bluuebunny/crossref_metadata_2025 huggingface dataset:
Symptoms of Women With High-Risk Early-Stage Ovarian Cancer
Authors: Chan John K. , Tian Chunqiao , Kesterson Joshua P. , Monk Bradley J. , Kapp Daniel S. , Davidson Brittany , Robertson Sharon , Copeland Larry J. , Walker Joan L. , Wenham Robert M. , Casablanca Yovanni , Spirtos Nick M. , Tewari Krishnansu S. , Bell Jeffrey G.
Published: January 2022

OBJECTIVE:

To assess the presentation, characteristics, and prognostic significance of symptoms in patients with high-risk early-stage epithelial ovarian cancer.

METHODS:

A retrospective chart review was performed on all patients enrolled in a phase III clinical trial (GOG 157). All patients had surgically staged, high-risk early-stage epithelial ovarian cancer (stage IA–IB and grade 3, any clear cell, stage IC or II). Chi-square and Kaplan-Meier estimates and Cox proportional hazards models were used for statistical analyses.

RESULTS:

Of 419 patients evaluated for symptoms, 301 (72%) presented with one or more symptoms, and 118 (28%) were asymptomatic but had a mass found on examination. Forty percent had only one symptom, and 32% had more than one symptom. Among those with at least one symptom, the most common were abdominal and pelvic pain (31%), and increased girth or fullness (26%). Overall, 23% of patients with tumors 10 cm or smaller, 27% of patients with tumors larger than 10 cm to 15 cm, and 46% of patients with tumors larger than 15 cm had multiple symptoms (P<.001). There was no significant difference in presentation of symptoms based on age, stage, or histologic subtype. Symptoms at diagnosis were not associated with recurrence or survival.

CONCLUSION:

More than 70% of patients with high-risk early-stage, epithelial ovarian cancer present with one or more symptoms, with the most common being abdominal or pelvic pain. The proportion of women with symptoms and the number of symptoms increase with enlarging tumor size.
Predictive Sentence Context Reduces Listening Effort in Older Adults With and Without Hearing Loss and With High and Low Working Memory Capacity
Authors: Hunter Cynthia R. , Humes Larry E.
Published: January 2022

Objectives:

Listening effort is needed to understand speech that is degraded by hearing loss, a noisy environment, or both. This in turn reduces cognitive spare capacity, the amount of cognitive resources available for allocation to concurrent tasks. Predictive sentence context enables older listeners to perceive speech more accurately, but how does contextual information affect older adults’ listening effort? The current study examines the impacts of sentence context and cognitive (memory) load on sequential dual-task behavioral performance in older adults. To assess whether effects of context and memory load differ as a function of older listeners’ hearing status, baseline working memory capacity, or both, effects were compared across separate groups of participants with and without hearing loss and with high and low working memory capacity.

Design:

Participants were older adults (age 60–84 years; n = 63) who passed a screen for cognitive impairment. A median split classified participants into groups with high and low working memory capacity. On each trial, participants listened to spoken sentences in noise and reported sentence-final words that were either predictable or unpredictable based on sentence context, and also recalled short (low-load) or long (high-load) sequences of digits that were presented visually before each spoken sentence. Speech intelligibility was quantified as word identification accuracy, and measures of listening effort included digit recall accuracy, and response time to words and digits. Correlations of context benefit in each dependent measure with working memory and vocabulary were also examined.

Results:

Across all participant groups, accuracy and response time for both word identification and digit recall were facilitated by predictive context, indicating that in addition to an improvement in intelligibility, listening effort was also reduced when sentence-final words were predictable. Effects of predictability on all listening effort measures were observed whether or not trials with an incorrect word identification response were excluded, indicating that the effects of predictability on listening effort did not depend on speech intelligibility. In addition, although cognitive load did not affect word identification accuracy, response time for word identification and digit recall, as well as accuracy for digit recall, were impaired under the high-load condition, indicating that cognitive load reduced the amount of cognitive resources available for speech processing. Context benefit in speech intelligibility was positively correlated with vocabulary. However, context benefit was not related to working memory capacity.

Conclusions:

Predictive sentence context reduces listening effort in cognitively healthy older adults resulting in greater cognitive spare capacity available for other mental tasks, irrespective of the presence or absence of hearing loss and baseline working memory capacity.
Rate of orthopedic resident and medical student recognition of nonaccidental trauma: a pilot study
Authors: Pilla Nicholas I. , Nasreddine Adam , Christie Kevin J. , Hennrikus William L.
Published: January 2022

The purpose of this study was to evaluate the efficacy and accuracy of mandated reporters to identify child abuse in children presenting with fractures. An Institutional Review Board approved survey-based study between January 2017 and December 2017 was conducted at a tertiary care academic medical center. 10 cases were combined to create one survey. Each case had information on presentation history, radiographic data, and social history. This study assesses the ability of 13 orthopedic residents and 11 medical students to diagnose child abuse. Participants had the option to explain their reasoning for a given case. To evaluate decision-making reasoning, we split responses into three cohorts, encompassing objective evidence, subjective evidence, or social evidence. Twenty-four participants completed the survey; 203 out of 240 (85%) included the rationale for the diagnosis of child abuse. The observed diagnostic odds ratio was 0.83 for medical students, 0.93 for junior residents, and 0.96 for senior residents. There was no statistically significant difference in diagnosing child abuse between a participant’s level of experience, age, or whether participants had their own children. Participants who used more than one source of evidence were significantly more likely to make the correct diagnosis (P = 0.013). Participant decisions were no more accurate than a coin toss. The use of several data sources led to increased diagnostic accuracy. There is low accuracy in correctly diagnosing child abuse in our cohort of mandated reporters. Participants who highlighted using several sources of evidence were more likely to diagnose child abuse accurately.
Simplified Chinese Version of the Back Pain Function Scale (BPFS) for Patients with Low Back Pain
Authors: Jia Cheng-Qi , Cao Shi-Qi , Wu Yu-Jie , Hu Fan-Qi , Zhang Zhen , Zhang Xue-Song
Published: January 2022

Study Design.

