence is needed. Our review suggests that the number of self-management components may not be important. With the increasing emphasis on self-management, to avoid exacerbating health inequalities, interventions should include tailoring for socio-economically deprived individuals.
To govern or be governed: an integrated framework for AI governance in the public sector
Authors: Choi Hyeri , Park Min Jae
Published: August 2023

There has been a significantly increased amount of literature on various aspects of artificial intelligence (AI), but research on AI governance has been a considerably underdeveloped area. This study proposes a comprehensive framework for designing AI governance in the public sector to overcome the limitations of previous studies that primarily dealt with the fragmentary aspect of AI. Also, we applied the developed framework to the case of Korea by combining it with the rank-order survey questions that target experts. This case study presents how to use the framework and provides insight for other countries.
‘Of One Blood?’: Gendered Propaganda and Blood Donor Behaviour in Wartime Bristol and South West England, 1939–1945
Authors: Beales John
Published: August 2023

This article explores civilian responses to the British army’s blood donor recruitment campaign in wartime Britain, revealing it to be an underexplored medium for the examination of the contribution of women to Britain’s war effort. However, despite extensive gender-targeted propaganda, it reveals evidence of a significant disparity between levels of volunteering to donate and actual donation throughout the war. Wartime donor behaviour was influenced by perceptions of personal or familial risk, with donor recruitment propaganda emphasising kinship ties to those in military service and promoting blood donation as a mutual insurance policy. Ultimately, this article argues that evidence of donor behaviour further undermines the mythologised narrative of Britain’s ‘People’s War’ and provides nuance to the understanding of blood donor motivation.
Secreted Effector Proteins of Poplar Leaf Spot and Stem Canker Pathogen Sphaerulina musiva Manipulate Plant Immunity and Contribute to Virulence in Diverse Ways
Authors: Zhao Yao , Zheng Xinyue , Tabima Javier F. , Zhu Sheng , Søndreli Kelsey L. , Hundley Hope , Bauer Diane , Barry Kerrie , Zhang Yaxin , Schmutz Jeremy , Wang Yuanchao , LeBoldus Jared M. , Xiong Qin
Published: August 2023

Fungal effectors play critical roles in manipulating plant immune responses and promoting colonization. Sphaerulina musiva is a heterothallic ascomycete fungus that causes Septoria leaf spot and stem canker disease in poplar ( Populus spp.) plantations. This disease can result in premature defoliation, branch and stem breakage, increased mortality, and plantation failure. However, little is known about the interaction between S. musiva and poplar. Previous work predicted 142 candidate secreted effector proteins in S. musiva (SmCSEPs), 19 of which were selected for further functional characterization in this study. SmCSEP3 induced plant cell death in Nicotiana benthamiana, while 8 out of 19 tested SmCSEPs suppressed cell death. The signal peptides of these eight SmCSEPs exhibited secretory activity in a yeast signal sequence trap assay. Confocal microscopy revealed that four of these eight SmCSEPs target both the cytoplasm and the nucleus, whereas four predominantly localize to discrete punctate structures. Pathogen challenge assays in N. benthamiana demonstrated that the transient expression of six SmCSEPs promoted Fusarium proliferatum infection. The expression of these six SmCSEP genes were induced during infection. SmCSEP2, SmCSEP13, and SmCSEP25 suppressed chitin-triggered reactive oxygen species burst and callose deposition in N. benthamiana. The candidate secreted effector proteins of S. musiva target multiple compartments in the plant cell and modulate different pattern-triggered immunity pathways.

[Formula: see text] The author(s) have dedicated the work to the public domain under the Creative Commons CC0 “No Rights Reserved” license by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law, 2023.
Population Structure and Reproductive Biology of Monilinia vaccinii-corymbosi in Vaccinium angustifolium in Maine
Authors: Ashley Katherine A. , Annis Seanna L.
Published: August 2023

