bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutralizing activity against Omicron BA.5 after tixagevimab/cilgavimab administration comparable to those after Omicron BA.1/BA.2 breakthrough infections
Authors: Yang Jinyoung , Won Gunho , Baek Jin Yang , Lee Young Ho , Kim Haein , Huh Kyungmin , Cho Sun Young , Kang Cheol-In , Chung Doo Ryeon , Peck Kyong Ran , Lee Kyo Won , Park Jae Berm , Yoon Sang Eun , Kim Seok Jin , Kim Won Seog , Yim Min Su , Kim Kwangwook , Hyeon Seokhwan , Kim Byung Chul , Lee Yoo-kyung , Ko Jae-Hoon
Published: March 2023

Introduction

The effect of tixagevimab/cilgavimab (Evusheld™; AstraZeneca, UK) should be evaluated in the context of concurrent outbreak situations.

Methods

For serologic investigation of tixagevimab/cilgavimab during the BA.5 outbreak period, sera of immunocompromised (IC) hosts sampled before and one month after tixagevimab/cilgavimab administration and those of healthcare workers (HCWs) sampled one month after a 3rd shot of COVID-19 vaccines, five months after BA.1/BA.2 breakthrough infection (BI), and one month after BA.5 BI were investigated. Semi-quantitative anti-spike protein antibody (Sab) test and plaque reduction neutralizing test (PRNT) against BA.5 were performed.

Results

A total of 19 IC hosts (five received tixagevimab/cilgavimab 300 mg and 14 received 600 mg) and 41 HCWs (21 experienced BA.1/BA.2 BI and 20 experienced BA.5 BI) were evaluated. Baseline characteristics did not differ significantly between IC hosts and HCWs except for age and hypertension. Sab significantly increased after tixagevimab/cilgavimab administration (median 130.2 BAU/mL before tixagevimab/cilgavimab, 5,665.8 BAU/mL after 300 mg, and 10,217 BAU/mL after 600 mg; both P < 0.001). Sab of one month after the 3rd shot (12,144.2 BAU/mL) or five months after BA.1/BA.2 BI (10,455.8 BAU/mL) were comparable with that of tixagevimab/cilgavimab 600 mg, while Sab of one month after BA.5 BI were significantly higher (22,216.0 BAU/mL; P < 0.001). BA.5 PRNT ND50 significantly increased after tixagevimab/cilgavimab administration (median ND50 29.6 before tixagevimab/cilgavimab, 170.8 after 300 mg, and 298.5 after 600 mg; both P < 0.001). The ND50 after tixagevimab/cilgavimab 600 mg was comparable to those of five months after BA.1 BI (ND50 200.9) while ND50 of one month after the 3rd shot was significantly lower (ND50 107.6; P = 0.019). The ND50 of one month after BA.5 BI (ND50 1,272.5) was highest among tested groups, but statistical difference was not noticed with tixagevimab/cilgavimab 600 mg.

Conclusion

Tixagevimab/cilgavimab provided a comparable neutralizing activity against the BA.5 with a healthy adult population who were vaccinated with a 3rd shot and experienced BA.1/BA.2 BI.
C-reactive protein – My perspective on its first half century, 1930-1982
Authors: Kushner Irving
Published: March 2023

C-reactive protein (CRP) was discovered in 1930 in the sera of patients during the acute phase of pneumococcal pneumonia and was so named because it bound to the C-polysaccharide of the pneumococcal cell wall. During the next half century many questions raised by this discovery were answered. Phosphorylcholine was found to be the moiety of the C-polysaccharide to which CRP bound. The molecular structure of CRP was elucidated: five identical subunits arranged in cyclic symmetry, giving rise to the term pentraxin. Initially felt to be not normally present in the blood, CRP was found to be a component of normal serum in trace amounts. Its site of origin was determined to be the hepatocyte. It became clear that the presumed humoral mediator responsible for CRP induction was of leukocytic origin. Binding of CRP to its ligand activated the complement system, one of the important effector mechanisms of innate immunity. CRP was found to stimulate phagocytosis of some bacterial species via binding to Fc receptors and was found to be protective in vivo against the pneumococcus in mice. It appeared likely that a related function of CRP was clearance of necrotic tissue. CRP was recognized as being a highly evolutionary conserved molecule. Its discovery during the acute phase of pneumococcal pneumonia led to its being dubbed an acute phase protein. What we today call “the acute phase response”, refers to the large number of behavioral, physiologic, biochemical, and nutritional changes that occur during inflammatory states.
JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases
Authors: Herrera-deGuise Claudia , Serra-Ruiz Xavier , Lastiri Ernesto , Borruel Natalia
Published: March 2023

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn’s disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients.
Femtosecond laser-assisted cataract surgery: Update and perspectives
Authors: Kecik Mateusz , Schweitzer Cedric
Published: March 2023