A cross-sectional study.

Objective.

To translate and cross-culturally adapt back pain function scale (BPFS) into a simplified Chinese version (SC-BPFS), and evaluate the reliability and validity of SC-BPFS in patients with low back pain.

Summary of Background Data.

The BPFS is a reliable and valid evaluation instrument for low back pain. However, simplified Chinese version of BPFS has not been validated.

Methods.

Cross-cultural adaptation was performed according to the internationally recognized guidelines of the American Academy of Orthopaedic Surgeons Outcome Committee. One-hundred and sixty-two participants with low back pain (LBP) were included in this study. Reliability was tested based on test-retest reliability and internal consistency. We calculated Cronbach alpha and intra-class correlation coefficient (ICC). Construct validity was analyzed by evaluating the correlations between SC-BPFS and the Oswestry disability index (ODI), the visual analogue scale (VAS), and the short form (36) health survey (SF-36).

Results.

The original version of the BPFS was cross-culturally well adapted and translated into simplified Chinese. Each item of the SC-BPFS was properly responded and correlated with the total items. SC-BPFS had good reliability (Cronbach alpha = 0.847, intra-class correlation coefficient [ICC] = 0.891, 95% confidence interval [CI] 0.864–0.914). Elimination of any one item in all did not result in a value of Cronbach alpha of <0.80. SC-BPFS had a high correlation with ODI (0.712, P < 0.01) and a moderate correlation with VAS (0.484, P < 0.01). And it was also fairly to very well correlated with physical domains of SF-36 (0.334–0.632, P < 0.01), and not correlated with mental domains of SF-36 (0.022–0.119, P > 0.05).

Conclusion.

SC-BPFS demonstrated outstanding acceptability, internal consistency, reliability, and construct validity, and could be recommended for patients with LBP in Mainland China.

Level of Evidence: 3
Target serum concentration of vancomycin may be reached earlier with a loading dose
Authors: Huang Yanxia , He Le , Deng Yunxin , Zhang Renjing , Meng Mei , Liu Jiao , Chen Dechang
Published: January 2022

Background:

Vancomycin treatment failure against vancomycin-susceptible gram-positive cocci is not rare in the intensive care unit (ICU). One of the reasons for this is the substandard drug trough concentration. We aimed to examine the hypothesis that the target serum concentration could be reached earlier with a loading dose of vancomycin.

Methods:

This retrospective cohort study was conducted at our ICU between June 2018 and June 2020 and involved patients who were suspected of having, or confirmed to have, gram-positive cocci infection and treated with vancomycin. One group of the patients was administered a loading dose of vancomycin (loading group) and compared with the group that did not receive a loading dose (control group). The baseline characteristics, vancomycin serum concentrations, and clinical outcomes were collected and analyzed.

Results:

Fifty-five patients were finally included, of which 29 received a loading dose of vancomycin. The serum concentration of vancomycin before the second dose was significantly higher for the loading group than for the control group (10.3 ± 6.1 mg/L vs. 5.7 ± 4.4 mg/L, P = 0.002). The results for both groups were similar before the fifth dose (12.4 ± 7.3 mg/L vs. 10.3 ± 6.3 mg/L in the loading and the control groups, respectively; P = 0.251). The 28-day mortality was lower for the loading group than for the control group (6.7% vs. 34.6% in the loading and control groups, respectively; P = 0.026). No significant differences were observed in serum creatinine (Cr) concentrations of the two groups.

Conclusion:

With the loading dose of vancomycin, the target serum concentration of vancomycin may be reached earlier without increasing the risk of acute kidney injury.

Trial registration:

https://www.chictr.org.cn; ChiCTR2000035369
Interleukins in the treatment of melanoma
Authors: Xu Xinyuan , Dai Wei , Li Chunying
Published: January 2022

Interleukins (ILs) and associated cytokines serve as the means of communication for immune cells and non-immune cells. The use of ILs in harnessing the immune system to cancer treatment has been a promising approach. ILs not only nurture an environment enabling cancer growth but also simultaneously trigger a productive tumor-directed immune response. These properties of ILs are increasingly being explored as a strategy to improve the outcomes of cancer. Here, we describe recently innovative technological approaches that have been developed to improve the pharmacokinetics, safety, and efficacies of IL-2, 15, 10, and 18 in the treatment of melanoma. Furthermore, the combination of ILs and immune checkpoint inhibition may synergize to reshape the tumor environment, thus yielding better clinical benefits in the future.
Biplanar Lipoabdominoplasty: Introducing the Subscarpal Lipo Aponeurotic System
Authors: Wolf Yoram , Weissman Oren , Dima Helena , Sandbank Judith , Fainzilber-Goldman Yifat
Published: January 2022

Background:

Preservation of Scarpa’s fascia in abdominoplasty has been previously presented. Herein we introduce the subscarpal lipo aponeurotic system (SLAS) and the technique of preserving the SLAS and its tightening in lipoabdominoplasty.