The fungus Monilinia vaccinii-corymbosi (Mvc) causes mummy berry disease in blueberries including lowbush blueberry, Vaccinium angustifolium, and is a significant pathogen of concern for Maine lowbush blueberry growers. This disease is typically managed with fungicides or by burning of plant debris containing overwintering pseudosclerotia. The population structure of Mvc in various fields in Maine was investigated using microsatellites and isolates collected from three stages in the Mvc lifecycle. The impacts of management strategies were also examined. A high level of genetic diversity was observed in Mvc from 12 lowbush blueberry fields with 199 unique multilocus haplotypes (MLHs) occurring in an original sample of 232 isolates. Twelve private alleles, including six private alleles with frequencies above 0.05, which indicated gene flow, were observed in six out of 12 fields. The population of Mvc in Maine as a whole is mostly a sexual, outcrossing population, as was seen in the diversity of MLHs and low amounts of linkage disequilibrium, although some apothecia appear to result from selfing. Three fields appear to have some clonal reproduction but were not strictly clonal, as multiple MLHs were noted in these fields. Management does not appear to affect population structure, and Mvc may be one large statewide population in Maine.
Hydroxyurea attenuates hepatic stellate cell proliferation in vitro and liver fibrogenesis in vivo
Authors: Haijer Floris , Koets‐Shajari Shiva , Heegsma Janette , Serna‐Salas Sandra , Blokzijl Tjasso , Buist‐Homan Manon , Moshage Han , Faber Klaas Nico
Published: August 2023

Liver fibrosis results from excessive proliferation of, and collagen production by hepatic stellate cells (HSCs) that is caused by chronic liver injury. No drugs are available to cure liver fibrosis. Hydroxyurea is an anti‐proliferative drug that is used in benign and malignant disorders. Here, we studied the effect of hydroxyurea on primary HSCs and its anti‐fibrotic effect in the CCl4 mouse model of liver fibrosis. Primary rat HSCs were cultured in the absence or presence of hydroxyurea (0.1–1.0 mmol/L). CCl4 or vehicle was administered to C57BL/6/J mice for 4 weeks, with or without hydroxyurea (100 mg/kg/day) co‐treatment. We used real‐time cell proliferation analysis, Oil Red O (lipid droplet) staining, immunohistochemistry, Acridine Orange staining (apoptosis), Sytox green staining (necrosis), RT‐qPCR, ELISA, and Western Blotting for analysis. Hydroxyurea dose‐dependently suppressed lipid droplet‐loss and mRNA levels of Col1α1 and Acta2 in transdifferentiating HSCs. In fully‐activated HSCs, hydroxyurea dose‐dependently attenuated PCNA protein levels and BrdU incorporation, but did not reverse Col1α1 and Acta2 mRNA expression. Hydroxyurea did not induce apoptosis or necrosis in HSCs or hepatocytes. Hydroxyurea suppressed accumulation of desmin‐positive HSCs and hepatic collagen deposition after CCl4 treatment. CCl4‐induced regenerative hepatocyte proliferation, Col1α1 and Acta2 mRNA expression and α‐SMA protein levels were not affected. This study demonstrates that hydroxyurea inhibits HSC proliferation in vitro and attenuates early development of liver fibrosis in vivo, while preserving hepatocyte regeneration after toxic insults by CCl4. Thus, hydroxyurea may have therapeutic value against liver fibrosis.
Continuous peripheral nerve blocks for analgesia following painful ambulatory surgery: a review with focus on recent developments in infusion technology
Authors: Finneran John J. , Ilfeld Brian M.
Published: August 2023

Purpose of review

Continuous peripheral nerve blocks (cPNB) decrease pain scores and opioid consumption while improving patient satisfaction following ambulatory surgery. This review focuses on the history and evolution of ambulatory cPNBs, recent developments in infusion technology that may prolong the duration of analgesia, optimal choice of cPNB for various surgical procedures, and novel analgesic modalities that may prove to be alternatives or supplements to cPNBs.

Recent findings

The primary factor limiting the duration of an ambulatory cPNB is the size of the local anesthetic reservoir. Recent evidence suggests the use of automated boluses, as opposed to continuous infusions, may decrease the rate of consumption of local anesthetic and, thereby, prolong the duration of analgesia. Utilizing a long-acting local anesthetic (e.g. ropivacaine) for initial block placement and an infusion start-delay timer may further increase this duration.

Patients undergoing painful ambulatory surgery are likely to have less pain and require fewer opioid analgesics when receiving a cPNB for postoperative analgesia. Advances in electronic pumps used for cPNBs may increase the duration of these benefits.
Etiology, management, and sequela of postdural puncture headache
Authors: Taraskiewicz Daniel , Sheeran Jessica , De Marco Paul , Tiouririne Mohamed , Elkassabany Nabil
Published: August 2023

Purpose

The purpose of this article is to provide readers with a concise overview of the cause, incidence, treatment of, and sequalae of postdural puncture headaches (PDPH). Over the past 2 years, much data has been published on modifiable risk factors for PDPH, treatments for PDPH, and sequalae of PDPH particularly long-term.