Cataract surgery is among the most frequently performed surgical procedures worldwide and has a tremendous impact on patients' quality of life. Phacoemulsification (PCS) is accepted as a standard of care; its technique has continuously evolved and already achieved good anatomical, visual, and refractive outcomes. Lasers in ophthalmology are widely used in clinical practice, femtosecond lasers (FSLs) for corneal surgery in particular. It was natural to assess the usefulness of FSL in cataract surgery as this technology was within reach. Indeed, precise and reproducible cuttings provided by FSL platforms could improve standardization of care and limit the risk associated with the human element in surgery and provide a step toward robot-assisted surgery. After docking and planning the procedure, femtosecond lasers are used to perform corneal incisions, capsulorhexis, lens fragmentation, and arcuate incisions in an automated manner. A well-constructed corneal incision is primordial as it offers safety during the procedure, self-seals afterward, and influences the refractive outcome. Capsulorhexis size, centration, and resistance to shearing influence the surgery, intraocular lens (IOL) centration and stability, and posterior capsular opacification formation. Lens fragmentation is where most of the energy is delivered into the eye, and its amount influences endothelial cell damage and potential damage to other ocular structures. The arcuate incisions offer an additional opportunity to influence postoperative astigmatism. Femtosecond laser-assisted cataract surgery (FLACS) has been a topic of research in many studies and clinical trials that attempted to assess its potential benefits and cost-effectiveness over PCS and is the subject of this mini-review.
Fallopian tubal histogenesis of ovarian endometriosis—A study of folate receptor-alpha expression
Authors: Wang Yiying , Li Qiyan , Zhao Ruijiao , Wang Jerry Y. , Wang Yan , Lin Wanrun , Yuan Zeng , Zhang Jing , Fadare Oluwole , Wang Yue , Zheng Wenxin
Published: March 2023

Background

Ovary is a common organ site involved by endometriosis. We previously found that fallopian tube may contribute to the histogenesis of ovarian endometriosis. The finding was novel and requires further studies. We addressed this issue by examining a differentially expressed gene folate receptor alpha (FOLR1) and its protein (FRA) in this study.

Results

A total of 144 tissue samples were studied. These included 32-paired tubal-endometrial-ovarian endometriosis samples (n = 96), 18 samples of ovarian endometriosis without corresponding fallopian tube or endometrium, and 30 ovarian tissue samples with ovarian surface epithelia but without endometriosis. Multiple comparisons among groups of ovarian endometriosis, normal fallopian tube and benign endometrium were performed. FOLR1 was highly expressed in the epithelia of fallopian tube and ovarian endometriosis, with paired endometrial samples showing a significantly lower level of expression. Similar differential studies for FRA protein were performed through Western blot and immunohistochemistry (IHC). The expression of folate receptor alpha at both mRNA and protein levels in the tissues (fallopian tube or ovarian endometriosis vs. the endometrium) were significantly different (p < 0.001). All ovarian surface mesothelial epithelia showed negative expression of FRA by IHC.

Conclusion

The results further support that the fallopian tube may contribute to the development of ovarian endometriosis. Understanding the tubal contribution to ovarian endometriosis should ultimately contribute to ongoing investigative efforts aimed at identifying alternative ways to prevent and treat endometriosis. High level of FRA expression in the fallopian tube and endometriosis might be considered as potential tissue sites for targeted therapy.
The koala gut microbiome is largely unaffected by host translocation but rather influences host diet
Authors: Blyton Michaela D. J. , Pascoe Jack , Hynes Emily , Soo Rochelle M. , Hugenholtz Philip , Moore Ben D.
Published: March 2023

Introduction

Translocation is a valuable and increasingly used strategy for the management of both threatened and overabundant wildlife populations. However, in some instances the translocated animals fail to thrive. Differences in diet between the source and destination areas may contribute to poor translocation outcomes, which could conceivably be exacerbated if the animals’ microbiomes are unsuited to the new diet and cannot adapt.

Methods

In this study we tracked how the faecal microbiome of a specialist Eucalyptus folivore, the koala (Phascolarctos cinereus), changed over the course of a year after translocation. We assessed microbiome composition by 16S rRNA amplicon sequencing of faecal pellets.

Results

We found no significant overall changes in the faecal microbiomes of koalas post-translocation (n = 17) in terms of microbial richness, diversity or composition when compared to the faecal microbiomes of koalas from an untranslocated control group (n = 12). This was despite the translocated koalas feeding on a greater variety of Eucalyptus species after translocation. Furthermore, while differences between koalas accounted for half of the microbiome variation, estimated diets at the time of sampling only accounted for 5% of the variation in the koala microbiomes between sampling periods. By contrast, we observed that the composition of koala faecal microbiomes at the time of translocation accounted for 37% of between koala variation in post-translocation diet. We also observed that translocated koalas lost body condition during the first month post-translocation and that the composition of the koalas’ initial microbiomes were associated with the magnitude of that change.

