bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of perampanel in managing chronic pain caused by the complex regional pain syndrome
Authors: Chang Min Cheol , Park Donghwi
Published: December 2021

Rationale:

The α-amino-3-hydroxy-5-methy-4-isoxazole propionate (AMPA) receptor plays a critical role in the development and persistence of pain, and AMPA receptor antagonists are considered possible therapeutic targets for controlling pain. This report describes a patient with complex regional pain syndrome (CRPS) type I in the right lower leg and foot who responded well to perampanel, an AMPA receptor antagonist, for managing the chronic pain.

Patient concern:

A 61-year-old woman complained of pain in her right lower leg and foot over a period of 7 year (numeric rating scale: 8) due to CRPS type I.

Diagnosis:

CRPS type 1.

Interventions:

Despite the combination of 300 mg pregabalin, 225 mg/1950 mg tramadol/acetaminophen, and 10 mg nortriptyline per day, her right lower leg and foot were nearly disabled due to the severity of the pain. High-dose prednisolone was found to be ineffective. Then, perampanel (4 mg; 2 mg twice) was administered to this patient daily.

Outcomes:

The day after treatment with perampanel, her pain completely disappeared. Additionally, at day 7 and 1 month follow-up, she reported no pain in the right lower leg and foot. Moreover, no adverse effects were reported after the application of perampanel.

Lessons:

These results suggest that perampanel may potentially be used to treat centralized pain.
Testicular tumors: discriminative value of conventional MRI and diffusion weighted imaging
Authors: Wang Weiwei , Sun Zhanguo , Chen Yueqin , Zhao Fan , Yu Hao , Guo Xiang , Shi Kewei
Published: December 2021

To explore the feasibility of using conventional MRI features combined with apparent diffusion coefficient (ADC) values for the differential diagnosis of testicular tumors.

A total of 63 patients with pathologically confirmed testicular tumors were enrolled in this study. In particular, there were 46 cases of malignant lesions and 17 cases of benign lesions. All patients underwent conventional magnetic resonance imaging (MRI) and diffusion weighted imaging. Multivariate logistic regression models and receiver operating characteristic curves were constructed to assess diagnostic accuracies.

T2-homogeneity, intratumoral septa, and peritumoral infiltration were more common in the malignant group, and capsule sign was more common in the benign group (P < .05 for all). The mean ADC value of the malignant group was lower than that of the benign group (P < .05). When the ADC value ≤ 0.90 × 10−3 mm2/s, the diagnosis tended to be malignancy. The conventional MRI model could achieve better diagnostic accuracy than ADC values alone (P < .05). Compared with the conventional MRI model, the specificity and accuracy of the full model (ADC and conventional MRI model) increased by 9.8% and 3.2%, respectively. T2-homogeneity and T2-hypointensity were more common in seminoma and lymphoma, cystic changes were more common in nonseminomatous germ cell tumor (NSGCT), and intratumoral septa was more common in seminoma (P < .05 for all). The ADC value of NSGCT was larger than seminoma, and lymphoma was the smallest (P < .05 for all). Cystic changes, T2-hypointensity, intratumoral septa, and ADC value were independent factors for differentiating the seminoma, NSGCT, and lymphoma subgroups.

A combination of conventional MRI features and ADC values can improve the diagnostic efficiency for differentiating benign and malignant testicular tumors, and can additionally distinguish different subtypes of malignant testicular tumors.
Association between vitamin D deficiency at one month of age and bronchopulmonary dysplasia
Authors: Byun Shin Yun , Bae Mi Hye , Lee Na Rae , Han Young Mi , Park Kyung Hee
Published: December 2021

Vitamin D deficiency is common and increases the likelihood of neonatal morbidities in preterm infants. This study assessed vitamin D levels at 1 month of age after 4 weeks of vitamin D supplementation and determined the association between vitamin D levels and neonatal morbidities.

This retrospective study included preterm infants with birth weight <1500 g or gestational age <32 weeks born in our hospital between January 2018 and December 2019. They were administered 400 IU of oral vitamin D supplementation after birth according to our policy. The infants were then divided into sufficient (≥20 ng/mL) and deficient (<20 ng/mL) groups according to their serum vitamin D levels at 1 month of age.

The vitamin D deficient and sufficient groups included 49 and 41 patients, respectively. The mean gestational age and birth weight. GHT in the vitamin D deficient group were 29.1 ± 2.1 weeks and 1216.1 ± 308.1 g, respectively, and 30.0 ± 1.7 weeks and 1387.6 ± 350.8 g, respectively, in the sufficient group. No significant differences were observed between the 2 groups in demographic and clinical outcomes except for bronchopulmonary dysplasia (BPD), which occurred significantly more often in the vitamin D-deficient group (odds ratio 2.21; 95% confidence interval, 1.85–2.78; P = .02).

The results of our study suggest that vitamin D deficiency at 1 month of age is associated with BPD in preterm infants.
Effects of robot (SUBAR)-assisted gait training in patients with chronic stroke
Authors: Kang Cheon Ji , Chun Min Ho , Lee Junekyung , Lee Ji Yeon
Published: December 2021

Background:

SUBAR is a new ground walking exoskeletal robot. The objective of this study is to investigate SUBAR-assisted gait training's effects in patients with chronic stroke.