Recent findings

There is emerging data about how modifiable risk factors for PDPH are not as absolute as once believed. There have been several new meta-analysis and clinical trials published, providing more data about effective therapies for PDPH. Significantly, much recent data has come out about the sequalae, particularly long-term of dural puncture.

Emerging evidence demonstrates that in patients who are at low risk of PDPH, needle type and gauge may be of no consequence in a patient developing a PDPH. Although epidural blood patch (EBP) remains the gold-standard of therapy, several other interventions, both medical and procedural, show promise and may obviate the need for EBP in patients with mild–moderate PDPH. Patients who endure dural puncture, especially accidental dural puncture (ADP) are at low but significant risk of developing short term issues as well as chronic pain symptoms.
Preclinical models to understand the biology and to discover new targets in brain metastases
Authors: Kindt Nadège , Kotecki Nuria , Awada Ahmad
Published: August 2023

Purpose of review

Incidence of brain metastases increases overtime therefore it is important to rapidly progress in the discovery of new strategies of treatment for these patients. In consequence, more and more preclinical models of brain metastases (BM) are established to study new treatments for melanoma, lung, and breast cancer BM. Here, we reviewed the most recent findings of new drugs assessed in BM mouse preclinical models.

Recent findings

BM are a common metastatic site of several types of solid cancers and can be difficult to treat due to the unique environment of the brain and the blood-brain barrier. Currently, several preclinical models of BM have been demonstrated that new molecular targeted therapies, small metabolic inhibitors, immunotherapies or a combination of these drugs with radiotherapy lead to a reduction of BM growth and an improvement of mouse survival.

The use of preclinical models of BM is crucial to discover new treatment strategies for patients with BM. In the last years, some new drugs have been highlighted in preclinical models and are now tested in clinical trials including patients with brain metastases.
Controversies in central nervous system prophylaxis of high-risk diffuse large B-cell lymphoma
Authors: Bobillo Sabela , Wilson Matthew R. , Cwynarski Kate
Published: August 2023

Purpose of review

Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an uncommon but devastating complication with an overall survival of less than 6 months. This article will review the recent updates on CNS prophylaxis including new potential advances in the identification of high-risk patients.

Recent findings

The identification of patients at a high risk of CNS relapse is based on clinical and biological features has improved over recent years; however, the of different CNS prophylaxis strategies including intrathecal chemotherapy and high-dose methotrexate have been recently questioned in several large retrospective studies. The analysis of cell-free circulating tumor DNA (ctDNA) in the cerebrospinal fluid has been shown to identify patients with a high risk of CNS involvement and work is ongoing to identify how this can be used as a prognostic biomarker.

Recent clinical retrospective data have questioned the effectiveness of intrathecal and high-dose methotrexate in the prevention of CNS relapse in high-risk DLBCL patients. The role of more sensitive methods to detect CNS involvement and the benefit of novel therapies in CNS relapse prevention are currently under evaluation.
Tailor-made three-dimensional printing vaginal pessary to treat pelvic organ prolapse: a pilot study
Authors: Lin Yi-Hao , Lim Chor-Kheng , Chang Shuenn-Dyh , Chiang Chih-Chien , Huang Chun-Hung , Tseng Ling-Hong
Published: August 2023

Objective

This study aimed to apply three-dimensional (3D) printing technology to treat women with pelvic organ prolapse (POP) and to evaluate efficacy based on the improvement by quality of life (QOL) questionnaires.

Methods

This was a pilot study at a tertiary urogynecology unit in Taiwan. Between January 2021 and June 6, 2021, participants who opted for self-management using Gellhorn pessaries to treat symptomatic POP were enrolled. For each woman, the original Gellhorn pessary was placed into the vagina to restore the prolapsed tissues and under transvaginal ultrasound guided to evaluate the gap which the Gellhorn pessary cannot cover. Otoform (an impression silicone) was used to make a model and have it hooked onto Gellhorn pessary (template). We collected templates and then applied 3D printing to customize the silicone vaginal pessary. All women completed multiple validated QOL questionnaires at baseline and at 3 and 6 months.