Methods:

A retrospective cohort study of patients who underwent lipoabdominoplasty performed by a single plastic surgeon (YW) between 2014 and 2019 was conducted. We compared postoperative complications, aesthetic outcomes, and procedure lengths between standard and biplanar lipoabdominoplasty with SLAS tightening. Supra-scarpal fat and SLAS tissue specimens were obtained for histological analysis.

Results:

In total, 179 patients underwent biplanar lipoabdominoplasty with SLAS tightening and were compared with a control group of 65 patients who underwent standard lipoabdominoplasty. Fifty-four patients (29.9%) underwent concomitant umbilical, epigastric, or postoperative ventral hernia (POVH) repair. No major complications were encountered other than one skin necrosis in a standard lipoabdominoplasty. Moderate complication rate was 10.05% in the biplanar group, compared with 16.92% in the standard lipoabdominoplasty. The average length of the procedure and overall aesthetic results were equivalent.

Conclusions:

The SLAS can be individually dissected and used during abdominoplasty. No statistically significant differences were found in complication rates, length of procedure, or aesthetic outcomes between standard and biplanar lipoabdominoplasty with SLAS tightening. Further investigation is needed. Nonetheless, we postulate that patients who would benefit the most from this procedure are those with weakening of the abdominal wall, and with some fullness of the hip line, as this technique adds reinforcement to the lower abdomen and “pulls in” the flanks.
Iliocostalis Muscle Rotational Flap: A Novel Flap for Esophagopleural Fistula Repair
Authors: Nam Arthur J. , Yoon Joshua , Krause Eric M. , Elegbede Adekunle I. , Carr Shamus R.
Published: January 2022

Intrathoracic fistulas present major challenges to reconstructive surgeons. Reconstruction with muscle flaps have been shown to improve patient outcomes; however, there are patients for whom one or more of the commonly used muscle flaps is not available for several reasons. We describe the use of an iliocostalis muscle rotational flap for the repair of a caudally located esophagopleural fistula in the setting of definitive chemoradiotherapy for treatment of nonsmall-cell lung cancer and reirradiation with photons for local recurrence 5 years later. Our repair remained intact through the nearly 12-month follow-up period during which the patient tolerated a regular diet. This report demonstrates that the iliocostalis lumborum muscle is a viable option for repair of intrathoracic fistulas that are located in the distal esophagus, even in the setting of previous thoracotomy and radiation, and should be part of the reconstructive surgeon’s armamentarium in the management of intrathoracic fistulas.
The Shadow Pandemic: A Qualitative Exploration of the Impacts of COVID-19 on Service Providers and Women Survivors of Intimate Partner Violence and Brain Injury
Authors: Haag Halina (Lin) , Toccalino Danielle , Estrella Maria Jennifer , Moore Amy , Colantonio Angela
Published: January 2022

Background:

Intimate partner violence (IPV) affects up to 1 in 3 women over their lifetime and has intensified during the COVID-19 pandemic. Although most injuries are to the head, face, and neck, the intersection of IPV and brain injury (BI) remains largely unrecognized. This article reports on unexplored COVID-19–related impacts on service providers and women survivors of IPV/BI.

Objectives:

To explore the impact of the COVID-19 pandemic on survivors and service providers.

Participants:

Purposeful sampling through the team's national Knowledge-to-Practice (K2P) network and snowball sampling were used to recruit 24 participants across 4 categories: survivors, executive directors/managers of organizations serving survivors, direct service providers, and employer/union representatives.

Design:

This project used a qualitative, participatory approach using semistructured individual or group interviews. Interviews were conducted via videoconferencing, audio-recorded, and transcribed. Transcripts were thematically analyzed by the research team to identify themes.

Findings:

COVID-19 has increased rates and severity of IPV and barriers to services in terms of both provision and uptake. Three main themes emerged: (1) implications for women survivors of IPV/BI; (2) implications for service delivery and service providers supporting women survivors of IPV/BI; and (3) key priorities. Increased risk, complex challenges to mental health, and the impact on employment were discussed. Adaptability and flexibility of service delivery were identified as significant issues, and increased outreach and adaptation of technology-based services were noted as key priorities.

Conclusions:

The COVID-19 pandemic has intensified IPV/BI, increased challenges for women survivors and service providers, and accentuated the continued lack of IPV/BI awareness. Recommendations for service delivery and uptake are discussed.
Bridging the Acute-to-Outpatient Care Gap in Mental Health
Authors: Kantaria Tina , Talag Germiniano , Fan Jia , Navarro Filda , Sonza Patrick , Fears Scott , Yang Calvin , Balsam Jeffrey , Birman Sharon , Lam Mona , Guze Barry , Raja Pushpa
Published: January 2022

Background:

A national Department of Veterans Affairs (VA) mental health (MH) quality metric tracks engagement in outpatient MH care after discharge from residential and inpatient settings, with recommendations for 2 or more visits 30 days postdischarge.

Local Problem:

A gap in transitioning patients from residential to outpatient MH care was identified at this site.

Methods:

A transition management process was developed and piloted, including a new MH Discharge Consult and an RN Transition Care Managers team.

Interventions:

Transition Care Managers triaged Discharge Consults, communicated with schedulers and patients pre- and postdischarge, and tracked MH engagement for 30 days postdischarge. Process, outcome, and balancing measures were developed and iteratively adjusted using Plan-Do-Study-Act (PDSA) cycles.