Methods:

This preliminary study is a prospective randomized controlled trial. Thirty adults were enrolled 6 months after the onset of stroke with functional ambulation category scores ≥ 3. Patients were randomly assigned to receive robot-assisted gait training (SUBAR group, n = 15) or conventional physiotherapy (control group, n = 15). All patients received a total of 10 treatment sessions of 30 minutes each for 3 weeks. Before and after the 10-treatment sessions, patients were evaluated. The primary outcome is the 10 meter walk test and the secondary outcomes were the functional ambulation category scale, the Motricity Index-Lower, Modified Ashworth Scale (MAS), timed up and go, Rivermead Mobility Index, Berg Balance Scale (BBS), and gait analysis.

Results:

In the SUBAR group, MAS and step length were significantly improved between pre- and posttreatment measurements (Δmean ± SD: −1.1 ± 1.6 and 5.5 ± 7.6, P = .019 and .016, respectively). The SUBAR group improved the stride length and step length of the affected limb but not significantly. The control group had significant improvements in the BBS, MAS, and stride length between pre- and posttreatment measurements (Δmean ± SD: 3.5 ± 4.6, −0.8 ± 1.5, and 6.5 ± 9.5; P = .004, .031, and .035, respectively). The BBS improved more in the control group than in the SUBAR group. There were no other differences between the SUBAR group and the control group.

Conclusion:

Our results suggest that SUBAR-assisted gait training improved gait parameters in patients with chronic stroke. However, there was no significant difference in most outcome measures compared to conventional physiotherapy. Further research is warranted to measure the effects of SUBAR-assisted gait training.
Severe Guillain–Barré syndrome associated with chronic hepatitis B
Authors: Wei Jiajun , Duan Shenhan
Published: December 2021

Rationale:

Guillain–Barré syndrome (GBS) is a postinfectious autoimmune peripheral neuropathy characterized by acute paralysis of the limbs. Clinically, extrahepatic manifestations of neurologic involvement in chronic hepatitis B (CHB) are uncommon. Little attention has been paid to the relationship between GBS and CHB viral infection.

Patient concerns:

We presented a severe case of a 34-year-old man with general fatigue, anorexia, jaundice, numbness, and even muscle atrophy in the limbs, and respiratory failure during an acute exacerbation of CHB.

Diagnoses:

Serological liver enzymes test confirmed an acute exacerbation of CHB. Nerve conduction studies revealed the features of acute motor and sensory axonal neuropathy combined with acute inflammatory demyelinating polyneuropathy, and cerebrospinal fluid analysis showed albuminocytologic dissociation. Clinical manifestations and the test results were consistent with a diagnosis of severe CHB-related GBS.

Interventions:

He was treated with mechanical ventilation, 2 courses of intravenous immunoglobulin, antichronic hepatitis B drugs therapy supplemented by hepatoprotection, acupuncture and rehabilitation.

Outcomes:

After 29 days of hospitalization, his neurological condition improved. At a 6-month follow-up visit, he was able to walk with the support of another person.

Lessons:

The acute exacerbation of CHB may be a potential predisposing factor for the onset of GBS. This case is a reminder to clinicians that during the acute exacerbation of CHB, patients with neurological symptoms in the limbs should be considered for potential CHB-related GBS.
Efficacy of complementary medicine for nonsteroidal anti-inflammatory drug-induced small intestinal injuries
Authors: Cho Minji , Bu Youngmin , Park Jae-Woo , Rahman Hasanur , Ko Seok-Jae
Published: December 2021

Nonsteroidal anti-inflammatory drug-induced small bowel injuries (NSIs) have been largely ignored for decades due to the focus on nonsteroidal anti-inflammatory drug gastropathy. With the visualization of the small intestines enabled by video capsule endoscopy, the frequency and severity of NSIs have become more evident. NSIs have a complex pathophysiology, and no effective preventive or treatment options have been proven. Complementary and alternative medicine (CAM) has been used to treat disorders of the small intestine, and more research on its effectiveness for NSIs has been conducted.

We reviewed the current evidence and mechanisms of action of CAMs on NSI. Clinical and experimental studies on the effect of CAMs on NSIs were performed using 10 databases.

Twenty-two studies (3 clinical and 19 in vivo experimental studies) were included in the final analysis involving 10 kinds of CAMs: bovine colostrum, Orengedokuto (coptis), muscovite, licorice, grape seed, wheat, brown seaweed, Ganoderma lucidum fungus mycelia, Chaenomeles speciosa (sweet) Nakai (muguasantie), and Jinghua Weikang capsule. The mechanisms of CAM include an increase in prostaglandin E2, reparation of the enteric nervous system, inhibition of pro-inflammatory cytokines, reduction of intestinal permeability and enteric bacterial numbers, decrease in oxidative stress, and modulation of small intestinal motility.

CAM may be a novel alternative option for treating and preventing NSI, and further studies on human and animal models with relevant comorbidities are warranted.
Systematic review of methodology and reporting quality of global guidelines on fever in children
Authors: Zhang Chuan , Zhang Lingli , Qiong Liao , Zeng Linan , Wu Di , Qin Fang
Published: December 2021

Objective:

This study aimed to evaluate the global clinical practice guidelines on fever in children. We also aimed to select a guideline with good methodology and reporting quality to provide scientific reference for diagnosis and treatment of fever in children.

Methods:

The Chinese and English databases Embase, PubMed, Cochrane library, China National Knowledge Infrastructure, Wanfang database, clinical guides, and the website of the Department of Public Health Administration were retrieved up to January 2020. The clinical practice guidelines on fever in children were included. The AGREE II instrument and Reporting Items for Practice Guidelines in Healthcare statement were used to evaluate the methodology and reporting quality of the guidelines.

