bluuebunny/crossref_metadata_2025 huggingface dataset:
IQ motif-containing GTPase-activating protein 1 is essential for the optimal maintenance of lung ILC2s
Authors: Tayama Shunichi , Okuyama Yuko , Phung Hai The , Asao Atsuko , Kobayashi Shuhei , Musha Tomomi , Machiyama Tomoaki , Sakurai Tsuyoshi , Zhang Chengming , Ushio-Fukai Masuko , Kawabe Takeshi , So Takanori , Ishii Naoto
Published: December 2019

Group 2 innate lymphoid cells (ILC2s) play critical roles in type 2 immunity and are crucial for pathogenesis of various types of inflammatory disease. IQ motif-containing GTPase-activating protein 1 (IQGAP1) is a ubiquitously expressed scaffold protein that is involved in multiple cellular functions such as cell survival and trafficking. While the roles for IQGAP1 in T and B lymphocytes have been uncovered, the physiological significance of IQGAP1 in innate lymphocytes remains to be elucidated. In the current study, we demonstrate that using bone marrow chimeras, the deficiency of IQGAP1 caused an impaired survival of lung ILC2s in a cell-intrinsic manner and that Iqgap1−/− mice displayed decreased accumulation of ILC2s after administration of papain and thereby reduced the pathology of the disease. Moreover, Iqgap1−/− ILC2s showed a significantly enhanced apoptosis as compared to wild-type ILC2s under both steady-state and inflammatory conditions. Together these results identify for the first time that IQGAP1 is essential for homeostasis of ILC2s in the lung.
Comparison of phenotypic and WGS-derived antimicrobial resistance profiles of Campylobacter jejuni and Campylobacter coli isolated from cases of diarrhoeal disease in England and Wales, 2015–16
Authors: Painset Anaïs , Day Martin , Doumith Michel , Rigby Jonathan , Jenkins Claire , Grant Kathie , Dallman Timothy J , Godbole Gauri , Swift Craig
Published: December 2019

Objectives

To compare and evaluate phenotypic and genotypic methods for the detection of antimicrobial resistance (AMR) in Campylobacter jejuni and Campylobacter coli in England and Wales.

Methods

WGS data from 528 isolates of Campylobacter spp. (452 C. jejuni and 76 C. coli) from human (494), food (21) and environmental (2) sources, collected between January 2015 and December 2016, and from the PHE culture collection (11) were mapped to genes known to be associated with phenotypic resistance to antimicrobials in the genus. Phenotypic antibiotic susceptibility (erythromycin, ciprofloxacin, tetracycline, gentamicin and streptomycin) testing using an in-agar dilution method was performed on all isolates.

Results

Concordance between phenotypic resistance and the presence of corresponding AMR determinants was 97.5% (515/528 isolates). Only 13 out of 528 isolates (10 C. jejuni and 3 C. coli) had discordant interpretations for at least one of the five antibiotics tested, equating to a total of 15 (0.6%) discrepancies out of 2640 isolate/antimicrobial combinations. Seven discrepant results were genotypically resistant but phenotypically susceptible (major errors) and eight discrepant results were genotypically susceptible but phenotypically resistant (very major errors).

Conclusions

The use of this bioinformatics approach for predicting AMR from WGS data for routine public health surveillance is a reliable method for real-time monitoring of changing AMR patterns in isolates of C. jejuni and C. coli.
Breast Cancer Mortality After Implementation of Organized Population-Based Breast Cancer Screening in Norway
Authors: Sebuødegård Sofie , Botteri Edoardo , Hofvind Solveig
Published: December 2019

Background

We estimated breast cancer (BC) mortality reduction associated with invitations to a nationwide population-based screening program and with changes in treatment.

Materials and methods

BreastScreen Norway started in 1996 and became nationwide in 2005. It invites women aged 50–69 years to biennial mammographic screening. We retrieved individual-level data for 1 340 333 women from national registries. During 1996–2014 (screening window), women contributed person-years in noninvited and invited periods. We created comparable periods for 1977–1995 (prescreening window) by dividing the follow-up time for each woman into pseudo-noninvited and pseudo-invited periods. We estimated BC mortality for the four periods, using the so-called evaluation model: counting BC deaths in each period for all women diagnosed within the period and counting BC deaths and person-years after screening-age for those diagnosed within screening age. We used a multivariable flexible parametric survival model to estimate hazard ratio (HR) for the effect of invitation and improved treatment.