Results:

Over 55 weeks, 443 Discharge Consults were placed. There was an average 89% success rate in connecting patients with 2 or more MH visits versus 53% preintervention.

Conclusions:

This pilot showed promising results in improving postdischarge MH engagement with the use of PDSA cycles to collect data and refine processes.
The Association Between Patterns of Social Engagement and Conversion From Mild Cognitive Impairment to Dementia
Authors: Amano Takashi , Park Sojung , Morrow-Howell Nancy , Carpenter Brian
Published: January 2022

Objectives:

This study examined the association between patterns of social engagement and conversion from cognitive impairment, no dementia (CIND) to dementia. It also tested whether social engagement is associated with conversion independently from physical and cognitive engagements.

Method:

Data from 2 waves (2010 and 2014) of the Health and Retirement Study (HRS) were used. The sample consisted of 1227 people who had CIND in 2010. To identify the heterogeneity of social engagement, latent class analysis was utilized. Multinomial logistic regression analysis was utilized to investigate the association between patterns of social engagement and probability of conversion to dementia and death or dropout.

Results:

The result showed that patterns of social engagement that represent higher level and more variety of social engagement were associated with lower probabilities of conversion to dementia in 4 years but not with probabilities of death or dropout. The relationship held after controlling for physical and cognitive engagements.

Discussion:

Findings implied that promoting social engagement may be protective against developing dementia even for the high-risk group of people with CIND. Future studies should investigate the mechanism behind the relationship between patterns of social engagement and lower probabilities of conversion to dementia.
Single-cell multi-omics analyses reveal EZH2 as a main driver of retinoic acid resistance in PLZF-RARA leukemia
Authors: Poplineau M. , Platet N. , Mazuel A. , Hérault L. , Koide S. , Kuribayashi W. , Carbuccia N. , N’Guyen L. , Vernerey J. , Oshima M. , Birnbaum D. , Iwama A. , Duprez E.
Published: January 2022

Cancer relapse is caused by a subset of malignant cells that are resistant to treatment. To characterize resistant cells and their vulnerabilities, we studied the retinoic acid (RA)-resistant PLZF-RARA acute promyelocytic leukemia (APL) using single-cell multi-omics. We uncovered transcriptional and chromatin heterogeneity in leukemia cells and identified a subset of cells resistant to RA that depend on a fine-tuned transcriptional network targeting the epigenetic regulator Enhancer of Zeste Homolog 2 (EZH2). Epigenomic and functional analyses validated EZH2 selective dependency of PLZF-RARA leukemia and its driver role in RA resistance. Targeting pan-EZH2 activities (canonical/non-canonical) was necessary to eliminate leukemia relapse initiating cells, which underlies a dependency of resistant cells on an EZH2 non-canonical activity and the necessity to degrade EZH2 to overcome resistance.

Our study provides critical insights into the mechanisms of RA resistance that allow us to eliminate treatment-resistant leukemia cells by targeting EZH2, thus highlighting a potential targeted therapy approach.

HIGHLIGHTS

- sc-RNAseq identifies PLZF-RARA leukemia heterogeneity and retinoic acid resistant cells

- sc-ATACseq refines leukemic cell identity and resolves retinoic acid resistant networks

- EZH2 is a selective dependency of PLZF-RARA leukemia and drives retinoic acid resistance

- Targeting pan-EZH2 activities (canonical/non-canonical) is necessary to overcome leukemia onset
Lack of evidence for functional luteinising hormone chorionic gonadotropin receptors in non-pregnant human endometrial stromal cells
Authors: Mann ON , Kong C-S , Lucas ES , Brosens JJ , Hanyaloglu AC , Brighton PJ
Published: January 2022

The human luteinising hormone chorionic gonadotropin receptor (LHCGR) is a G-protein coupled receptor activated by both human chorionic gonadotropin (hCG) and luteinizing hormone (LH), two structurally related gonadotropins with essential roles in ovulation and maintenance of the corpus luteum. LHCGR expression predominates in ovarian tissues where it elicits functional responses through cyclic adenosine mononucleotide (cAMP), Ca2+ and extracellular signal-regulated kinase (ERK) signalling. LHCGR has also been localized to the human endometrium, with purported roles in decidualization and implantation. However, these observations are contentious. In this investigation, transcripts encoding LHCGR were undetectable in bulk RNA sequencing datasets from whole cycling endometrial tissue and cultured human endometrial stromal cells (EnSC). However, analysis of single-cell RNA sequencing data revealed cell-to-cell transcriptional heterogeneity and identified a small subpopulation of stromal cells with discernible LHCGR transcripts. In HEK-293 cells expressing recombinant LHCGR, both hCG and LH elicited robust cAMP, Ca2+ and ERK signals that were absent in wild type HEK-293 cells. However, none of these responses were recapitulated in primary EnSC cultures. In addition, proliferation, viability and decidual transformation of EnSC were refractory to both hCG and LH, irrespective of treatment to induce differentiation. Although we challenge the assertion that LHCGR is expressed at a functionally active level in the human endometrium, the discovery of a discrete subpopulation of EnSC that express LHCGR transcripts may plausibly account for the conflicting evidence in the literature.
Discovery of novel compounds as potent activators of Sirt3
Authors: Reverdy Célina , Gitton Gaetan , Guan Xiangying , Adhya Indranil , Dumpati Rama Krishna , Roy Samir , Chall Santu , Errasti Gauthier , Delacroix Thomas , Chakrabarti Raj
Published: January 2022