Results:

Eight clinical guidelines for fever in children were included. Methodological quality assessment showed that the recommendation level of ISP, South Africa, National Institute for Health and Care Excellence, China, and American College of Emergency Physicians were grade B (recommended with modification), while that of American Academy of Pediatrics, New South Wales, and South Australia was grade C recommendation (not recommended). No grade A recommendation guideline was found. The reporting quality from higher to lower was National Institute for Health and Care Excellence, the Chinese guideline, American College of Emergency Physicians, ISP, South Africa, New South Wales, South Australia, and American Academy of Pediatrics. The guideline recommendations were similar in various countries, but they were slightly different in various aspects, including body temperature measurement and the timing of drug administration.

Conclusion:

There are limitations in the methodology and reporting quality of all eight global guidelines on fever in children. For future development of these guidelines, attention should be paid to improving applicability of the guidelines in terms of methodology. Additionally, the principles and explanations for formation of recommendations should be described, as well as the limitations of the reporting guideline in detail in terms of the reporting quality. Treatments of fever in children are similar in different countries, but there are still differences that require further research.
Possible association between oral health and sleep duration
Authors: Han Sungjun , Jee Donghyun , Kang Yun-Jin , Park Yong-Jin , Cho Jung-Hae
Published: December 2021

This study was performed to investigate the association between oral health and sleep duration in South Korean subjects using 2010–2015 data from the Korean National Health and Nutrition Examination Survey (KNHANES).

Cross-sectional data on 35,599 adults over the age of 19 years who completed KNHANES were analyzed. All participants reported subjective oral health status and their daily average sleep duration using a self-reported questionnaire. Sleep duration and oral health status were divided into 3 categories: ≤5, 6–8, ≥9 h/day and good, fair, poor, respectively.

The overall prevalence of poor oral health status was 43.8%. Univariate analysis demonstrated that poor oral health status was significantly associated with age, smoking, alcohol, diabetes, education, income, depression, marital status, and sleep duration. After adjusting for covariates (age, sex, diabetes mellitus, hypertension, obesity, smoking, income, education, marital status), sleep durations of ≤5 hours (OR = 1.42; 95% CI, 1.26–1.60) and ≥9 hours (OR = 1.21; 95% CI, 1.04–1.40) were significantly associated with poor oral health, compared to a sleep duration of 6–8 hours. Short or long sleep duration was more likely to have an impact on the development of poor oral health status in men than in women. A significant relationship between sleep duration and oral health status was found in participants younger than 60 years.

This is the first report that both short and long sleep durations are significantly associated with the development of poor oral health status. The effect of short or long sleep duration on poor oral health was more significant in younger subjects and in men.
GPR116 overexpression correlates with poor prognosis in gastric cancer
Authors: Zheng Tian , Sun Mingyao , Liu Lanzai , Lan Yanfen , Wang Lihua , Lin Fan
Published: December 2021

The G protein-coupled receptor 116 (GPR116) is an adhesion subtype of the G protein-coupled receptor family and has been reported to be involved in tumorigenesis and cancer progression. Moreover, it has been shown to predict poor prognosis in breast and colorectal cancers. However, little is known about the role of GPR116 in gastric cancer (GC). In this study, we aimed to investigate the expression and clinical prognostic significance of GPR116 in GC.The mRNA expression levels of GPR116 in GC were analyzed using Gene Expression Omnibus and UALCAN databases, and GPR116 protein expression in GC tissues was detected using immunohistochemistry. The relationship between GPR116 expression and prognosis in patients with GC was analyzed and further validated using the Kaplan–Meier Plotter database. The correlation between GPR116 and the differentially expressed genes identified was analyzed using the LinkedOmics database. Gene set enrichment analysis was performed using WebGestalt. The results revealed that GPR116 expression was significantly upregulated in GC tissues, which was positively correlated with tumor node metastasis (TNM) staging and tumor invasion. Prognostic analysis suggested that high GPR116 expression contributed to poor overall survival in GC patients. Multivariate Cox analysis indicated that GPR116 overexpression was an independent prognostic indicator in patients with GC (HR = 1.855, 95% CI 1.021–3.370, P = .043). Enrichment analysis showed that GPR116 co-expression genes were mainly involved in extracellular matrix-receptor interaction, focal adhesion, cell adhesion, PI3K-Akt signaling, DNA replication, and cell cycle pathways. In conclusion, GPR116 was highly expressed in GC tissues and associated with poor prognosis in patients with GC, Thus GPR116 may be a novel prognostic marker and a potential therapeutic target for GC treatment.
Increased risk of bladder cancer in young adult men with hyperlipidemia
Authors: Shih Hung-Jen , Lin Ke-Hsun , Wen Yu-Ching , Fan Yen-Chun , Tsai Pei-Shan , Huang Chun-Jen
Published: December 2021

A high-cholesterol diet increases the risk of bladder cancer. The purpose of this nationwide longitudinal population-based retrospective cohort study is to investigate whether hyperlipidemia is a risk factor for bladder cancer.

Data from Taiwan National Health Insurance Database were analyzed. The primary study end point was the occurrence of newly diagnosed bladder cancer. The relative risk of bladder cancer in a hyperlipidemia cohort was compared with that in an age- and gender-matched non-hyperlipidemia cohort by using the Cox proportional hazards regression model. Cox regression analyses were further adjusted by the propensity score.