Results

Using the regression approach, we found 5818 BC deaths across 16 533 281 person-years. Invitations to screening reduced BC mortality by 20% (HR = 0.80, 95% confidence interval [CI] = 0.70 to 0.91) among women 50 years and older and by 25% (HR = 0.75, 95% CI = 0.65 to 0.86) among screening-aged women. The treatment effect was 23% (HR = 0.77, 95% CI = 0.65 to 0.92) for women 50 years and older and 17% (HR = 0.83, 95% CI = 0.74 to 0.94) for screening-aged women.

Conclusion

We observed a similar reduction in BC mortality associated with invitations to screening and improvements in treatment during 1977–2014, among women 50 years and older.
Unique repression domains of Pumilio utilize deadenylation and decapping factors to accelerate destruction of target mRNAs
Authors: Arvola René M , Chang Chung-Te , Buytendorp Joseph P , Levdansky Yevgen , Valkov Eugene , Freddolino Lydia , Goldstrohm Aaron C
Published: December 2019

Pumilio is an RNA-binding protein that represses a network of mRNAs to control embryogenesis, stem cell fate, fertility and neurological functions in Drosophila. We sought to identify the mechanism of Pumilio-mediated repression and find that it accelerates degradation of target mRNAs, mediated by three N-terminal Repression Domains (RDs), which are unique to Pumilio orthologs. We show that the repressive activities of the Pumilio RDs depend on specific subunits of the Ccr4–Not (CNOT) deadenylase complex. Depletion of Pop2, Not1, Not2, or Not3 subunits alleviates Pumilio RD-mediated repression of protein expression and mRNA decay, whereas depletion of other CNOT components had little or no effect. Moreover, the catalytic activity of Pop2 deadenylase is important for Pumilio RD activity. Further, we show that the Pumilio RDs directly bind to the CNOT complex. We also report that the decapping enzyme, Dcp2, participates in repression by the N-terminus of Pumilio. These results support a model wherein Pumilio utilizes CNOT deadenylase and decapping complexes to accelerate destruction of target mRNAs. Because the N-terminal RDs are conserved in mammalian Pumilio orthologs, the results of this work broadly enhance our understanding of Pumilio function and roles in diseases including cancer, neurodegeneration and epilepsy.
Resonance width for a particle–core coupling model with a square-well potential
Authors: Hagino K , Sagawa H , Kanaya S , Odahara A
Published: December 2019

We derive a compact formula for the width of a multi-channel resonance state. To this end, we use a deformed square-well potential and solve the coupled-channels equations. We obtain the $S$-matrix in the Breit–Wigner form, from which partial widths can be extracted. We apply the resultant formula to a deformed nucleus and discuss the behavior of partial width for an $s$-wave channel.
Serological testing in small vessel vasculitis
Authors: Segelmark Mårten
Published: December 2019

Serological analysis has a central role in the diagnostic work-up of patients with suspected small vessel vasculitis, both for establishing a specific diagnosis and for the monitoring of response to therapy. Autoantibodies can be detected in all forms of primary small vessel vasculitis as well as in the most common forms of secondary vasculitis. For primary vasculitis the most important serological test is for ANCA. ANCA can be found in 75–95% of patients with pauci-immune small vessel vasculitis leading to this subgroup of vasculitides being named ANCA associated vasculitis. ANCA levels often follow this disease course, but the value of serial ANCA testing is controversial. Other important autoantibodies in primary small vessel vasculitis are anti-glomerular basement membrane antibodies, anti-C1q, anti-galactose deficient IgA and cryoglobulins. A wide variety of systemic inflammatory diseases and infections can be complicated by small vessel vasculitis and detected by serological testing. Important examples are SLE, rheumatoid arthritis, Hepatitis C and HIV.
Nerve Growth Factor Protects Against Pyrethroid-Induced Endoplasmic Reticulum (ER) Stress in Primary Hippocampal Neurons
Authors: Hossain Muhammad M , Richardson Jason R
Published: December 2019