Results

Six women completed the study. The QOL questionnaires revealed significant improvements across the board.

Conclusions

Our study demonstrates that a tailor made 3D pessary can be used for women with POP. A customized pessary can be made with the help of transvaginal ultrasound and 3D printing technology.
POSTINFECTIOUS NONPARANEOPLASTIC AUTOIMMUNE RETINOPATHY IN THE PEDIATRIC AGE GROUP: A HIGH INDEX OF SUSPICION, MULTIMODAL IMAGING AND EARLY TREATMENT CAN RESTORE VISION
Authors: R Neena , Borgohain Ashapurna , Anantharaman Giridhar , Baby Neena
Published: August 2023

Purpose:

To report a case of nonparaneoplastic autoimmune retinopathy in a pediatric patient who showed excellent visual recovery with early diagnosis and prompt treatment.

Methods:

Retrospective case report.

Results:

A 5-year-old girl presented to us with bilateral profound vision loss of subacute onset after an episode of high fever, without any previous visual abnormality. A diagnosis of nonparaneoplastic autoimmune retinopathy was made based on history, clinical findings, and multimodal imaging. IV methylprednisolone was started urgently followed by oral steroid. The visual acuity showed good improvement along with gradual restoration of anatomy of retinal layers in optical coherence tomography over a period of 3 months.

Conclusion:

Our case highlights the importance of suspecting nonparaneoplastic autoimmune retinopathy in pediatric patients presenting with sudden bilateral painless progressive loss of vision without prior visual difficulties and the role of multimodal imaging to aid in diagnosis. The recovery of vision with restoration of the photoreceptor layer also shows the nature of the disease to recover with early intervention despite a negative antiretinal antibody test but with features highly suggestive of nonparaneoplastic autoimmune retinopathy.
Hybrid Schwannoma-Perineurioma of the Orbit
Authors: Zhou Benjamin , Milman Tatyana , Rodriguez Fausto J. , Turbin Roger E. , Langer Paul D.
Published: August 2023

A 52-year-old woman presented with a 6-month history of progressive right proptosis associated with intermittent right retrobulbar and facial pain. MRI revealed a heterogeneously enhancing, well-circumscribed, ovoid, soft tissue mass in the intraconal space near the right orbital apex displacing the optic nerve medially. Excisional biopsy established the diagnosis of a schwannoma-perineurioma hybrid peripheral nerve sheath tumor (HPNST). This case represents only the second reported occurrence, to our knowledge, of an orbital schwannoma-perineurioma HPNST.
Hydroxyapatite Use in Repair of Lateral Skull Base CSF Leaks Via Transmastoid Approach: When Does It Work?
Authors: Shah Rema , Kveton John , Schwartz Nofrat
Published: August 2023

Objective

The objective of this study is to evaluate the efficacy and outcomes of using a transmastoid approach with hydroxyapatite cement to repair lateral skull base cerebrospinal fluid (CSF) leaks.

Study Design

Retrospective cohort study.

Setting

Tertiary-level care hospital.

Patients

Surgical patients 18 years or older between 2013 and 2022 with spontaneous CSF leak.

Interventions

Trans-mastoid approach for skull base repair using hydroxyapatite cement.

Main Outcome Measures

Failure rate of repair; location and size of defect, patient demographic factors.

Results

Of the 60 total defects (55 patients, 5 bilateral repairs) that underwent CSF leak repair using hydroxyapatite cement, the success rate was 91.66% (55 successful repairs). The average defect size in unsuccessful repairs was 1.15 cm compared with 0.71 cm for successful repairs. In addition, 80% (4/5) of the failed repairs were in the tegmen tympani region. Higher failure rate was noted in women (3/5) and in former smokers (4/5). Average time to recurrent symptoms was 1.75 years in the failed repair cohort. Of the patients with failed repairs, 4/5 were prescribed acetazolamide before their second procedure with successful second repair. In addition, five patients experienced postoperative headaches, three (5.4%) of whom required placement of VP shunts to relieve increased intracranial pressure. Two patients (3.6%) had complications of either infection or hearing loss.