Our data revealed that the hyperlipidemia cohort (n = 33,555) had a significantly higher subsequent risk of bladder cancer than did the non-hyperlipidemia cohort (n = 33,555) (adjusted hazard ratio [HR] = 1.37, P = .005) after propensity score adjustment. Subgroup analyses revealed that men in the hyperlipidemia cohort had a significantly higher subsequent risk of bladder cancer than did those in the non-hyperlipidemia cohort (adjusted HR = 1.36, P = .040). However, the risk of bladder cancer was not significantly different between women in the hyperlipidemia cohort and those in the non-hyperlipidemia cohort. Subgroup analyses further revealed that the risk of bladder cancer was significantly higher in men aged 20 to 39 years in the hyperlipidemia cohort than in those in the non-hyperlipidemia cohort (adjusted HR = 5.45, P = .029).

In conclusion, hyperlipidemia is a risk factor for bladder cancer in young adult men.
French experience with telemedicine in inflammatory bowel disease: a patients and physicians survey
Authors: Guillo Lucas , Bonnaud Guillaume , Nahon Stéphane , Caron Bénédicte , Olympie Alain , Laurain Anne , Serrero Mélanie , Buisson Anne , Peyrin-Biroulet Laurent
Published: December 2021

Background and aims

The use of telemedicine dramatically increased during the COVID-19 pandemic. We collected patients and physicians experience on telemedicine in the field of inflammatory bowel disease (IBD).

Methods

We conducted a nationwide survey between September 2020 and January 2021. A self-administered questionnaire was sent to participants through mailing lists of the national patients’ association and IBD expert groups.

Results

Overall, 300 patients and 110 gastroenterologists filled out the survey. On a 10 points scale of satisfaction with telemedicine, 60% of patients noted a score ≥8 and 52.7% of physicians ≥7. Patients and gastroenterologists felt that the duration of teleconsultations appeared to be shorter than in-person visits in 57.5 and 55.1% of cases, respectively. All participants agreed that telemedicine is appropriate in dedicated situations and not for flare-up consultations. For 55.1% of patients, quality of care was the same via telemedicine, whereas 51.4% of gastroenterologists believed they managed less well their patients. Lack of clinical examination being pointed out as the main limitation of telemedicine. Three-quarters of patients and gastroenterologists would agree to use telemedicine more often in the future.

Conclusion

Patients and gastroenterologists were satisfied with telemedicine and would be willing to use it in the future. However, telemedicine does not replace in-person visits and should be discussed on a case-by-case basis.
Differences in walking-to-turning characteristics between older adult fallers and nonfallers: a prospective and observational study using wearable inertial sensors
Authors: Yeh Ting-Ting , Liang Pei-Jung , Lee Shu-Chun
Published: December 2021

Wearable inertial sensors have gradually been used as an objective technology for biomechanical assessments of both healthy and pathological movement patterns. This paper used foot-worn sensors for characterizing the spatiotemporal characteristics of walking and turning between older fallers and nonfallers. Thirty community-dwelling older fallers and 30 older nonfallers performed 10-m straight walking, turned 180° around a cone, and then walked 10-m back to the starting point. Specific algorithms were used to measure spatiotemporal gait (double support phase of the gait cycle, swing width, and minimal toe clearance) and turning parameters (turn duration and turn steps) using two foot-worn Physiolog inertial sensor system. The researchers directly exported data as reported by the system. Our findings indicated that older fallers showed 26.58% longer time (P = 0.036) and 13.21% more steps (P = 0.038) compared to nonfallers during turning. However, both groups decreased their walking velocity (both P < 0.001), increased double support (both P = 0.001), and increased the swing width (both P = 0.001) during the transition from walking to turning. The older nonfallers additionally increased toe clearance (P = 0.001). Compared with the fallers, the older nonfallers showed a larger change in the swing width (P = 0.025) and toe clearance (P = 0.025) in walking to turning. Older fallers may adopt a cautionary strategy while turning to reduce the risk of falls. Wearable sensors can provide the temporospatial characteristics of turning and reveal significant differences by fall status, indicating the potential of turning measures as possible markers for identifying those at fall risk.
Posttraumatic Growth as a Model to Measure and Guide Implementation of COVID-19 Recovery and Resiliency
Authors: Cunningham Tim , Pfeiffer Kate
Published: December 2021

The COVID-19 pandemic has forced leaders to reconsider the various factors that attribute to work-life balance, a healthy work environment, and resilience among nurses. Posttraumatic growth (PTG) provides a lens through which clinicians and leaders can measure, articulate, and espouse resilient recovery through unprecedented times. This article suggests the use of PTG as a framework, measured by the Posttraumatic Growth Inventory to guide leaders as they implement job-specific resiliency interventions for professional nurses. This article also suggests 3 science-based interventions intended to increase PTG. Published data support the efficacy of these interventions: resilience retreats, resilience rounds, and “The Pause,” while longitudinal impacts of PTG following these interventions remain currently unknown.
Persistent SARS-CoV-2 Nucleocapsid Protein Presence in the Intestinal Epithelium of a Pediatric Patient 3 Months After Acute Infection
Authors: Arostegui Dalia , Castro Kenny , Schwarz Steven , Vaidy Katherine , Rabinowitz Simon , Wallach Thomas
Published: December 2021