Among the sirtuin enzymes, Sirt3 is one of the most important deacetylases as it regulates acetylation levels in mitochondria, which are linked to the metabolism of multiple organs and therefore involved in many types of age-related human diseases such as cancer, heart diseases and metabolic diseases. Given the dearth of direct activators of Sirt3, the identification of new modulators could be a key step in the development of new therapeutics. Here we report the discovery of Sirt3 modulators, including activators, through the use of DNA encoded library technology (DEL). The most enriched compounds after DEL selection against SIRT3 were evaluated according to their activity and affinity. Our best activator seems at least as potent as Honokiol (HKL) while the docking studies suggest that our modulators interact with Sirt3 at an atypical site. Our results establish the attractiveness of the DEL technology in identifying novel and potent Sirt3 activators and, therefore, in associated therapeutic applications.
Genomic dissection of the microevolution of Australian epidemic Bordetella pertussis
Authors: Xu Zheng , Hu Dalong , Wai Luu Laurence Don , Octavia Sophie , Keil Anthony D , Sintchenko Vitali , Tanaka Mark M. , Mooi Frits R. , Robson Jenny , Lan Ruiting
Published: January 2022

Whooping cough (pertussis) is a highly contagious respiratory disease caused by the bacterium Bordetella pertussis. Despite high vaccine coverage, pertussis has re-emerged in many countries and caused two large epidemics in Australia since 2007. Here, we undertook a genomic and phylogeographic study of 385 Australian B. pertussis isolates collected from 2008 to 2017. The Australian B. pertussis population was found to be composed of mostly ptxP3 strains carrying different fim3 alleles, with ptxP3-fim3A genotype expanded far more than ptxP3-fim3B. Within the former, there were six co-circulating epidemic lineages (EL1 to EL6). The multiple ELs emerged, expanded, and then declined at different time points over the two epidemics, likely driven by immune selection from pertussis vaccination and natural infection in addition to local and global transmission events. Both hard and soft selective sweeps through vaccine selection pressures determined the current B. pertussis population dynamics. Relative risk analysis found that once a new B. pertussis lineage emerged, it was more likely to spread locally within the first 1.5 years. However, after 1.5 years, any new lineage was likely to expand to a wider region and became no longer spatially structured across the country. Phylogenetic analysis revealed the expansion of ptxP3 strains was also associated with replacement of the type III secretion system allele bscI1 with bscI3. This study advanced our understanding of the epidemic population structure and spatial and temporal dynamics of B. pertussis in a highly immunised population.
Differential serotonergic modulation of principal neurons and interneurons in the anterior piriform cortex
Authors: Piszár Ildikó , Lőrincz Magor L.
Published: January 2022

Originating from the brainstem raphe nuclei, serotonin is an important neuromodulator involved in a variety of physiological and pathological functions. Specific optogenetic stimulation of serotonergic neurons results in the divisive suppression of spontaneous, but not sensory evoked activity in the majority of neurons in the primary olfactory cortex and an increase in firing in a minority of neurons. To reveal the mechanisms involved in this dual serotonergic control of cortical activity we used a combination of in vitro electrophysiological recordings from identified neurons in the primary olfactory cortex, optogenetics and pharmacology and found that serotonin suppressed the activity of principal neurons, but excited local interneurons. The results have important implications in sensory information processing and other functions of the olfactory cortex and related brain areas.
Staphylococcus aureus activates the Aryl Hydrocarbon Receptor in Human Keratinocytes
Authors: Stange Eva-Lena , Rademacher Franziska , Drerup Katharina Antonia , Heinemann Nina , Möbus Lena , Gläser Regine , Harder Jürgen
Published: January 2022

Staphylococcus (S.) aureus is an important pathogen causing various infections including - as most frequently isolated bacterium - cutaneous infections. Keratinocytes as the first barrier cells of the skin respond to S. aureus by the release of defense molecules such as cytokines and antimicrobial peptides. Although several pattern recognition receptors expressed in keratinocytes such as Toll-like and NOD-like receptors have been reported to detect the presence of S. aureus, the mechanisms underlying the interplay between S. aureus and keratinocytes are still emerging. Here we report that S. aureus induced gene expression of CYP1A1 and CYP1B1, responsive genes of the aryl hydrocarbon receptor (AhR). AhR activation by S. aureus was further confirmed by AhR gene reporter assays. AhR activation was mediated by factor(s) < 2 kDa secreted by S. aureus. Whole transcriptome analyses and real-time PCR analyses identified IL-24, IL-6 and IL-1beta as cytokines induced in an AhR-dependent manner in S. aureus-treated keratinocytes. AhR inhibition in a 3D organotypic skin equivalent confirmed the crucial role of the AhR in mediating the induction of IL-24, IL-6 and IL-1beta upon stimulation with living S. aureus. Taken together, we further highlight the important role of the AhR in cutaneous innate defense and identified the AhR as a novel receptor mediating the sensing of the important skin pathogen S. aureus in keratinocytes.
Retrospective analysis of long‐term survival factors in patients with advanced non‐small cell lung cancer treated with nivolumab
Authors: Murakami Yusuke , Tamiya Akihiro , Taniguchi Yoshihiko , Adachi Yuichi , Enomoto Takatoshi , Azuma Koji , Inagaki Yuji , Kouno Shunichi , Matsuda Yoshinobu , Okishio Kyoichi , Atagi Shinji
Published: January 2022

Background

Nivolumab, an immune checkpoint inhibitor (ICI), has changed the treatment paradigm for advanced non‐small cell lung cancer (NSCLC). However, factors associated with long‐term survival in NSCLC patients treated with ICIs remain unknown. This study aimed to evaluate patient characteristics and clinical laboratory changes related to long‐term survival in NSCLC patients treated with nivolumab, using real‐world data.