Conclusions

Transmastoid approach utilizing hydroxyapatite is a successful approach for CSF leak repair, with a low complication and failure rate. Women, prior smoking history, and larger defects in the tegmen tympani region may need alternative materials or approach for repair. Long follow-up is warranted as recurrence of symptoms might be delayed. In cases of benign intracranial hypertension, adjuvant treatment with either acetazolamide or VP shunt placement may prevent failures.
The common trisomy syndromes, their cardiac implications, and ethical considerations in care
Authors: Kosiv Katherine A. , Mercurio Mark R. , Carey John C.
Published: August 2023

Purpose of review

To review the incidence of congenital heart disease in the trisomies, highlight the history of cardiac surgery in trisomy 21 comparing it to the increase in cardiac surgery in trisomies 13 and 18, discuss ethical issues specific to trisomies 13 and 18, and suggest a pathway of shared decision-making in the management of congenital heart disease in trisomy 13 and 18, specifically congenital heart surgery.

Recent findings

Congenital heart disease is prevalent in the trisomies and the management of these defects, especially surgical intervention, has changed. In the late 20th century, survival after cardiac surgery in trisomy 21 vastly improved, significantly decreasing morbidity and mortality secondary to pulmonary hypertension. Similarly, procedures and surgeries have been performed with increasing frequency in trisomy 13 and 18 patients and concomitantly, survival in this patient population is increasing. Yet across the United States, the willingness to perform cardiac surgery in trisomy 13 and 18 is variable, and there is ethical controversy about the correct action to take. To address this concern, a shared decision-making approach with an informed parent(s) is advised.

As the care and management of congenital heart disease changed in trisomy 21, so too it has with trisomy 13 and 18. Physicians and parents should develop goal-directed treatment plans balancing the risk versus benefit and consider cardiac surgical repair if feasible and beneficial.
EarWell Infant Ear Molding Device: Experience and Parent Survey
Authors: Ahmed Moumen , Al Saadawi Ghaith , Mendonca Derek A.
Published: August 2023

Background:

EarWell infant ear molding device is a noninvasive, nonsurgical option to treat ear deformities in early infancy. There are no studies involving the parents’ perspective to the use of the EarWell.

Aim:

To investigate our experience with EarWell infant ear molding device and to assess the parents’ satisfaction.

Study Design:

A retrospective case series study of infants with congenital ear deformities who were treated with EarWell device from October 2021 to November 2022. Demographic and clinical data were collected. Clinical photographs were obtained before, during, and after treatment. Parents’ satisfaction level was assessed through telephone encounters and surveys, and issues associated with device application were identified. Clinical improvement of ear deformity was graded into poor, fair, good, and excellent.

Results:

A total of 9 patients with congenital ear deformities were identified and included in this study (7 bilateral deformities and 2 unilateral deformities). The mean adjusted age of the initial treatment is 17 weeks (4–23 weeks), and the mean treatment duration is 5.7 weeks. The authors received full 8 responses from the parents’ survey, and all parents were satisfied with post-treatment results (4 satisfied, 1 fully satisfied, and 2 very satisfied). Issues associated with device application were 3 superficial skin ulcers and 4 skin irritation. Clinical Improvement grades were: 5 excellent improvement, 2 good improvement, and 2 fair improvement.

Conclusions:

On the basis of our experience, the EarWell device has shown a high success rate and a low complication rate. It is well accepted by parents, but it needs close follow-up to detect minor device-related issues. The device is safe for multiple skin types.
Effects of feedback reliability on event-related potentials in an arrow flanker task
Authors: Jia MeiXue , Wang AiLi , Sui Li
Published: August 2023

The processing of feedback is essential for learning, error detection, and correction. However, the underlying mechanisms of the feedback’s characteristics, such as its reliability, valence, and expectations in the processing of error information, are not completely clear. The two degrees of feedback reliability, reliable feedback and unreliable feedback, respectively, were established by manipulating the feedback valence. The time course of event-related potentials (ERP) during the arrow flanker tasks was used to investigate the effects of feedback reliability and responses on brain activity. Three ERP components, the error-related negativity (ERN), feedback-related negativity (FRN), and P3, respectively, were measured. The impacts of feedback reliability and responses on ERN, FRN, and P3 had a different profile. Specifically, ERN and P3 are associated with the responses but not the feedback reliability, while FRN is associated with feedback reliability and feedback expectations but not the responses. The ERN, FRN, and P3 reflect distinct cognitive processes in the processing of error information.
Capillary blood sampling for the determination of clozapine concentrations: analytical validation and patient experience
Authors: Breken Bianca D. , Grootens Koen P. , Vermeulen Windsant – van den Tweel Annemieke M. , Hermens Walter A. , Derijks Hieronymus J.
Published: August 2023