In addition to the severe impact of acute respiratory disease during the SARS-CoV-2 pandemic, the issue of “Long COVID” illness has impacted large numbers of patients following the initial infection. Wide ranges of Long Covid incidence have been reported, ranging from 30 to 87%. Long COVID has a variety of clinical manifestations, including gastrointestinal symptoms. Here, we report a case of persistent abdominal pain, 3 months following a SARS-CoV-2 diagnosis, associated with chronic colonic inflammation and the presence of mucosal SARS-CoV-2 virions.
Risk of Hypersensitivity Reactions to Iopromide in Children and Elderly
Authors: Endrikat Jan , Chernova Julia , Gerlinger Christoph , Pracz Marcin , Lengsfeld Philipp , Bhatti Aasia , Michel Alexander
Published: December 2021

Purpose

The aim of this study was to analyze the risk of hypersensitivity reactions (HSRs) to iopromide in children and elderly patients in comparison to adults.

Materials and Methods

Four observational studies were pooled and analyzed (analysis I). In addition, spontaneous reports from 1985 to 2020 from the pharmacovigilance database were evaluated (analysis II). All patients received iopromide for angiographic procedures or contrast-enhanced computed tomography in various indications. In analysis I, a nested case-control analysis, including a multivariable logistic regression model, based on pooled observational study data, was performed. Cases were defined as patients with a typical and unequivocal HSR; controls were patients without any recorded reaction. In analysis II, all spontaneous reports on HSRs after iopromide administration recorded in the pharmacovigilance database were descriptively analyzed. Exposure estimates on the size of the exposed age groups were derived from sales data and data from market research. The primary target variable was the risk of HSR to iopromide in children (<18 years) and elderly patients (≥65 years) compared with adults (≥18 to <65 years).

Results

In analysis I, a total of 132,850 patients were included (2978 children, 43,209 elderly, and 86,663 adults). Hypersensitivity reactions were significantly less frequent in children (0.47%) and elderly (0.38%) compared with adults (0.74%). The adjusted odds ratio (vs adults) for children was 0.58 (95% confidence interval, 0.34–0.98; P < 0.043), and that for the elderly was 0.51 (95% confidence interval, 0.43–0.61; P < 0.001), indicating a lower risk for both subpopulations as compared with adults. In analysis II, of the overall >288 million iopromide administrations, 5.87, 114.18, and 167.97 million administrations were administered to children, elderly, and adults, respectively. The reporting rate for HSRs in children (0.0114%) and elderly (0.0071%) was significantly lower as compared with adults (0.0143%) (P < 0.0001).

Conclusions

Hypersensitivity reactions to iopromide were significantly less frequent in children and elderly compared with adults.
Development of a Prognostic Model for Predicting Multiple Sclerosis After Optic Neuritis: A Secondary Analysis of Data From the Optic Neuritis Treatment Trial
Authors: Luo Wenjing , Deng Xinlei , Xu Xiaoyu , Song Ruitong , Luo Meifeng , Moss Heather E. , Du Yi
Published: December 2021

Background:

Optic neuritis can be the initial manifestation of multiple sclerosis (MS). The purpose of this study was to develop a prognostic model for predicting the risk of MS development among patients with optic neuritis.

Methods:

The data from 388 patients with optic neuritis were retrieved from the Optic Neuritis Treatment Trial (ONTT). Cox proportional hazards regression analysis was used to develop a prognostic model. The performance of the model was assessed by using Harrell's C-index and calibration curves. The rates of MS development were estimated using the Kaplan–Meier method.

Results:

Among the enrolled subjects, a total of 154 (39.7%) patients developed clinically definite MS during a median follow-up period of 15.8 years (interquartile range, 7.2–16.9 years). The factors associated with the development of MS were the presence of brain lesions as on baseline MRI, previous nonspecific neurologic symptoms, commencing low-dose corticosteroids treatment, ocular pain, and absence of optic disc/peripapillary hemorrhage. After incorporating these 5 factors into the prognostic model, a C-index of 0.72 (95% confidence interval [CI], 0.69–0.76) and good calibration curves were obtained. The C-index of the model was significantly higher than the C-indexes of any single factor (P < 0.001 in all cases). The model was able to stratify the ONTT patient cohort into 3 risk groups with significantly different intergroup rates of developing MS (rates for developing MS within a 15-year period: high-risk group, 75.7% [95% CI, 65.6%–82.9%], intermediate-risk group, 44.7% [95% CI, 31.4%–55.4%]; and low-risk group, 20.8% [95% CI, 14.2%–26.8%]; log-rank P < 0.001).

Conclusions:

This prognostic model had a better prediction ability when compared with the standard practice that relies solely on using brain lesions on MRI. It can, therefore, help guide decision-making to initiate earlier disease-modifying therapy for patients with optic neuritis at risk of developing MS.
Alterations in chromosomal genes nfsA, nfsB, and ribE are associated with nitrofurantoin resistance in Escherichia coli from the United Kingdom
Authors: Wan Yu , Mills Ewurabena , Leung Rhoda C.Y. , Vieira Ana , Zhi Xiangyun , Croucher Nicholas J. , Woodford Neil , Jauneikaite Elita , Ellington Matthew J. , Sriskandan Shiranee
Published: December 2021

Antimicrobial resistance in enteric or urinary

Escherichia coli

is a risk factor for invasive

E. coli

infections. Due to widespread trimethoprim resistance amongst urinary

E. coli

and increased bacteraemia incidence, a national recommendation to prescribe nitrofurantoin for uncomplicated urinary tract infection was made in 2014. Nitrofurantoin resistance is reported in <6% urinary