Neurotrophins are a family of growth factors crucial for growth and survival of neurons in the developing and adult brain. Reduction in neurotrophin levels is associated with reduced neurogenesis and cognitive deficits in rodents. Recently, we demonstrated that long-term exposure to low levels of the pyrethroid pesticide deltamethrin causes hippocampal endoplasmic reticulum (ER) stress and learning deficits in mice. Here, we found that nerve growth factor (NGF) mRNA and protein were selectively reduced in the hippocampus of deltamethrin-treated mice. To explore potential mechanisms responsible for this observation, we employed mouse primary hippocampal neurons. Exposure of neurons to deltamethrin (1–5 μM) caused ER stress as indicated by increased levels of C/EBP-homologous protein (CHOP) and glucose-regulated protein 78 (GRP78). These changes were accompanied by increased levels of caspase-12, activated caspase-3, and decreased levels of NGF. Inhibition of ER stress with the eukaryotic initiation factor 2 alpha (eIF2α) inhibitor salubrinal abolished deltamethrin-induced activation of caspase-12 and caspase-3, and restored NGF levels. Furthermore, deltamethrin decreased Akt (protein kinase B) phosphorylation, which was significantly prevented by co-treatment with NGF or SC-79 in cells. Collectively, these results demonstrate that the loss of NGF following ER stress may contribute to deltamethrin-induced apoptosis in the hippocampus through the Akt signaling pathway, and that this may provide a plausible mechanism for impaired learning and memory observed following exposure of mice to deltamethrin.
Patients with left ventricle assist devices presenting for thoracic surgery and lung resection: tips, tricks and evidence
Authors: Hayes Tim , Charlesworth Mike , Garcia Miguel
Published: December 2019

Purpose of review

Over a thousand left ventricular-assist device (LVAD) implants were performed for heart failure destination therapy in 2017. With increasing survival, we are seeing increasing numbers of patients present for noncardiac surgery, including resections for cancer. This article will review the relevant literature and guidelines for patients with LVADs undergoing thoracic surgery, including lung resection.

Recent findings

The International Society for Heart and Lung Transplant Mechanically Assisted Circulatory Support Registry has received data on more than 16 000 patients with LVADs. Four-year survival is more than 60% for centrifugal devices. There are increasing case reports, summaries and recommendations for patients with LVADs undergoing noncardiac surgery. However, data on thoracic surgery is restricted to case reports.

Successful thoracic surgery requires understanding of the LVAD physiology. Modern devices are preload dependent and afterload sensitive. The effects of one-lung ventilation, including hypoxia and hypercapnia, may increase pulmonary vascular resistance and impair the right ventricle. Successful surgery necessitates a multidisciplinary approach, including thorough preoperative assessment; optimization and planning of intraoperative management strategies; and approaches to anticoagulation, right ventricular failure and LVAD flow optimization. This article discusses recent evidence on these topics.
Cochlear Implant Data Logs Predict Children’s Receptive Vocabulary
Authors: Busch Tobias , Vermeulen Anneke , Langereis Margreet , Vanpoucke Filiep , van Wieringen Astrid
Published: December 2019

Objectives:

The data logs of Cochlear Nucleus cochlear implant (CI) sound processors show large interindividual variation in children’s daily CI use and auditory environments. This study explored whether these differences are associated with differences in the receptive vocabulary of young implanted children.

Design:

Data of 52 prelingually deaf children, who had received a CI before 3 years of age, were obtained from their clinical records. In total, 73 Peabody Picture Vocabulary tests and CI data logs for 1 year preceding each test were collected. The data logs were used to determine the children’s average daily amount of CI use and exposure to speech, speech in noise, noise, music, and quiet. In addition, information was collected about other potential predictors of language abilities, namely gender, age, age at implantation, etiology of deafness, educational placement, and implantation mode (unilateral, bilateral). Model selection with Akaike’s information criterion was used to determine which data-logging metrics, other variables, and combinations of both best predict receptive vocabulary scores.

Results:

The data showed a strong positive association between receptive vocabulary and daily CI use, and a negative association between receptive vocabulary and daily exposure to music. Associations with the data logs’ speech and noise metrics were less clear. The most important other variable was educational placement. The best model performance was achieved when data logs and other information were combined.