Discussion

These findings suggest that the koala gut microbiome was largely unaffected by dietary change and support previous findings suggesting that the koala gut microbiome influences the tree species chosen for feeding. They further indicate that future research is needed to establish whether the koalas’ gut microbiomes are directly influencing their health and condition or whether aspects of the koala gut microbiomes are an indicator of underlying physiological differences or pathologies. Our study provides insights into how animal microbiomes may not always be affected by the extreme upheaval of translocation and highlights that responses may be host species-specific. We also provide recommendations to improve the success of koala translocations in the future.
Specific TLR-mediated HSP70 activation plays a potential role in host defense against the intestinal parasite Giardia duodenalis
Authors: Liu Min , Yang Yongwu , Zhu Weining , Wu Jingxue , Yu Xiran , Li Wei
Published: March 2023

Giardia duodenalis, an important flagellated noninvasive protozoan parasite, infects the upper small intestine and causes a disease termed giardiasis globally. Few members of the heat shock protein (HSP) family have been shown to function as potential defenders against microbial pathogens, while such information is lacking for Giardia. Here we initially screened and indicated that in vitro Giardia challenge induced a marked early upregulation of HSP70 in intestinal epithelial cells (IECs). As noted previously, apoptotic resistance, nitric oxide (NO)-dependent cytostatic effect and parasite clearance, and epithelial barrier integrity represent effective anti-Giardia host defense mechanisms. We then explored the function of HSP70 in modulating apoptosis, NO release, and tight junction (TJ) protein levels in Giardia-IEC interactions. HSP70 inhibition by quercetin promoted Giardia-induced IEC apoptosis, viability decrease, NO release reduction, and ZO-1 and occludin downregulation, while the agonist celastrol could reverse these Giardia-evoked effects. The results demonstrated that HSP70 played a previously unrecognized and important role in regulating anti-Giardia host defense via attenuating apoptosis, promoting cell survival, and maintaining NO and TJ levels. Owing to the significance of apoptotic resistance among those defense-related factors mentioned earlier, we then elucidated the anti-apoptotic mechanism of HSP70. It was evident that HSP70 could negatively regulate apoptosis in an intrinsic way via direct inhibition of Apaf-1 or ROS-Bax/Bcl-2-Apaf-1 axis, and in an extrinsic way via cIAP2-mediated inhibition of RIP1 activity. Most importantly, it was confirmed that HSP70 exerted its host defense function by downregulating apoptosis via Toll-like receptor 4 (TLR4) activation, upregulating NO release via TLR4/TLR2 activation, and upregulating TJ protein expression via TLR2 activation. HSP70 represented a checkpoint regulator providing the crucial link between specific TLR activation and anti-Giardia host defense responses. Strikingly, independent of the checkpoint role of HSP70, TLR4 activation was proven to downregulate TJ protein expression, and TLR2 activation to accelerate apoptosis. Altogether, this study identified HSP70 as a potentially vital defender against Giardia, and revealed its correlation with specific TLR activation. The clinical importance of HSP70 has been extensively demonstrated, while its role as an effective therapeutic target in human giardiasis remains elusive and thus needs to be further clarified.
Clonal relatedness of coagulase-positive staphylococci among healthy dogs and dog-owners in Spain. Detection of multidrug-resistant-MSSA-CC398 and novel linezolid-resistant-MRSA-CC5
Authors: Abdullahi Idris Nasir , Lozano Carmen , Zarazaga Myriam , Saidenberg Andre Becker Simoes , Stegger Marc , Torres Carmen
Published: March 2023

Introduction

Nasal carriage of coagulase-positive staphylococci (CoPS) in healthy dogs could indicate increased risks of colonization for in-contact people or vice versa. This study determined the nasal carriage rate of CoPS among healthy dogs and in-contact people, their genotypic characteristics and phylogenetic relatedness.

Methods

Nasal samples were collected from 27 households (34 dogs and 41 humans) in Spain. Staphylococci were identified by MALDI-TOF-MS, their antimicrobial resistance (AMR) genes and spa-types were tested by PCR/sequencing. The relatedness of CoPS from the same households was assessed by core genome single nucleotide polymorphisms (SNPs) analyses.

Results

Staphylococcus aureus carriage was found in 34.1% of humans (including one methicillin-resistant S. aureus MRSA-CC5-t2220-SCCmec type-IV2B) and 5.9% of dogs; Staphylococcus pseudintermedius in 2.4% of humans and 32.4% of dogs; while Staphylococcus coagulans was only detected in dogs (5.4%). Remarkably, one human co-carried S. aureus/S. pseudintermedius, while a dog co-carried the three CoPS species. Household density was significantly associated with S. pseudintermedius carriage in households with > than 1 dog and >than 1 human (OR = 18.10, 95% CI: 1.24–260.93, p = 0.034). Closely related (<15 SNPs) S. aureus or S. pseudintermedius were found in humans or dogs in three households. About 56.3% S. aureus carriers (dog or human) harboured diverse within-host spa-types or AMR genotypes. Ten clonal complexes (CCs) were detected among the S. aureus, of which methicillin-susceptible S. aureus-CC398-IEC-type C (t1451 and t571) was the most frequent, but exclusive to humans. S. aureus and S. pseudintermedius isolates harboured resistance genes or mutations associated to 9 classes of antimicrobials including linezolid (G2261A & T1584A point mutations in 23S rDNA). The S. coagulans isolates were susceptible to all antimicrobials. Most of the S. pseudintermedius carried lukS/F-I, siet, and sient genes, and all S. aureus were negative for lukS/F-PV, tst-1, eta and etb genes.