E. coli

isolates in the UK, however, mechanisms underpinning nitrofurantoin resistance in these isolates remain unknown. This study aimed to identify the genetic basis of nitrofurantoin resistance in urinary

E. coli

isolates collected from north west London and then elucidate resistance-associated genetic alterations in available UK

E. coli

genomes. As a result, an algorithm was developed to predict nitrofurantoin susceptibility. Deleterious mutations and gene-inactivating insertion sequences in chromosomal nitroreductase genes nfsA and/or nfsB were identified in genomes of nine confirmed nitrofurantoin-resistant urinary

E. coli

isolates and additional 11

E. coli

isolates that were highlighted by the prediction algorithm and subsequently validated to be nitrofurantoin-resistant. Eight categories of allelic changes in nfsA, nfsB, and the associated gene ribE were detected in 12412

E. coli

genomes from the UK. Evolutionary analysis of these three genes revealed homoplasic mutations and explained the previously reported order of stepwise mutations. The mobile gene complex oqxAB, which is associated with reduced nitrofurantoin susceptibility, was identified in only one of the 12412 genomes. In conclusion, mutations and insertion sequences in nfsA and nfsB were leading causes of nitrofurantoin resistance in UK

E. coli

. As nitrofurantoin exposure increases in human populations, the prevalence of nitrofurantoin resistance in carriage

E. coli

isolates and those from urinary and bloodstream infections should be monitored.
Third COVID-19 Vaccine Dose Boosts Neutralising Antibodies in Poor Responders
Authors: Lake Douglas F. , Roeder Alexa J. , Gonzalez-Moa Maria J. , Koehler Megan , Kaleta Erin , Jasbi Paniz , Vanderhoof John , McKechnie Davis , Forman Jack , Edwards Baylee , Seit-Nebi Alim , Svarovsky Sergei
Published: December 2021

Objective

To determine if poor responders to COVID-19 RNA vaccines (<50% neutralisation) after two doses would remain poor responders, or if a third dose could elicit high levels of NAbs.

Design

Clinical follow-up study

Setting

Academic and medical institutions in USA

Participants

269 healthy individuals ranging in age from 19 to 80 (Average age = 51; 165 females and 104 males) who received either BNT162b2 (Pfizer) or mRNA1273 (Moderna) vaccines.

Main Outcome Measures

NAb levels were measured: i) 2-4 weeks after a second vaccine dose, ii) 2-4 months after the second dose, iii) within 1-2 weeks prior to a third dose and iv) 2-4 weeks after a third RNA vaccine dose.

Results

In 269 study participants, percent neutralisation ranged from 0% to 99% 2-4 weeks after a second vaccine dose. The majority of vaccine recipients (154/269, 57%) demonstrated NAb levels at ≥75% 2-4 weeks after their second dose. Our study also revealed that 25% of vaccine recipients did not neutralise above 50% (Median neutralisation = 21%, titers <1:80) within a month after their second dose. We called these individuals “vaccine poor responders” (VPRs). Twenty-three VPRs ranging in age from 31 to 79 (10 males, 13 females, average age = 62.5) independently obtained a third dose of either BNT162b2 or mRNA-1273 vaccine 1-8 months (average = 5 months) after their second dose. Within a month after their third dose, poor responders showed an average 20-fold increase in NAb levels (range 46%-99%).

Conclusions

The results suggest that poor responders are not permanently poor responders; they can generate high NAb levels with an additional vaccine dose–independent of mRNA vaccine manufacturer. Previous reports indicate that NAb levels decline much more rapidly than clinical protection from hospitalisation and disease, but that does not account for vaccine recipients who never generated high levels of NAbs after two doses. It is possible that poor responders are a source of breakthrough infections. Although it is not known what levels of NAbs protect from infection or disease, many vaccine recipients in high-risk professions may wish to keep peripheral NAb levels high, limiting infection, asymptomatic viral replication, and potential transmission.
A robust and adaptive framework for interaction testing in quantitative traits between multiple genetic loci and exposure variables
Authors: Hecker Julian , Prokopenko Dmitry , Moll Matthew , Lee Sanghun , Kim Wonji , Qiao Dandi , Voorhies Kirsten , Kim Woori , Vansteelandt Stijn , Hobbs Brian D. , Cho Michael H. , Silverman Edwin K. , Lutz Sharon M. , DeMeo Dawn L. , Weiss Scott T. , Lange Christoph
Published: December 2021

The identification and understanding of gene-environment interactions can provide insights into the pathways and mechanisms underlying complex diseases. However, testing for gene-environment interaction remains a challenge since statistical power is often limited, the specification of environmental effects is nontrivial, and such misspecifications can lead to false positive findings. To address the lack of statistical power, recent methods aim to identify interactions on an aggregated level using, for example, polygenic risk scores. While this strategy increases power to detect interactions, identifying contributing key genes and pathways is difficult based on these global results.

Here, we propose RITSS (Robust Interaction Testing using Sample Splitting), a gene-environment interaction testing framework for quantitative traits that is based on sample splitting and robust test statistics. RITSS can incorporate multiple genetic variants and/or multiple environmental factors. Using sample splitting, a screening step enables the selection and combination of potential interactions into scores with improved interpretability, based on the user’s unrestricted choices for statistical/machine learning approaches. In the testing step, the application of robust test statistics minimizes the susceptibility of the results to main effect misspecifications.