Conclusions:

The results emphasize the importance of consistent CI use and a rich auditory environment for the early language development of young CI users. The study also shows that CI data logs capture information about children’s environment and CI use that are related to language performance and can help to detect and address problems and improve the auditory rehabilitation after cochlear implantation.
Spectral Contrast Effects Reveal Different Acoustic Cues for Vowel Recognition in Cochlear-Implant Users
Authors: Feng Lei , Oxenham Andrew J.
Published: December 2019

Objectives:

The identity of a speech sound can be affected by the spectrum of a preceding stimulus in a contrastive manner. Although such aftereffects are often reduced in people with hearing loss and cochlear implants (CIs), one recent study demonstrated larger spectral contrast effects in CI users than in normal-hearing (NH) listeners. The present study aimed to shed light on this puzzling finding. We hypothesized that poorer spectral resolution leads CI users to rely on different acoustic cues not only to identify speech sounds but also to adapt to the context.

Design:

Thirteen postlingually deafened adult CI users and 33 NH participants (listening to either vocoded or unprocessed speech) participated in this study. Psychometric functions were estimated in a vowel categorization task along the /i/ to /ε/ (as in “bit” and “bet”) continuum following a context sentence, the long-term average spectrum of which was manipulated at the level of either fine-grained local spectral cues or coarser global spectral cues.

Results:

In NH listeners with unprocessed speech, the aftereffect was determined solely by the fine-grained local spectral cues, resulting in a surprising insensitivity to the larger, global spectral cues utilized by CI users. Restricting the spectral resolution available to NH listeners via vocoding resulted in patterns of responses more similar to those found in CI users. However, the size of the contrast aftereffect remained smaller in NH listeners than in CI users.

Conclusions:

Only the spectral contrasts used by listeners contributed to the spectral contrast effects in vowel identification. These results explain why CI users can experience larger-than-normal context effects under specific conditions. The results also suggest that adaptation to new spectral cues can be very rapid for vowel discrimination, but may follow a longer time course to influence spectral contrast effects.
Activation of Src mediates acquired cisplatin resistance in human lung carcinoma cells
Authors: Jiang Guojun , Liu Yaming , Wang Ru , Yu Meiling , Zhang Yuelin , Dong Shuying , Liu Hao , Tong Xuhui
Published: December 2019

Cisplatin (CDDP) is the most effective chemotherapeutic drug against lung carcinoma. However, the emergence of resistant clones has severely limited its clinical application. We found that the cisplatin-resistant lung carcinoma cell line A549/CDDP had increased levels of the phosphorylated gap junction protein Cx43 and SRC tyrosine kinase, and low levels of total Cx43 protein and reduced gap junction formation. The SRC kinase inhibitor PP2 increased the expression of total Cx43 protein and enhanced cisplatin sensitivity, indicating that activated SRC kinase induces chemoresistance by decrease total Cx43 level. Furthermore, Cx43 gene silencing in the drug-resistant cell lines abrogated the sensitizing effect of PP2. Taken together, targeting SRC kinase by PP2 reverses cisplatin resistance by upregulating Cx43 protein levels, indicating a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention.
The Link Between Social Determinants of Health, Sleep, and Cardiovascular Disease
Authors: Siengsukon Catherine F.
Published: December 2019

Chronic sleep insufficiency or long-sleep duration appears to contribute to the development of cardiovascular disease (CVD) and other related metabolic conditions, including obesity and type 2 diabetes mellitus. Emerging evidence suggests that effective treatment of a sleep disorder may prevent subsequent cardiovascular events. Therefore, promotion of optimal sleep and the identification and adequate treatment of sleep disorders earlier in life may prevent or reduce the risk of CVD and the subsequent consequences of CVD. Promotion of optimal health behaviors, including sleep health, need to consider how social determinants of health (SDOH) influence and affect the ability of individuals to adequately and effectively incorporate health behavior recommendations into their daily lives. Therefore, the purpose of this perspective article is to (1) discuss how persistent deviation from the recommended amount and quality of sleep contributes to the development of CVD; and (2) discuss how SDOH across the levels of the Social–Ecological Model influence sleep health and potentially CVD.
Real-world Safety and Effectiveness of Infliximab in Pediatric Patients With Acute Kawasaki Disease
Authors: Miura Masaru , Kobayashi Tohru , Igarashi Toru , Hamada Hiromichi , Iwata Naomi , Sasaki Yoshifumi , Matsukawa Miyuki , Sato Noriko , Kubo Hajime , Takei Syuji
Published: December 2019

Background:

In 2015, infliximab was approved for the treatment of patients with intravenous immunoglobulin-refractory Kawasaki disease (KD) in Japan. However, limited real-world data exist on the usefulness of infliximab for acute KD patients. We conducted a postmarketing surveillance study in patients with acute KD refractory to conventional therapies to evaluate the safety (including any live vaccine-related infections) and the effectiveness of infliximab.