Discussion

Clonally related human-to-human MSSA and dog-to-human MSSP were found. The detection of the MSSA-CC398 clade highlights the need for its continuous surveillance from One Health perspective.
Hypertension, cerebral Amyloid, aGe Associated Known neuroimaging markers of cerebral small vessel disease Undertaken with stroke REgistry (HAGAKURE) prospective cohort study: Baseline characteristics and association of cerebral small vessel disease with prognosis in an ischemic stroke cohort
Authors: Ikeda Shuhei , Yakushiji Yusuke , Tanaka Jun , Nishihara Masashi , Ogata Atsushi , Eriguchi Makoto , Ono Shohei , Kosugi Masafumi , Suzuyama Kohei , Mizoguchi Megumi , Shichijo Chika , Ide Toshihiro , Nagaishi Yukiko , Mori Hodo , Ono Natsuki , Yoshikawa Masaaki , Ide Kiku , Minagawa Hiromu , Iida Kotaro , Kawamoto Kazuhiro , Katsuki Yoshiko , Irie Hiroyuki , Abe Tatsuya , Hara Hideo
Published: March 2023

Introduction

Cerebral small vessel disease (SVD) is one of the leading causes of stroke; each neuroimaging marker of SVD is correlated with vascular risk factors and associated with poor prognosis after stroke. However, longitudinal studies investigating the association between comprehensive SVD burden scoring system, “total SVD score” – which encompasses the established neuroimaging markers of lacunae, cerebral microbleeds (CMBs), white matter hyperintensities (WMH) including periventricular hyperintensities, and perivascular spaces in basal ganglia– and clinical outcomes are limited. The aim of this study is to determine the association between SVD burden and long-term prognosis in patients with ischemic stroke.

Methods and design

This prospective, single-center, observational study enrolled patients with acute ischemic stroke, including cerebral infarction and transient ischemic attack. Magnetic resonance imaging scans were performed, and then total SVD score (range, 0–4) was calculated. We recorded baseline characteristics and evaluated the relationships of long-term outcomes to SVD neuroimaging markers and total SVD score. Stroke recurrence was thought as primary outcome. Hazard ratios (HRs) of events during follow-up were calculated using Cox proportional hazards modeling with adjustments for age, sex, hypertension, dyslipidemia, diabetes mellitus, atrial fibrillation, and smoking. Cumulative event rates were estimated using the Kaplan–Meier method.

Results

Consecutive 564 acute ischemic stroke patients were enrolled according to inclusion and exclusion criteria. A total of 467 participants with first-ever ischemic stroke were analyzed (median age 75.0 [interquartile range, 64.0–83.0] years, 59.3% male). Total SVD score was 0 point in 47 individuals (12.0%), 1 point in 83 (21.2%), 2 points in 103 (26.3%), 3 points in 85 (21.7%), and 4 points in 73 (18.7%). Twenty-eight recurrent stroke events were identified during follow-up. Total SVD score ≥ 2, presence of CMBs, and moderate-to-severe WMH were associated with increased risk of recurrent stroke events (HR 9.31, 95% confidence interval [CI] 2.33–64.23; HR 2.81, 95% CI 1.08–7.30; HR 2.90, 95% CI 1.22–6.88, respectively).

Conclusion

The accumulation of SVD biomarkers as determined by total SVD score offered a reliable predictor of stroke recurrence. This study established a firm understanding of SVD prognosis in clinical settings.
Prognostic capacity of the systemic inflammation response index for functional outcome in patients with aneurysmal subarachnoid hemorrhage
Authors: Hou Yuyang , Fan Jingxin , Yuan Huisheng , Zheng Hu , Yang Hongkuan , Li Hua , Chen Rudong , Yu Jiasheng
Published: March 2023

Objective

We aimed to investigate the relationship between systemic inflammatory response index (SIRI) and functional outcome after aneurysmal subarachnoid hemorrhage (aSAH).

Methods

A retrospective cohort study was performed involving all consecutive aSAH patients admitted to our institution. The modified Rankin Scale (mRS) score was performed to determine the functional outcomes of all patients at 3 months after aSAH. Results were categorized as favorable (mRS score 0–2) and unfavorable (mRS score 3–6). Univariate and multivariate logistic regressive analyses were utilized to identify the prognostic significance of SIRI. To minimize the effects of confounding factors, patients were stratified according to the optimal cut-off value of SIRI with propensity score matching (PSM). Further subgroup analysis was conducted to verify the consistency of our findings and Pearson's correlation analysis was used to assess the relationship between SIRI and the severity of aSAH.

Results

In this study, 350 patients were enrolled and 126 (36.0%) of them suffered unfavorable outcomes. The SIRI of 5.36 × 109/L was identified as the optimal cut-off value. Two score-matched cohorts (n = 100 in each group) obtained from PSM with low SIRI and high SIRI were used for analysis. A significantly higher unfavorable functional outcome rate was observed in patients with high SIRI before and after PSM (p < 0.001 and 0.017, respectively). Multivariate logistic regression analysis demonstrated that SIRI value ≥ 5.36 × 109/L was an independent risk factor for poor outcomes (OR 3.05 95% CI 1.37–6.78, p = 0.006) after adjusting for possible confounders. A identical result was discovered in the PSM cohort. In ROC analysis, the area under the curve (AUC) of SIRI was 0.774 which shown a better predictive value than other inflammatory markers observed in previous similar studies. Pearson's correlation analysis proved the positive association between SIRI and aSAH severity.