Using extensive simulation studies, we demonstrate that RITSS controls the type 1 error rate in a wide range of scenarios. In an application to lung function phenotypes and human height in the UK Biobank, RITSS identified genome-wide significant interactions with subcomponents of genetic risk scores. While the contributing single variant interactions are moderate, our analysis results indicate interesting interaction patterns that result in strong aggregated signals that provide further insights into gene-environment interaction mechanisms.
MAL suppresses OSCC tumorigenesis by maintaining epithelial cell differentiation
Authors: Zhu Xueqin , Liu Zheqi , Qi Shengcai , Zou Xin , Lu Tingwei , Ke Xing , Qin Xing , Wang Xiaoning , Yan Ming , Xu Qin , Zhang Jianjun , Wang Xu , Zhang Zhen , Cao Wei , Wu Xiangbing , Chen Wantao
Published: December 2021

Oral squamous cell carcinoma (OSCC) is widely recognized as an optimal model for precise medicine guided molecular biomarkers of cancer, however, few clinical practices were applied till now. Based on the data from our own studies and published papers, it was found that the expression of MAL was significantly decreased in epithelial cancer as compared with normal tissues, and exhibited a opposite association with pathological grade. To study the molecular events related to deficiency of MAL during carcinogenesis, occurrence and development, a Mal knockout mouse model was constructed and consistently reproduced and bred. The Mal knockout mice are highly vulnerable to tumor induction by carcinogen of 4NQO, evidenced by their extremely earlier carcinogenesis, higher incidence, and more aggressive growth. Analysis of scRNA-seq data indicated that Mal knockout mice lost the ability in maintaining epithelial cell differentiation and get more prone to carcinogen with a remarkably higher incidence of epithelial malignancy. Further analyses identified putative co-functional genes of MAL, including DSG1, AQP3 and S100A8, which are key factors in maintaining epithelial cell differentiation. To conclude, the current study exhibits the clinical significance and explains the tumor suppressing function of MAL. The results also suggest the potential of MAL and its co-functional genes being biomarkers for designing the prevention and/or differentiation therapy strategies in OSCC.

Significance

MAL is found to be strongly opposite with tumor pathological grade from clinical and in vivo studies in OSCC. We propose MAL and its co-functional genes, including DSG1, AQP3 and S100A8, as key factors in maintaining epithelial cell differentiation and are valuable targets for designing prevention and differentiation therapy strategies in OSCC.
Non-zero Mean Alpha Oscillations are Evident in Computational Model and Empirical Data
Authors: Studenova Alina A. , Villringer Arno , Nikulin Vadim V.
Published: December 2021

Oscillations and evoked responses are two main types of neuronal activity recorded non-invasively with EEG/MEG. Although typically studied separately, they might in fact represent the same neuronal process. One possibility to unite them is to demonstrate that neuronal oscillations have non-zero mean which would indicate that stimulus- or task-triggered amplitude modulation of oscillations will unavoidably lead to the generation of evoked responses. We validated this mechanism using computational modelling and analysis of a large EEG data set. With a biophysical model, we indeed demonstrated that the mean of alpha oscillations is non-zero for a wide range of model parameters. In EEG data we detected non-zero mean alpha oscillations in about 96% of the participants. Furthermore, using complementary neuronal-ensemble modelling, we provided an explanation for the previously observed discrepancies between evoked responses and oscillatory amplitude changes after stimulus presentation. Overall, our results provide strong support for the unification of neuronal oscillations and evoked responses.
Sex-specific Stress and Behavioural Responses to Human Experimenters in Rats
Authors: Faraji Jamshid , Ambeskovic Mirela , Sauter Nevyn , Toly Jaxson , Whitten Kera , Lopes Nayara Antunes , Olson David M. , Metz Gerlinde A. S.
Published: December 2021

The sex of the experimenter may cause stress in animal models and be a major confounding factor in preclinical research. We studied the effects of the sex of the experimenter on female and male rat anxiety behaviours using thigmotaxis in the open field test, anxiety-induced changes in brain and back temperature using infra-red thermography, and alterations in plasma concentrations of stress hormones, corticosterone and oxytocin. Female rats displayed consistently exacerbated anxiety-related behaviours along with increased infrared cutaneous temperature during repeated exposure to male experimenters. Experimental stress further intensified thermal responses to a male experimenter, especially in female rats. These behavioural responses to a male experimenter in females were associated with higher circulating corticosterone and lower oxytocin levels. Similar responses were induced by a T-shirt worn by a human male. These findings suggest that emotional and physiological responses of female rats to a male experimenter are influenced by visual and olfactory cues. These results emphasize the need to standardize and report experimenter sex throughout a study to avoid ambiguity in interpretation of the results.
Age-related differences in the neural network interactions underlying the predictability gain
Authors: Rysop Anna Uta , Schmitt Lea-Maria , Obleser Jonas , Hartwigsen Gesa
Published: December 2021