Methods:

This was a multicenter, prospective, open-label, single-cohort, observational study in patients with acute KD refractory to conventional therapy who were prescribed a single 5 mg/kg dose of infliximab. Safety and effectiveness of infliximab were evaluated at 1 month, and live vaccine-related infections were further observed until 6 months from KD onset. Effectiveness assessments included fever resolution rate, the incidence of coronary artery lesions and change in coronary diameter Z scores.

Results:

A total of 291 patients were enrolled, and all patients completed the study. Adverse drug reactions and serious adverse drug reactions were reported in 12.4% and 3.1% of patients, respectively. Live vaccine-related infections were not observed. In the 208 patients with effectiveness assessments, the fever resolution rate within 48 hours after infliximab infusion was 77.4% (95% confidence interval: 71.1–82.9). Median time until fever resolution was 16.6 hours. After infliximab administration, the incidence (at baseline: 10.9%; at the final observation point: 12.0%; maximum value: 14.6%) and severity of coronary artery lesions did not change notably.

Conclusions:

In this study, Infliximab for patients with acute KD refractory to conventional therapies was well tolerated and effective.
Acceptability and Feasibility of Using Raltegravir Oral Granules for the Treatment of Neonates in a Low-resource Setting
Authors: Archary Moherndran , Zanoni Brian , Lallemant Marc , Suwannaprom Puckwipa , Clarke Diana , Penazzato Martina
Published: December 2019

Background:

Raltegravir granules for oral suspension, now recommended by World Health Organization for use in neonates with HIV infection, may be challenging for caregivers because of the multistep preparation required.

Methods:

We evaluated the acceptability and feasibility of preparing granules for oral suspension in a low-to-middle-income country setting. Thirty-four caregivers and 10 health-care workers were enrolled from an HIV clinic in Durban, South Africa. Health-care workers were provided with pictorial instruction booklet, demonstration kit and guidance on preparation of granules for oral suspension. The health-care workers then trained caregivers on the preparation of granules for oral suspension. Caregivers were evaluated during the preparation process and instructed to practice at home with a sample kit and return to the clinic for repeat evaluation 5–7 days later. Caregivers and health-care workers were interviewed and participated in a focus group discussion regarding their experiences.

Results:

The median age of the caregivers was 31 years (interquartile range: 9.7); 70% had received secondary-level education, 37% were employed. The median preparation time was 7.95 minutes (interquartile range: 5.08 minutes) and 7.48 minutes (3.55 minutes) at initial and repeated observation, respectively. Major errors were insufficient mixing time and incorrect suspension volume. The average number of errors between the 2 observation time points was significantly reduced at the repeat session (2.5 vs. 0.87, P = 0.023). Most participants found the preparation difficult at first but gained confidence over time.

Conclusion:

Despite the complexity involved in the preparation of the granules for oral suspension, with practice, this formulation was found to be acceptable and feasible to majority of participants in this low-resource setting. As a result, this formulation was included in the 2018 World Health Organization recommendations for first line in neonates living with HIV.
Personal, biomechanical, psychosocial, and organizational risk factors for carpal tunnel syndrome: a structural equation modeling approach
Authors: Roquelaure Yves , Garlantézec Ronan , Evanoff Bradley A. , Descatha Alexis , Fassier Jean-Baptiste , Bodin Julie
Published: December 2019