Conclusions

Elevated SIRI at admission is associated with worse clinical status and poorer functional outcomes among patients with aSAH. SIRI is a useful inflammatory marker with prognostic value for functional outcomes after aSAH.
Enhancing upper-limb neurorehabilitation in chronic stroke survivors using combined action observation and motor imagery therapy
Authors: Binks Jack Aaron , Emerson Jonathan Reyes , Scott Matthew William , Wilson Christopher , van Schaik Paul , Eaves Daniel Lloyd
Published: March 2023

Introduction

For people who have had a stroke, recovering upper-limb function is a barrier to independence. When movement is difficult, mental practice can be used to complement physical therapy. In this within-participants study we investigated the effects of combined action observation and motor imagery (AO + MI) therapy on upper-limb recovery in chronic stroke survivors.

Methods

A Graeco-Latin Square design was used to counterbalance four mental practice conditions (AO + MI, AO, MI, Control) across four cup-stacking tasks of increasing complexity. Once a week, for five consecutive weeks, participants (n = 10) performed 16 mental practice trials under each condition. Each trial displayed a 1st person perspective of a cup-stacking task performed by an experienced model. For AO, participants watched each video and responded to an occasional color cue. For MI, participants imagined the effort and sensation of performing the action; cued by a series of still-images. For combined AO + MI, participants observed a video of the action while they simultaneously imagined performing the same action in real-time. At three time points (baseline; post-test; two-week retention test) participants physically executed the three mentally practiced cup-stacking tasks, plus a fourth unpractised sequence (Control), as quickly and accurately as possible.

Results

Mean movement execution times were significantly reduced overall in the post-test and the retention test compared to baseline. At retention, movement execution times were significantly shorter for combined AO + MI compared to both MI and the Control. Individual participants reported clinically important changes in quality of life (Stroke Impact Scale) and positive qualitative experiences of AO + MI (social validation).

Discussion

These results indicate that when physical practice is unsuitable, combined AO + MI therapy could offer an effective adjunct for neurorehabilitation in chronic stroke survivors.
Clinical phenotypic and genotypic characterization of NPRL3-related epilepsy
Authors: Zhang Hongwei , Deng Jie , Wang Xiaohui , Chen Chunhong , Chen Shuhua , Dai Lifang , Fang Fang
Published: March 2023

Background

As one of the assembly factors of the GATOR1 protein complex in the mechanism of rapamycin pathway, NPRL3 plays an important role in the pathogenesis of epilepsy. However, the correlation between genotype and clinical phenotype in patients with NPRL3-related epilepsy has not been clarified.

Methods

A total of 11 Chinese children with NPRL3-related epilepsy were identified through whole-exome sequencing (WES). The data from the clinical presentation, laboratory data, brain imaging findings, genetic results, and treatment methods were collected. All previously reported cases with NPRL3-related epilepsy were collected and reviewed through PubMed search.

Results

Among the 11 children, eight have not been reported, and two of them presented infantile spasms (ISs) as a new phenotype of NPRL3-related epilepsy. In addition, WES identified five frameshift mutations, three nonsense mutations, two missense mutations, and one exon deletion. Based on bioinformatics analysis, it was found that two missense mutation sites were highly conserved, and the c.400G>A mutation site of the NPRL3 gene caused the alteration of the protein structure. To date, 88 patients have been reported with NPRL3-related defects, including our 11 cases. The most common presentations were sleep-related hypermotor epilepsy (SHE), frontal lobe epilepsy (FLE), and temporal lobe epilepsy. A majority of patients (70%) presented normal neuroimaging results, and focal cortical dysplasia was the most common neuroimaging abnormality (62.5%). Among the NPRL3 gene mutations, loss of function (nonsense mutations, frameshift mutations, and exons deletion) was the most common genetic variation (75%). For 73% of patients with NPRL3-related epilepsy, monotherapy of sodium channel blockers was effective. Surgery was effective for 75% of children with neuroimaging abnormalities. Two cases unresponsive to surgery or anti-seizure medications were treated with ketogenic diets (KD), which were effective. One case was treated with rapamycin at an early stage of epilepsy, which was effective as well.

Conclusion

NPRL3-related epilepsy has high clinical and genetic heterogeneity. SHE and FLE are the most common clinical presentations. Furthermore, ISs are the new phenotypes of NPRL3-related epilepsy, while the variants c.275G>A, c.745G>A, and c.1270C>T may be the most common NPRL3 gene mutations. Sodium channel blockers, surgery, KD, and rapamycin may be the potential treatments for these patients. Our study expanded the clinical and genetic spectrum of NPRL3-related epilepsy and provided important information for the precise treatment of patients.
Etiological classification and management of dizziness in children: A systematic review and meta-analysis
Authors: Zhang Jifang , Zhu Qi , Shen Jiali , Chen Jianyong , Jin Yulian , Zhang Qing , Duan Maoli , Yang Jun
Published: March 2023

Background

Dizziness in children, which could not be diagnosed at an early stage in the past, is becoming increasingly clear to a large extent. However, the recognition of the diagnosis and management remains discrepant and controversial due to their complicated and varied etiology. Central and peripheral vestibular disorders, psychogenic and systemic diseases, and genetic pathogeny constitute childhood etiological entities. Further understanding of the etiology and the prevalence of vertigo disorders is of crucial importance and benefit in the diagnosis and management of pediatric patients.