Speech comprehension is often challenged by increased background noise, but can be facilitated via the semantic context of a sentence. This predictability gain relies on an interplay of language-specific semantic and domain-general brain regions. However, age-related differences in the interactions within and between semantic and domain-general networks remain poorly understood. Using functional neuroimaging, we investigated commonalities and differences in network interactions enabling processing of degraded speech in healthy young and old participants. Participants performed a sentence repetition task while listening to sentences with high and low predictable endings and varying intelligibility. Stimulus intelligibility was adjusted to individual hearing abilities. Older adults showed an undiminished behavioural predictability gain. Likewise, both groups recruited a similar set of semantic and cingulo-opercular brain regions. However, we observed age-related differences in effective connectivity for high predictable speech of increasing intelligibility. Young adults exhibited stronger connectivity between regions of the cingulo-opercular network and between left insula and the posterior middle temporal gyrus. Moreover, these interactions were excitatory in young adults but inhibitory in old adults. Finally, the degree of the inhibitory influence between cingulo-opercular regions was predictive of the behavioural sensitivity towards changes in intelligibility for high predictable sentences in older adults only. Our results demonstrate that the predictability gain is relatively preserved in older adults when stimulus intelligibility is individually adjusted. While young and old participants recruit similar brain regions, differences manifest in underlying network interactions. Together, these results suggest that ageing affects the network configuration rather than regional activity during successful speech comprehension under challenging listening conditions.
The PNUTS-PAD domain recruits MYC to the PNUTS:PP1 phosphatase complex via the oncogenic MYC-MB0 region
Authors: Wei Yong , Ahlner Alexandra , Redel Cornelia , Lemak Alexander , Johansson-Åkhe Isak , Houliston Scott , Kenney Tristan M.G. , Tamachi Aaliya , Morad Vivian , Duan Shili , Andrews David W. , Wallner Björn , Sunnerhagen Maria , Arrowsmith Cheryl H. , Penn Linda Z.
Published: December 2021

Despite MYC dysregulation in most human cancers, strategies to target this potent oncogenic driver remains an urgent unmet need. Recent evidence shows the PP1 phosphatase and its regulatory subunit PNUTS control MYC phosphorylation and stability, however the molecular basis remains unclear. Here we demonstrate that MYC interacts directly with PNUTS through the MYC homology Box 0 (MB0), a highly conserved region recently shown to be important for MYC oncogenic activity. MB0 interacts with PNUTS residues 1-148, a functional unit here termed, PNUTS amino-terminal domain (PAD). Using NMR spectroscopy we determined the solution structure of PAD, and characterised its interaction with MYC. Point mutations of residues at the MYC-PNUTS interface significantly weaken their interaction both in vitro and in vivo. These data demonstrate the MB0 binding pocket of the PAD represents an attractive site for pharmacological disruption of the MYC-PNUTS interaction.

In Brief

Solving the structure of MYC-PNUTS direct interaction reveals how the intrinsically disordered MYC-Box0 (MB0) region anchors into a binding pocket in the N-terminal PAD domain of PNUTS. These data provide insight into the molecular mechanism of how the PNUTS:PP1 phosphatase complex regulates MYC phosphorylation.

Highlights

A region critical for MYC oncogenesis, MYC-Box0 (MB0), directly interacts with PNUTS

PNUTS amino-terminal domain (PAD) is a structural domain that interacts with MYC MB0

Mutation of single residues at the interaction interface disrupts MYC-PNUTS binding in cells

MYC-PNUTS binding releases MYC intramolecular interactions to enable PP1substrate access
Learning progress mediates the link between cognitive effort and task engagement
Authors: Sayalı Ceyda , Heling Emma , Cools Roshan
Published: December 2021

While a substantial body of work has shown that cognitive effort is aversive and costly, a separate line of research on intrinsic motivation suggests that people spontaneously seek challenging tasks. According to one prominent account of intrinsic motivation, the Learning Progress Motivation theory, the preference for difficult tasks reflects the dynamic range that these tasks yield for changes in task performance (Oudeyer, Kaplan & Hafner, 2007). Here we test this hypothesis, by asking whether greater engagement with intermediately difficult tasks, indexed by subjective ratings and objective pupil measurements, is a function of trial-wise changes in performance. In a novel paradigm, we determined each individual’s capacity for task performance and used difficulty levels that are too low, intermediately challenging or high for that individual. We demonstrated that challenging tasks resulted in greater liking and engagement scores compared with easy tasks. Pupil size tracked objective task difficulty, where challenging tasks were associated with greater pupil responses than easy tasks. Most importantly, pupil responses were predicted by trial-to-trial changes in average accuracy as well as learning progress (derivative of average accuracy), while greater pupil responses also predicted greater subjective engagement scores. Together, these results substantiate the Learning Progress Motivation hypothesis stating that the link between task engagement and cognitive effort is mediated the dynamic range for changes in task performance.
Miniature Structured Illumination Microscope for in vivo 3D Imaging of Brain Structures with Optical Sectioning
Authors: Supekar Omkar D. , Sias Andrew , Hansen Sean R. , Martinez Gabriel , Peet Graham C. , Peng Xiaoyu , Bright Victor M. , Hughes Ethan G. , Restrepo Diego , Shepherd Douglas P. , Welle Cristin G. , Gopinath Juliet T. , Gibson Emily A.
Published: December 2021

We present a high-resolution miniature, light-weight fluorescence microscope with electrowetting lens and onboard CMOS for high resolution volumetric imaging and structured illumination for rejection of out-of-focus and scattered light. The miniature microscope (SIMscope3D) delivers structured light using a coherent fiber bundle to obtain optical sectioning with an axial resolution of 18 μm. Volumetric imaging of eGFP labeled cells in fixed mouse brain tissue at depths up to 220 μm is demonstrated. The functionality of SIMscope3D to provide background free 3D imaging is shown by recording time series of microglia dynamics in awake mice at depths up to 120 μm in the brain.