Methods

We retrospectively reviewed the medical records of consecutive patients with advanced NSCLC with Eastern Cooperative Oncology Group performance status (ECOG‐PS) ≤1 treated with nivolumab. We defined patients with overall survival (OS) ≥3 years as long‐term survivors. We evaluated the differences in patient characteristics and tumor response between nonlong‐term survivors and long‐term survivors and performed univariate and multivariate analyses of factors associated with long‐term survival.

Results

Out of 213 patients with advanced NSCLC treated with nivolumab, 162 patients with ECOG‐PS ≤1 were included in the study. Young age, ECOG‐PS 0, absolute neutrophil count decrease, lymphocyte percentage increase, and neutrophil‐to‐lymphocyte ratio (NLR) change (ΔNLR) <1 were significantly associated with long‐term survival. Long‐term survivors had significantly higher response and disease control rates than nonlong‐term survivors. Multivariate analysis showed that ΔNLR <1 was significantly associated with long‐term survival. Further, OS was significantly different between the PS 0 and PS 1 groups (median OS: 32.0 months vs. 10.6 months) and the nonincreasing NLR and increasing NLR groups (median OS: 20.8 months vs. 5.7 months).

Conclusions

ΔNLR <1 was a significant long‐term survival factor compared to ΔNLR ≥1 in advanced NSCLC patients treated with nivolumab.
Reproductive changes among women in their 40s: A cross‐sectional study
Authors: Lindh Ingela , Skjeldestad Finn Egil , Heikinheimo Oskari , Hognert Helena , Lidegaard Øjvind , Bergh Christina , Gemzell‐Danielsson Kristina
Published: January 2022

Introduction

The aim was to describe and compare changes in the reproductive pattern of women in their 40s observed over a decade in Scandinavia.

Material and Methods

Cross‐sectional study using the total population of women aged 40–49 years between 2008–2018 in Denmark, Norway and Sweden (on average n = 1.5 million). Aggregated data concerning birth and induced abortion rate were collected and analyzed from national health registers. National data on redeemed prescriptions of hormonal contraceptives in the three countries were collected from prescription registers. Births after spontaneous and assisted conceptions were identified by using cross‐linked data on deliveries from the Medical Birth Registers and National Registers of Assisted Reproduction in the three countries.

Results

Use of hormonal contraception increased among women aged 40–44 years in Denmark from 24% to 31%, in Sweden from 27% to 30%, and in Norway from 22% to 24%. The levonorgestrel‐releasing intrauterine device was the most frequently used method in all countries. Birth rates among women 40–44 years increased continuously from 9.5 to 12/1000 women in Denmark and from 11.7 to 14.3/1000 in Sweden, but remained stable in Norway at ~11/1000 women. There was a doubling of assisted conceptions in Denmark from 0.71 to 1.71/1000 women, Sweden from 0.43 to 0.81/1000 and Norway from 0.25 to 0.53/1000 women 40–49 years of age. Sweden had the highest induced abortion rate (7.7 to 8.1/1000 women) in women aged 40–49 years during the study period.

Conclusions

From 2008 to 2018, birth rates continuously increased among women aged 40–49 years in Denmark and Sweden and births resulting from assisted reproductive technology doubled in all three countries.
Psychiatric comorbidity in childhood onset immune‐mediated diseases—A systematic review and meta‐analysis
Authors: Jansson Sabine , Malham Mikkel , Wewer Vibeke , Rask Charlotte Ulrikka
Published: January 2022

Aim

To estimate psychiatric comorbidity in childhood onset immune‐mediated inflammatory diseases (IMID).

Methods

The PRISMA guidelines were followed, and the protocol was registered at Prospero (ID: CRD42021233890). Literature was searched in PubMed, PsycINFO and Embase. Original papers on prevalence rates of diagnosed psychiatric disorders and/or suicide in paediatric onset inflammatory bowel disease (pIBD), rheumatic diseases (RD) and autoimmune liver diseases were selected. Pooled prevalence rates of psychiatric disorders (grouped according to ICD‐10 criteria) within the various IMID were calculated using random‐effects meta‐analysis. Risk of bias was evaluated by the Newcastle‐Ottawa scale.

Results

Twenty‐three studies were included; 13 describing psychiatric disorders in pIBD and 10 in RD. Anxiety and mood disorders were mostly investigated with pooled prevalence rates in pIBD of 6% (95% confidence interval (CI): 4%–9%) and 4% (95%CI: 2%–8%), respectively, in register‐based studies, and 33% (95%CI: 25%–41%) and 18% (95%CI: 12%–26%), respectively, in studies using psychiatric assessment. In RD, rates were 13% (95%CI: 12%–15%) for anxiety disorders and 20% (95%CI: 15%–26%) for mood disorders based on psychiatric assessment.

Conclusion

Anxiety and depression are commonly reported in childhood onset IMID. Physicians should be attentive to mental health problems in these patients as they seem overlooked.
Functional MRI research involving healthy children: Ethics, safety and recommended procedures
Authors: Kraus Dror , Horowitz‐Kraus Tzipi
Published: January 2022

Aim

This specific review aims to expose clinicians, researchers and administrators in hospitals to the importance, procedures and safety of fMRI studies to promote the increased utilisation of such studies in different geographical places worldwide. The child's brain is developing rapidly, both structurally and functionally. These functional changes can only be detected using functional scans generated from an MRI machine and referred to as a functional MRI (fMRI). This method may be used clinically in complex medical and surgical conditions (e.g., epilepsy surgery), but these days are often used for research purposes. However, due to ethical and logistical considerations, fMRI in the paediatric population is not widely and equally used in different geographical places.