Methods

This systematic review and meta-analysis were conducted by systematically searching Embase, PubMed, the Cochrane Library, CNIK, the Chinese Wan-Fang database, CBM, the Chinese VIP database, and the Web of Science for literature on childhood vertigo disorders published up to May 2022. The literature was evaluated under strict screening and diagnostic criteria. Their quality was assessed using the Agency for Healthcare and Research Quality (AHRQ) standards. The test for homogeneity was conducted to determine the fixed effects model or random-effect model employed.

Results

Twenty-three retrospective cross-sectional studies involving 7,647 children with vertigo disorders were finally included, with an AHRQ score >4 (high or moderate quality). Our results demonstrated that peripheral vertigo (52.20%, 95% CI: 42.9–61.4%) was more common in children than central vertigo (28.7%, 95% CI: 20.8–37.4%), psychogenic vertigo (7.0%, 95% CI: 4.8–10.0%), and other systemic vertigo (4.7%, 95% CI: 2.6–8.2%). The five most common etiological diagnoses associated with peripheral vertigo included benign paroxysmal vertigo of childhood (BPVC) (19.50%, 95% CI: 13.5–28.3%), sinusitis-related diseases (10.7%, 95% CI: −11.2–32.6%), vestibular or semicircular canal dysfunction (9.20%, 95% CI: 5.7–15.0%), benign paroxysmal positional vertigo (BPPV)(7.20%, 95% CI: 3.9–11.5%), and orthostatic dysregulation (6.8%, 95% CI: 3.4–13.0%). Vestibular migraine (20.3%, 95% CI: 15.4–25.2%) was the most seen etiological diagnosis associated with central vertigo in children. In addition, we found the sex-based difference influenced the outcome of psychogenic vertigo and vestibular migraine, while there was no significant difference in other categories of the etiology. For the management of vertigo, symptomatical management is the first choice for most types of vertigo disorder in pediatrics.

Conclusion

Complex etiology and non-specific clinical manifestations of vertigo in pediatrics are challenging for their diagnoses. Reliable diagnosis and effective management depend on the close cooperation of multiple disciplines, combined with comprehensive consideration of the alternative characteristics of vertigo in children with growth and development.
An accessible and versatile deep learning-based sleep stage classifier
Authors: Hanna Jevri , Flöel Agnes
Published: March 2023

Manual sleep scoring for research purposes and for the diagnosis of sleep disorders is labor-intensive and often varies significantly between scorers, which has motivated many attempts to design automatic sleep stage classifiers. With the recent introduction of large, publicly available hand-scored polysomnographic data, and concomitant advances in machine learning methods to solve complex classification problems with supervised learning, the problem has received new attention, and a number of new classifiers that provide excellent accuracy. Most of these however have non-trivial barriers to use. We introduce the Greifswald Sleep Stage Classifier (GSSC), which is free, open source, and can be relatively easily installed and used on any moderately powered computer. In addition, the GSSC has been trained to perform well on a large variety of electrode set-ups, allowing high performance sleep staging with portable systems. The GSSC can also be readily integrated into brain-computer interfaces for real-time inference. These innovations were achieved while simultaneously reaching a level of accuracy equal to, or exceeding, recent state of the art classifiers and human experts, making the GSSC an excellent choice for researchers in need of reliable, automatic sleep staging.
Individualized network analysis: A novel approach to investigate tau PET using graph theory in the Alzheimer’s disease continuum
Authors: Protas Hillary , Ghisays Valentina , Goradia Dhruman D. , Bauer Robert , Devadas Vivek , Chen Kewei , Reiman Eric M. , Su Yi
Published: March 2023

Introduction

Tau PET imaging has emerged as an important tool to detect and monitor tangle burden in vivo in the study of Alzheimer’s disease (AD). Previous studies demonstrated the association of tau burden with cognitive decline in probable AD cohorts. This study introduces a novel approach to analyze tau PET data by constructing individualized tau network structure and deriving its graph theory-based measures. We hypothesize that the network- based measures are a measure of the total tau load and the stage through disease.

Methods

Using tau PET data from the AD Neuroimaging Initiative from 369 participants, we determine the network measures, global efficiency, global strength, and limbic strength, and compare with two regional measures entorhinal and tau composite SUVR, in the ability to differentiate, cognitively unimpaired (CU), MCI and AD. We also investigate the correlation of these network and regional measures and a measure of memory performance, auditory verbal learning test for long-term recall memory (AVLT-LTM). Finally, we determine the stages based on global efficiency and limbic strength using conditional inference trees and compare with Braak staging.

Results

We demonstrate that the derived network measures are able to differentiate three clinical stages of AD, CU, MCI, and AD. We also demonstrate that these network measures are strongly correlated with memory performance overall. Unlike regional tau measurements, the tau network measures were significantly associated with AVLT-LTM even in cognitively unimpaired individuals. Stages determined from global efficiency and limbic strength, visually resembled Braak staging.