This longitudinal study aimed at exploring the direct and indirect relationships between organizational, psychosocial, biomechanical, and personal factors and carpal tunnel syndrome (CTS) in French workers. Between 2002 and 2005, 3710 workers were included in the Cosali cohort. Between 2007 and 2010, 1611 workers were re-examined using the same standardized clinical protocol. Subjects free from CTS at baseline were studied (804 men and 563 women). We used structural equation models to examine the relationships between incident CTS cases and organizational (machine-paced work or work pace dependent on customers' demand), psychosocial (job strain model), biomechanical (Borg's rating perceived exertion, wrist bending, pinching, and hand-transmitted vibrations), and personal factors at baseline. Symptomatic CTS risk was directly increased by biomechanical factors (standardized coefficient = 0.19, P = 0.011), female gender (0.25, P < 0.001), and age (0.15, P = 0.042). No psychosocial factors had a direct impact on CTS, but decision authority and skill discretion had an indirect impact by influencing biomechanical exposure. Exposure to machine-paced work had an indirect impact on increasing CTS, either by raising biomechanical exposure (0.19, P < 0.001) or by lowering decision authority (−0.18, P < 0.001) and skill discretion (−0.20, P < 0.001), which in turn increased biomechanical exposure. Similar complex relationships were observed between risk factors and CTS defined by a more strict case definition. Biomechanical exposure had a direct impact on CTS, while organizational factors and psychosocial factors had an indirect impact on CTS. The findings support conceptual models linking work organization to CTS.
Activation of µ-δ opioid receptor heteromers inhibits neuropathic pain behavior in rodents
Authors: Tiwari Vinod , He Shao-Qiu , Huang Qian , Liang Lingli , Yang Fei , Chen Zhiyong , Tiwari Vineeta , Fujita Wakako , Devi Lakshmi A. , Dong Xinzhong , Guan Yun , Raja Srinivasa N.
Published: December 2019

Several reports support the idea that µ- and δ-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of µ-δ heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on µ-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-δ heteromer–targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-δ heteromer expression in L5 DRG but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC50: 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, subcutaneously). HEK-293T cell surface-labeled with µ- and δ-ORs internalized both receptors after exposure to CYM51010. By contrast, in cells transfected with µ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats but was markedly attenuated in µ-OR knockout mice. Our studies show that spinal nerve injury may increase µ-δ heterodimerization in uninjured DRG neurons, and that µ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.
Temporal instability of salience network activity in migraine with aura
Authors: Veréb Dániel , Szabó Nikoletta , Tuka Bernadett , Tajti János , Király András , Faragó Péter , Kocsis Krisztián , Tóth Eszter , Bozsik Bence , Kincses Bálint , Vécsei László , Kincses Zsigmond Tamás
Published: December 2019

This study aims to investigate whether intranetwork dynamic functional connectivity and causal interactions of the salience network is altered in the interictal term of migraine. Thirty-two healthy controls, 37 migraineurs without aura, and 20 migraineurs with aura were recruited. Participants underwent a T1-weighted scan and resting-state fMRI protocol inside a 1.5T MR scanner. We obtained average spatial maps of resting-state networks using group independent component analysis, which yielded subject-specific time series through a dual regression approach. Salience network regions of interest (bilateral insulae and prefrontal cortices, dorsal anterior cingulate cortex) were obtained from the group average map through cluster-based thresholding. To describe intranetwork connectivity, average and dynamic conditional correlation was calculated. Causal interactions between the default-mode, dorsal attention, and salience network were characterised by spectral Granger's causality. Time-averaged correlation was lower between the right insula and prefrontal cortex in migraine without aura vs with aura and healthy controls (P < 0.038, P < 0.037). Variance of dynamic conditional correlation was higher in migraine with aura vs healthy controls and migraine with aura vs without aura between the right insula and dorsal anterior cingulate cortex (P < 0.011, P < 0.026), and in migraine with aura vs healthy controls between the dorsal anterior cingulate and left prefrontal cortex (P < 0.021). Causality was weaker in the <0.05 Hz frequency range between the salience and dorsal attention networks in migraine with aura (P < 0.032). Overall, migraineurs with aura exhibit more fluctuating connections in the salience network, which also affect network interactions, and could be connected to altered cortical excitability and increased sensory gain.
Gene variants in four pedigrees with hereditary coagulation factor XI deficiency and one novel mutation identification
Authors: Lin Fen , Weng Miao-Shan , Wu Jiao-Ren , Fang Sen-Hai , Yang Li-Ye
Published: December 2019

Coagulation factor XI (FXI) deficiency is a bleeding disorder with unpredictable severity. Patients with this condition usually suffer bleeding manifestations after trauma or surgery and are poorly correlated with plasma FXI activity (FXI:C). In the current study, we examined and identified the phenotype and genotype in four unrelated probands and their 32 relatives with hereditary FXI deficiency. The probands with severely reduced FXI:C but bleeding symptoms were only found in two probands. Mutation analysis showed that all the probands were FXI homozygous mutation or compound heterozygous mutation. Five mutations were identified including three nonsense mutations c.841C>T (p.Gln263X), c.1107C>A (p.Tyr351X) and c.1033A>T (p.Lys327X), respectively, one frameshift mutation c.1325delT (p.Leu424CysfsX8), and one splicing mutation c.326-1G>A. c.1033A>T (p. Lys327X), a novel mutation which lead to a premature stop codon at amino acid position 327, it may have an influence on protein characteristics and cause the corresponding disease.
Incretin therapy for diabetes mellitus type 2
Authors: Holst Jens Juul
Published: December 2019