Conclusions

The benefits of using this method to define the functional changes occurring in the developing brain are discussed in this review, along with desensitisation methods recommended when working with this vulnerable population in research and even in a clinical setting.
Acute normobaric hypoxia blunts contraction‐mediated mTORC1‐ and JNK‐signaling in human skeletal muscle
Authors: Moberg Marcus , Apró William , Horwath Oscar , van Hall Gerrit , Blackwood Sarah Joan , Katz Abram
Published: January 2022

Aim

Hypoxia has been shown to reduce resistance exercise‐induced stimulation of protein synthesis and long‐term gains in muscle mass. However, the mechanism whereby hypoxia exerts its effect is not clear. Here, we examine the effect of acute hypoxia on the activity of several signalling pathways involved in the regulation of muscle growth following a bout of resistance exercise.

Methods

Eight men performed two sessions of leg resistance exercise in normoxia or hypoxia (12% O2) in a randomized crossover fashion. Muscle biopsies were obtained at rest and 0, 90,180 minutes after exercise. Muscle analyses included levels of signalling proteins and metabolites associated with energy turnover.

Results

Exercise during normoxia induced a 5‐10‐fold increase of S6K1Thr389 phosphorylation throughout the recovery period, but hypoxia blunted the increases by ~50%. Phosphorylation of JNKThr183/Tyr185 and the JNK target SMAD2Ser245/250/255 was increased by 30‐ to 40‐fold immediately after the exercise in normoxia, but hypoxia blocked almost 70% of the activation. Throughout recovery, phosphorylation of JNK and SMAD2 remained elevated following the exercise in normoxia, but the effect of hypoxia was lost at 90‐180 minutes post‐exercise. Hypoxia had no effect on exercise‐induced Hippo or autophagy signalling and ubiquitin‐proteasome related protein levels. Nor did hypoxia alter the changes induced by exercise in high‐energy phosphates, glucose 6‐P, lactate or phosphorylation of AMPK or ACC.

Conclusion

We conclude that acute severe hypoxia inhibits resistance exercise‐induced mTORC1‐ and JNK signalling in human skeletal muscle, effects that do not appear to be mediated by changes in the degree of metabolic stress in the muscle.
Costly immunometabolic remodelling in disused muscle buildup through physical exercise
Authors: Padilha Camila S. , Figueiredo Caique , Deminice Rafael , Krüger Karsten , Seelaender Marília , Rosa‐Neto José Cesar , Lira Fabio S.
Published: January 2022

The mechanisms underlying the immunometabolic disturbances during skeletal muscle atrophy caused by a plethora of circumstances ranging from hospitalization to spaceflight missions remain unknown. Here, we outline the possible pathways that might be dysregulated in such conditions and assess the potential of physical exercise to mitigate and promote the recovery of muscle morphology, metabolism and function after intervals of disuse. Studies applying exercise to attenuate disuse‐induced muscle atrophy have shown a pivotal role of circulating myokines in the activation of anabolic signalling pathways. These muscle‐derived factors induce accretion of contractile proteins in the myofibers, and at the same time decrease protein breakdown and loss. Regular exercise plays a crucial role in re‐establishing adequate immunometabolism and increasing the migration and presence in the muscle of macrophages with an anti‐inflammatory phenotype (M2) and T regulatory cells (Tregs) after disease‐induced muscle loss. Additionally, the switch in metabolic pathways (glycolysis to oxidative phosphorylation [OXPHOS]) is important for achieving rapid metabolic homeostasis during muscle regeneration. In this review, we discuss the molecular aspects of the immunometabolic response elicited by exercise during skeletal muscle regeneration. There is not, nevertheless, consensus on a single optimal intensity of exercise required to improve muscle strength, mass and functional capacity owing to the wide range of exercise protocols studied so far. Despite the absence of agreement on the specific strategy, physical exercise appears as a powerful complementary strategy to attenuate the harmful effects of muscle disuse in different scenarios.
Loss of plant cover mediates the negative effect of anthropogenic disturbance on the multifunctionality of a dryland
Authors: Manhães Adriana Pellegrini , Mazzochini Guilherme Gerhardt , Marinho Felipe , Ganade Gislene , Carvalho Adriana Rosa
Published: January 2022

Aims

Anthropogenic disturbances due to human economic activities may affect ecosystem services, which are the benefits provided by the ecosystem properties, such as soil water content and soil fertility. Also, these disturbances affect plant community biodiversity and cover, which are also known to affect multiple ecosystem properties. However, the strength of the relative effects of the disturbance itself and of the effect that is mediated by changes in the plant community is still unclear.

Questions

We evaluated the relative direct and indirect effects (mediated by changes in the plant community) of the anthropogenic disturbances on ecosystem multifunctionality.

Location

Dry forests within the Sustainable Development Reserve Ponta do Tubarão, northeastern Brazil.

Methods

We measured standing biomass, litter mass, soil fertility and soil water content in 52 vegetation plots along a gradient of anthropogenic disturbance. Also, we measured woody plant cover and species’ functional traits to characterize the plant community functional structure. We measured livestock grazing, selective logging and past clear‐cuts as proxies of anthropogenic disturbance to create an index that characterizes the additive effect of these human activities. By building a theoretical model using the structural equation modelling approach, we investigated how the plant community changes in cover and biodiversity due to anthropogenic disturbances mediate changes in ecosystem properties.