Discussion

The strong correlations with memory particularly in CU suggest the proposed technique may be used to characterize subtle early tau accumulation. Further investigation is ongoing to examine this technique in a longitudinal setting.
A conjoint analysis of bulk RNA-seq and single-nucleus RNA-seq for revealing the role of ferroptosis and iron metabolism in ALS
Authors: Fu Xiujuan , He Yizi , Xie Yongzhi , Lu Zuneng
Published: March 2023

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive and selective degeneration of motor neurons in the motor cortex of brain and spinal cord. Ferroptosis is a newly discovered form of cell death and reported to mediate selective motor neuron death in the mouse model of ALS. The growing awareness of ferroptosis and iron metabolism dysfunction in ALS prompted us to investigate the expression pattern of ferroptosis and iron metabolism-related genes (FIRGs) in ALS. Here, we performed a conjoint analysis of bulk-RNA sequence and single-nucleus RNA sequence data using the datasets from Gene Expression Omnibus (GEO) to reveal the role of FIRGs in ALS, especially in selective motor neuron death of ALS. We first investigated the differentially expressed genes (DEGs) between ALS and non-neurological controls. Weighted gene co-expression network analysis constructed the gene co-expression network and identified three modules closely associated with ALS. Fifteen FIRGs was identified as target genes based on least absolute shrinkage and selection operator regression analysis as follows: ACSL4, ANO6, ATP6V0E1, B2M, CD44, CHMP5, CYBB, CYBRD1, HIF1A, MOSPD1, NCF2, SDCBP, STEAP2, TMEM14C, ULK1. These genes could differentiate ALS patients from non-neurological controls (p < 2.2e−16) and had a valid value in predicting and diagnosing ALS (AUC = 0.881 in primary dataset and AUC = 0.768 in validation dataset). Then we performed the functional enrichment analysis of DEGs between ALS cases, the most significantly influenced by target genes, and non-neurological controls. The result indicated that the most significantly influenced functions in ALS pathogenesis by these identified FIRGs are synapse pathways, calcium signaling pathway, cAMP signaling pathway, and phagosome and several immune pathways. At last, the analysis of single- nuclear seq found that CHMP5, one of the 15 FIRGs identified by bulk single-nucleus RNA-seq data, was expressed significantly higher in ALS than pathologically normal (PN), specifically in excitatory neuron populations with layer 2 and layer 3 markers (Ex L2_L3), layer 3 and layer 5 markers (Ex L3_L5). Taken together, our study indicates the positive correlation between FIRGs and ALS, presents potential markers for ALS diagnosis and provides new research directions of CHMP5 function in selective motor neuron death in ALS.
The molecular basis of p21-activated kinase-associated neurodevelopmental disorders: From genotype to phenotype
Authors: Dobrigna Manon , Poëa-Guyon Sandrine , Rousseau Véronique , Vincent Aline , Toutain Annick , Barnier Jean-Vianney
Published: March 2023

Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding of their etiology, there are still major obstacles in the way of developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical and genetic heterogeneity, rarity of recurrent pathogenic variants, and comorbidity with other psychiatric traits. Moreover, a large intragenic mutational landscape is at play in some NDDs, leading to a broad range of clinical symptoms. Such diversity of symptoms is due to the different effects DNA variations have on protein functions and their impacts on downstream biological processes. The type of functional alterations, such as loss or gain of function, and interference with signaling pathways, has yet to be correlated with clinical symptoms for most genes. This review aims at discussing our current understanding of how the molecular changes of group I p21-activated kinases (PAK1, 2 and 3), which are essential actors of brain development and function; contribute to a broad clinical spectrum of NDDs. Identifying differences in PAK structure, regulation and spatio-temporal expression may help understanding the specific functions of each group I PAK. Deciphering how each variation type affects these parameters will help uncover the mechanisms underlying mutation pathogenicity. This is a prerequisite for the development of personalized therapeutic approaches.
Cerebral cortex and hippocampus neural interaction during vagus nerve stimulation under in vivo large-scale imaging
Authors: Xu Hanyun , Jin Tingting , Zhang Rujin , Xie Hao , Zhuang Chaowei , Zhang Yanyang , Kong Dongsheng , Xiao Guihua , Yu Xinguang
Published: March 2023

Objective

The purpose of this study was to study mechanisms of VNS modulation from a single neuron perspective utilizing a practical observation platform with single neuron resolution and widefield, real-time imaging coupled with an animal model simultaneously exposing the cerebral cortex and the hippocampus.

Methods

We utilized the observation platform characterized of widefield of view, real-time imaging, and high spatiotemporal resolution to obtain the neuronal activities in the cerebral cortex and the hippocampus during VNS in awake states and under anesthesia.

Results

Some neurons in the hippocampus were tightly related to VNS modulation, and varied types of neurons showed distinct responses to VNS modulation.