Purpose of review

Among the gastrointestinal hormones, the incretins: glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 have attracted interest because of their importance for the development and therapy of type 2 diabetes and obesity. New agonists and formulations of particularly the GLP-1 receptor have been developed recently showing great therapeutic efficacy for both diseases.

Recent findings

The status of the currently available GLP-1 receptor agonists (GLP-1RAs) is described, and their strengths and weaknesses analyzed. Their ability to also reduce cardiovascular and renal risk is described and analysed. The most recent development of orally available agonists and of very potent monomolecular co-agonists for both the GLP-1 and GIP receptor is also discussed.

The GLP-1RAs are currently the most efficacious agents for weight loss, and show potential for further efficacy in combination with other food-intake-regulating peptides. Because of their glycemic efficacy and cardiorenal protection, the GLP-1 RAs will be prominent elements in future diabetes therapy.
Peptide-based therapy in portal hypertension
Authors: Mohanty Arpan
Published: December 2019

Purpose of review

To summarize the use of gastrointestinal peptides in the management of portal hypertension.

Recent findings

Vasoactive peptides are commonly used in the management of acute variceal hemorrhage and hepatorenal syndrome, which are portal hypertensive complications of cirrhosis. The main vasoactive peptides that are used are somatostatin and its long-acting analogue octreotide, and vasopressin and its analogue terlipressin. Early initiation of vasoactive peptides in the management of acute variceal hemorrhage and hepatorenal syndrome is associated with improved outcomes. Octreotide is the available vasoactive peptide in the Unites States. Recent developments and ongoing clinical trials may improve our understanding of hepatorenal syndrome and influence the use of vasoactive peptides, particularly terlipressin.

Here, we review the literature on the use of vasoactive peptides in the management of acute variceal hemorrhage and hepatorenal syndrome.
Clubfoot for the primary care physician: frequently asked questions
Authors: Yau Annie , Doyle Shevaun M.
Published: December 2019

Purpose of review

This review aims to provide primary care physicians with updates on recent literature regarding clubfoot and answer questions asked by parents and caregivers of children with clubfoot. The topics discussed include prenatal counseling, relapse after Ponseti treatment, long-term outcomes following successful treatment of clubfoot, and the effect of diagnosis and treatment on the parent or caregiver.

Recent findings

Clubfoot is one of the most commonly searched orthopaedic conditions on the internet by parents. There is a lack of evidence-based guidelines on clubfoot worldwide. Recent systematic reviews have identified emerging evidence of genetic and modifiable risk factors that lead to clubfoot. Patients treated by the Ponseti method show better ankle power and strength compared with those treated with surgery for residual deformity or recurrence.

The treatment of clubfoot is a long and involved process. Exposure to and familiarity with the Ponseti method will aid primary care physicians and parents in the optimization of children's clubfoot deformity correction using largely nonoperative management.
Update on mesenchymal stromal cell studies in organ transplant recipients
Authors: Fiori Sonia , Remuzzi Giuseppe , Casiraghi Federica
Published: December 2019

Purpose of review

Mesenchymal stromal cells (MSC) have been proposed as a novel cell therapy for immune-mediated diseases, including solid organ transplantation. Here, we provide an overview of recent preclinical and clinical studies in solid organ transplantation using MSC immunomodulatory therapy.

Recent findings

MSC have been tested successfully in models of corneal and lung transplantation, suggesting that either the programmed cell death protein 1/programmed death ligand 1 pathway or the generation of intermediary immune-regulatory monocyte-macrophage population are the main mechanisms of the protolerogenic effect of MSC. In clinical transplantation, allogeneic MSC from bone marrow or umbilical cord have been evaluated in kidney and lung transplantation with an excellent safety profile. Recent data from kidney transplant patients given autologous bone marrow-MSC enrolled in our phase 1 study demonstrated a good long term safety profile. Extensive immunomonitoring of this initial cohort provided evidence of the development of a protolerogenic environment in some MSC-treated patients. One of these patients has been weaned off immunosuppression successfully.