Patients may be reluctant to start clozapine (CLZ) because of the frequent blood sampling needed for white blood cell monitoring, but also therapeutic drug monitoring of CLZ. Finger prick, instead of venepuncture, might lower the threshold to CLZ use. The aim of this study was to determine whether CLZ concentrations are the same in capillary and venous blood samples. Capillary blood was drawn by finger prick and collected in the Hem-Col tube. Paired capillary and venous blood samples were collected from inpatients and outpatients of a mental health institute. Patients were asked to rate pain, experience, and preference for blood sampling method. Passing-Bablok analysis of 40 paired samples showed that CLZ concentrations were statistically equal in capillary and venous samples {slope 0.96 [95% confidence interval (CI): 0.88–1.04], intercept −6.86 (95% CI: −30.75 to 24.13)}. Venepuncture was the preferred method based on the experience (P = 0.009) and preference (P = 0.043) items. In conclusion, CLZ concentrations were similar in venous and capillary blood samples. Venepuncture appeared to be preferred to finger prick for blood sampling. Our results emphasize the importance of consulting patients’ individual preference for blood sampling method.
l-carnitine adjunct to risperidone for treatment of autism spectrum disorder-associated behaviors: a randomized, double-blind clinical trial
Authors: Nasiri Mehry , Parmoon Zohal , Farahmand Yalda , Moradi Ali , Farahmand Kimia , Moradi Kamyar , Basti Fatemeh A. , Mohammadi Mohammad-Reza , Akhondzadeh Shahin
Published: August 2023

The present study was designed to evaluate the efficacy and safety of l-carnitine as an adjuvant agent to risperidone in the treatment of autism spectrum disorder (ASD)-associated behaviors. In this study, 68 children with confirmed ASD were randomly allocated to receive either l-carnitine (150 mg/day) or matched placebo in addition to risperidone. We utilized the Aberrant Behavior Checklist-Community Edition scale (ABC-C) and a checklist of potential adverse effects to assess changes in behavioral status and safety profile at weeks 0, 5 and 10 of the trial. The primary outcome was defined as a change in the irritability subscale score. Sixty patients with similar baseline characteristics completed the trial period. Although scores of ABC-C subscales significantly decreased in both groups over the trial period, the combination of l-carnitine and risperidone resulted in more reduction on the irritability and hyperactivity subscales compared to the combination of risperidone and placebo (P = 0.033 andP < 0.001, respectively). However, changes in lethargy, stereotypic behavior and inappropriate speech subscales were similar between groups. In conclusion, l-carnitine adjuvant to risperidone could improve irritability and hyperactivity features in children with ASD. Results of this study should be considered preliminary and further clinical trials with larger sample sizes and longer follow-up periods are warranted.
Differential effectiveness between Ketamine and Esketamine: the predictive role of dissociative features. A treatment-resistant depression case
Authors: Ragone Nicola , Barbini Barbara , Passani Carolina , Seghi Federico , Colombo Cristina
Published: August 2023

More than 10 years ago, the discovery of the antidepressant effects of Ketamine opened the opportunity to develop a novel class of antidepressants. Ketamine induces dissociative symptoms as a major side effect. This rapid-acting antidepressant is available as an endovenous racemic compound and as an intranasal S-enantiomer: Esketamine; which is four-fold more potent for the NMDA receptor. Here we present the critical case of a patient who took both molecules experiencing remission just with endovenous Ketamine, whose impact in terms of dissociative symptoms was greater. In this short report, we discuss the differences between the two drugs and the possibility of dissociative features to predict their efficacy.
Efficacy of cariprazine in patients with bipolar depression and higher or lower levels of baseline anxiety: a pooled post hoc analysis
Authors: Jain Rakesh , McIntyre Roger S. , Cutler Andrew J. , Earley Willie R. , Nguyen Huy-Binh , Adams Julie L. , Yatham Lakshmi N.
Published: August 2023