Results

Our results show that anthropogenic disturbances had negative effects on ecosystem properties. Plant cover loss caused by anthropogenic disturbances was the major determinant of the negative effect of disturbances. The functional structure of the plant community had a weak effect on these properties.

Conclusions

By assessing the effect of human activities on multifunctionality, we found a stronger negative effect of anthropogenic disturbances when compared to its effect on single ecosystem properties. The recovery of plant cover should be a major focus of projects aiming to restore and maintain the multifunctionality of this dryland.
GlaciDat – a GIS database of submarine glacial landforms and sediments in the Arctic
Authors: Streuff Katharina T. , Ó Cofaigh Colm , Wintersteller Paul
Published: January 2022

A digital database for submarine glacial landforms and sediments formed in the Arctic during and since the Last Glacial Maximum was created in order to facilitate and underpin new research on palaeo‐ice sheets and tidewater glacier dynamics. The glacimarine database (GlaciDat) documents and standardises evidence of previous glacial activity as visible on the contemporary seafloor of fjords and continental shelves around Svalbard, Greenland, Alaska, northern Russia and north of 66°30′N in Canada and Norway. An extensive literature search was conducted to create GlaciDat, which compiles nearly 60 000 individual submarine landforms, more than 1000 sediment cores and 232 radiocarbon dates. Glacial landforms included are cross‐shelf troughs, trough‐mouth fans, grounding‐zone wedges, lateral moraines, overridden moraines, (mega‐scale) glacial lineations, drumlins, crag‐and‐tails, medial moraines, terminal moraines, debris‐flow lobes (including glacier‐contact fans), recessional moraines, De Geer moraines, crevasse‐fill ridges, eskers, hill‐hole pairs, crescentic scours, and submarine channels. They were digitised as point, line and polygon features alongside a list of their individual characteristics. Sediment core locations are attributed with a description of the sampled lithofacies and sedimentation rates where available. Landforms and sediments have been standardised according to predefined nomenclatures to make the glacial evidence as consistent as possible. Marine radiocarbon dates were included when thought to be relevant for constraining the timing of large‐scale palaeo‐ice dynamics. Outlines of bathymetric data sets, which have previously been used for glacial geomorphological mapping, were also included to give an overview of already investigated research areas. GlaciDat is available for download (https://doi.pangaea.de/10.1594/PANGAEA.937782) and will aid researchers in the reconstruction of past ice dynamics and the interpretation of Arctic glacial landform–sediment assemblages. Moreover, as well as providing a comprehensive bibliography on Arctic glacial geomorphological and sedimentological research, it is intended to serve as a basis for future modelling of Arctic glacier and ice‐sheet dynamics.
CXCR4 promotes the growth and metastasis of esophageal squamous cell carcinoma as a critical downstream mediator of HIF‐1α
Authors: Wu Xianxian , Zhang Hongdian , Sui Zhilin , Gao Yongyin , Gong Lei , Chen Chuangui , Ma Zhao , Tang Peng , Yu Zhentao
Published: January 2022

C–X–C motif chemokine receptor 4 (CXCR4) belongs to the CXC chemokine receptor family, which mediates the metastasis of tumor cells and promotes the malignant development of cancers. However, its biological role and regulatory mechanism in esophageal squamous cell carcinoma (ESCC) remain unclear. Here, we found that CXCR4 expression was associated with lymph node metastasis and a poor prognosis. In vitro and in vivo studies demonstrated that CXCR4 overexpression promoted ESCC cell proliferation, migration, invasion, and survival, whereas silencing CXCR4 induced the opposite effects. Mechanically, HIF‐1α transcriptionally regulates CXCR4 expression by binding to a hypoxia response element in its promoter. HIF‐1α‐induced ESCC cell migration and invasion were reversed by CXCR4 knockdown or treatment with MSX‐122, a CXCR4 antagonist. Collectively, these data revealed that the HIF‐1α/CXCR4 axis plays key roles in ESCC growth and metastasis and indicated CXCR4 as a potential target for ESCC treatment.
Reduced speed limit is ineffective for mitigating the effects of roads on ungulates
Authors: Riginos Corinna , Fairbank Elizabeth , Hansen Erica , Kolek Jaron , Huijser Marcel P.
Published: January 2022

Roads obstruct wildlife movements, and wildlife‐vehicle collisions are a hazard to both animals and humans. Wildlife and transportation managers often consider reducing the speed limit to reduce wildlife‐vehicle collisions, but there is little empirical data to support or refute this measure. We experimentally reduced the nighttime speed limit from 70 to 55 mph on six stretches of highway that cross mule deer (Odocoileus hemionus) winter range or migration paths. Drivers consistently reduced their speeds, but only by 3–5 mi/h. Reduced speed limit did not make it any easier for deer to cross the road, indicating no benefit for habitat connectivity. At winter sites, the number of deer‐vehicle collisions was not affected by the reduced speed limit whereas at migration sites, collisions were modestly lower under the reduced speed limit. Given the small reduction in vehicle speeds, it is not surprising that there was little benefit of reduced speed limit for deer or people. We conclude that reduced nighttime speed limit is not an effective way to reduce wildlife‐vehicle collisions or make roads more permeable to wildlife due to poor compliance from motorists.