Conclusion

We utilized such an observation platform coupled with a novel animal model to obtain more information on neuron activities in the cerebral cortex and the hippocampus, providing an effective method to further study the mechanisms of therapeutic effects modulated by VNS.
Interventional strategies for ischemic stroke based on the modulation of the gut microbiota
Authors: Wang Jing , Liu Xiaofeng , Li Qun
Published: March 2023

The microbiota-gut-brain axis connects the brain and the gut in a bidirectional manner. The organism’s homeostasis is disrupted during an ischemic stroke (IS). Cerebral ischemia affects the intestinal flora and microbiota metabolites. Microbiome dysbiosis, on the other hand, exacerbates the severity of IS outcomes by inducing systemic inflammation. Some studies have recently provided novel insights into the pathogenesis, efficacy, prognosis, and treatment-related adverse events of the gut microbiome in IS. In this review, we discussed the view that the gut microbiome is of clinical value in personalized therapeutic regimens for IS. Based on recent non-clinical and clinical studies on stroke, we discussed new therapeutic strategies that might be developed by modulating gut bacterial flora. These strategies include dietary intervention, fecal microbiota transplantation, probiotics, antibiotics, traditional Chinese medication, and gut-derived stem cell transplantation. Although the gut microbiota-targeted intervention is optimistic, some issues need to be addressed before clinical translation. These issues include a deeper understanding of the potential underlying mechanisms, conducting larger longitudinal cohort studies on the gut microbiome and host responses with multiple layers of data, developing standardized protocols for conducting and reporting clinical analyses, and performing a clinical assessment of multiple large-scale IS cohorts. In this review, we presented certain opportunities and challenges that might be considered for developing effective strategies by manipulating the gut microbiome to improve the treatment and prevention of ischemic stroke.
Calcium signaling in astrocytes and gliotransmitter release
Authors: Goenaga Julianna , Araque Alfonso , Kofuji Paulo , Herrera Moro Chao Daniela
Published: March 2023

Glia are as numerous in the brain as neurons and widely known to serve supportive roles such as structural scaffolding, extracellular ionic and neurotransmitter homeostasis, and metabolic support. However, over the past two decades, several lines of evidence indicate that astrocytes, which are a type of glia, play active roles in neural information processing. Astrocytes, although not electrically active, can exhibit a form of excitability by dynamic changes in intracellular calcium levels. They sense synaptic activity and release neuroactive substances, named gliotransmitters, that modulate neuronal activity and synaptic transmission in several brain areas, thus impacting animal behavior. This “dialogue” between astrocytes and neurons is embodied in the concept of the tripartite synapse that includes astrocytes as integral elements of synaptic function. Here, we review the recent work and discuss how astrocytesviacalcium-mediated excitability modulate synaptic information processing at various spatial and time scales.
Memory retrieval, reconsolidation, and extinction: Exploring the boundary conditions of post-conditioning cue exposure
Authors: Ferrara Nicole C. , Kwapis Janine L. , Trask Sydney
Published: March 2023

Following fear conditioning, behavior can be reduced by giving many CS-alone presentations in a process known as extinction or by presenting a few CS-alone presentations and interfering with subsequent memory reconsolidation. While the two share procedural similarities, both the behavioral outcomes and the neurobiological underpinnings are distinct. Here we review the neural and behavioral mechanisms that produce these separate behavioral reductions, as well as some factors that determine whether or not a retrieval-dependent reconsolidation process or an extinction process will be in effect.
Enhancing intestinal barrier efficiency: A novel metabolic diseases therapy
Authors: Zhang Yaoyuan , Zhu Xiao , Yu Xinyuan , Novák Petr , Gui Qingjun , Yin Kai
Published: March 2023

Physiologically, the intestinal barrier plays a crucial role in homeostasis and nutrient absorption and prevents pathogenic entry, harmful metabolites, and endotoxin absorption. Recent advances have highlighted the association between severely damaged intestinal barriers and diabetes, obesity, fatty liver, and cardiovascular diseases. Evidence indicates that an abated intestinal barrier leads to endotoxemia associated with systemic inflammation, insulin resistance, diabetes, and lipid accumulation, accelerating obesity and fatty liver diseases. Nonetheless, the specific mechanism of intestinal barrier damage and the effective improvement of the intestinal barrier remain to be explored. Here, we discuss the crosstalk between changes in the intestinal barrier and metabolic disease. This paper also highlights how to improve the gut barrier from the perspective of natural medicine, gut microbiota remodeling, lifestyle interventions, and bariatric surgery. Finally, potential challenges and prospects for the regulation of the gut barrier-metabolic disease axis are discussed, which may provide theoretical guidance for the treatment of metabolic diseases.
Molecular crosstalk between circadian clock and cancer and therapeutic implications
Authors: Qu Meng
Published: March 2023

The circadian clock governs activity of many physiological processes, thereby playing a pivotal role in human health. Circadian disruption is closely associated with cancer development; in particular, recent discoveries have provided strong evidence supporting specific functions of different molecular clock components in either promoting or inhibiting tumorigenesis. This narrative review aims to summarize the existing data on molecular connections between the clock and cancer. These results along with future efforts pave the road to targeting the circadian clock as a novel pathway for therapeutic intervention. Given the implications of chrono-nutrition interventions such as time-restricted feeding in extending lifespan, chrono-nutrition may have preventive and therapeutic applications for individuals with and at-risk of age-related diseases including cancer.