Post hoc analyses evaluated cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist, in patients with bipolar I depression and high baseline anxiety. Data were pooled from two phase 3, randomized, double-blind, placebo-controlled studies in adults with bipolar I disorder and a major depressive episode (NCT02670538, NCT02670551). Cariprazine 1.5 and 3 mg/d were evaluated in patient subgroups with higher and lower baseline anxiety. In patients with higher baseline anxiety, significant differences for cariprazine 1.5 mg/d versus placebo were observed on change in Montgomery-Åsberg Rating Scale (MADRS) total score, Hamilton Anxiety Rating Scale (HAM-A) total score and subscale scores, and rates of MADRS remission (P < 0.05 all); nonsignificant numerical improvements were observed for cariprazine 3 mg/d versus placebo. In patients with lower anxiety, differences versus placebo were significant for HAM-A (cariprazine 3 mg/d) and MADRS (cariprazine 1.5 and 3 mg/d) total score changes (P < 0.05 all). Rates of treatment-emergent mania were low and similar for cariprazine and placebo. Cariprazine 1.5 mg/d had consistent effects on anxiety and depression symptoms in patients with bipolar I depression and higher baseline anxiety; tolerability was favorable. Given few proven treatments for this common comorbidity, these preliminary results are promising.
Spatial positioning of preimplantation mouse embryo cells is regulated by mTORC1 and m
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G-cap-dependent translation at the 8- to 16-cell transition
Authors: Gahurova Lenka , Tomankova Jana , Cerna Pavlina , Bora Pablo , Kubickova Michaela , Virnicchi Giorgio , Kovacovicova Kristina , Potesil David , Hruska Pavel , Zdrahal Zbynek , Anger Martin , Susor Andrej , Bruce Alexander W.
Published: August 2023

Preimplantation mouse embryo development involves temporal–spatial specification and segregation of three blastocyst cell lineages: trophectoderm, primitive endoderm and epiblast. Spatial separation of the outer-trophectoderm lineage from the two other inner-cell-mass (ICM) lineages starts with the 8- to 16-cell transition and concludes at the 32-cell stages. Accordingly, the ICM is derived from primary and secondary contributed cells; with debated relative EPI versus PrE potencies. We report generation of primary but not secondary ICM populations is highly dependent on temporal activation of mammalian target of Rapamycin (mTOR) during 8-cell stage M-phase entry, mediated via regulation of the 7-methylguanosine-cap (m
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G-cap)-binding initiation complex (EIF4F) and linked to translation of mRNAs containing 5′ UTR terminal oligopyrimidine (TOP-) sequence motifs, as knockdown of identified TOP-like motif transcripts impairs generation of primary ICM founders. However, mTOR inhibition-induced ICM cell number deficits in early blastocysts can be compensated by the late blastocyst stage, after inhibitor withdrawal; compensation likely initiated at the 32-cell stage when supernumerary outer cells exhibit molecular characteristics of inner cells. These data identify a novel mechanism specifically governing initial spatial segregation of mouse embryo blastomeres, that is distinct from those directing subsequent inner cell formation, contributing to germane segregation of late blastocyst lineages.
Development and repair of blood vessels in the zebrafish spinal cord
Authors: Ribeiro Ana , Rebocho da Costa Mariana , de Sena-Tomás Carmen , Rodrigues Elsa Charas , Quitéria Raquel , Maçarico Tiago , Rosa Santos Susana Constantino , Saúde Leonor
Published: August 2023

The vascular system is inefficiently repaired after spinal cord injury (SCI) in mammals, resulting in secondary tissue damage and immune deregulation that contribute to the limited functional recovery. Unlike mammals, zebrafish can repair the spinal cord (SC) and restore motility, but the vascular response to injury has not been investigated. Here, we describe the zebrafish SC blood vasculature, starting in development with the initial vessel ingression in a body size-dependent manner, the acquisition of perivascular support and the establishment of ventral to dorsal blood circulation. The vascular organization grows in complexity and displays multiple barrier specializations in adulthood. After injury, vessels rapidly regrow into the lesion, preceding the glial bridge and axons. Vascular repair involves an early burst of angiogenesis that creates dysmorphic and leaky vessels. Dysfunctional vessels are later removed, as pericytes are recruited and the blood–SC barrier is re-established. This study demonstrates that zebrafish can successfully re-vascularize the spinal tissue, reinforcing the value of this organism as a regenerative model for SCI.