The available clinical studies in kidney, liver and lung transplantation indicate that autologous and allogeneic MSC therapy from different sources are safe. Now it's time to focus on well-designed efficacy clinical trials, possibly including extensive immunomonitoring.
Germline MUTYH Mutation in a Pediatric Cancer Survivor Developing a Secondary Malignancy
Authors: Lavergne Vincent , Sabnis Amit , Tupule Asmin , Davidson Philip R. , Kline Cassie , Matthay Katherine , Nicolaides Theodore , Goldsby Robert , Braunstein Steve , Fogh Shannon E. , Sneed Penny K. , Menzel Paul , Nakamura Alice , DuBois Steven G. , Haas-Kogan Daphne A. , Nakamura Jean L.
Published: December 2019

Radiotherapy-induced second malignant neoplasms (SMNs) are a severe late complication in pediatric cancer survivors. Germline mutations in tumor suppressor genes contribute to SMNs; however, the most relevant germline variants mediating susceptibility are not fully defined. The authors performed matched whole-exome sequencing analyses of germline and tumor DNA from 4 pediatric solid tumor survivors who subsequently developed radiation-associated SMNs. Pathogenic and predicted deleterious germline variants were identified for each patient and validated with Sanger sequencing. These germline variants were compared with germline variants in a cohort of 59 pediatric patients diagnosed with primary sarcomas. Pathway analysis was performed to test for similarities in the germline variant profiles between individuals diagnosed with SMNs or primary sarcomas. One index patient was found to have a pathogenic germline monoallelic mutation in the MUTYH gene, which encodes the base excision repair enzyme adenine DNA glycosylase. This specific germline mutation is associated with a form of familial adenomatous polyposis, a new diagnosis in the patient. Germline-level genetic similarity exists between SMN-developing patients and patients developing primary sarcomas, with relevant genes involved in signal transduction and DNA repair mechanisms. The authors identify a germline MUTYH mutation in a pediatric cancer survivor developing an SMN. Germline mutations involving specific pathways such as base excision repair may identify individuals at risk for developing SMNs. The composition of germline variants in individual patients may enable estimates of patient-specific risk for developing SMNs. The authors anticipate that further analyses of germline genomes and epigenomes will reveal diverse genes and mechanisms influencing cancer risk.
Family Resilience From the Perspective of Caregivers of Youth With Sickle Cell Disease
Authors: Reader Steven K. , Pantaleao Ashley , Keeler Colleen N. , Ruppe Nicole M. , Kazak Anne E. , Rash-Ellis Diana L. , Wadman Jean , Miller Robin E. , Deatrick Janet A.
Published: December 2019

Families coping with sickle cell disease (SCD) often face heightened psychosocial risk factors, and research in pediatric SCD has often focused more on this area than resiliency factors. The aim of this study was to gain a better understanding of family resiliency in SCD based on caregiver perspectives. A secondary qualitative analysis was conducted with data from a mixed-methods study of caregivers of youth with SCD (n=22). Qualitative analyses involved coding based on 2 resiliency frameworks, organizing coding categories into themes, and systematically reintegrating these themes into a conceptualization that reflected family resiliency. Themes aligned well with the resiliency frameworks and related to family belief systems and meaning-making around SCD (acceptance of SCD, positive attitude, religious faith), family organization and adaptation (flexibility, stability, social supports), and the importance of communication and problem-solving. Study findings emphasize the importance of assessing resilience in families of youth with SCD and suggest the potential clinical benefits of developing psychosocial interventions based on family strengths.
A Phase I/IIa Study of Antidisialoganglioside Antibody Dinutuximab in Japanese Patients With Neuroblastoma
Authors: Hara Junichi , Nitani Chika , Kawamoto Hiroshi , Taguchi Tomoaki , Kimura Toshimi , Yoshimura Kenichi , Yoshimura Kiyoshi
Published: December 2019

Japanese patients with neuroblastoma completing induction therapy and high-dose chemotherapy received antidisialoganglioside antibody dinutuximab 17.5 mg/m2 for 4 days during each of 5 consecutive 28-day cycles. Patients also received macrophage colony-stimulating factor (M-CSF) or granulocyte colony-stimulating factor (G-CSF) during cycles 1, 3, and 5 combined with interleukin-2 teceleukin during cycles 2 and 4. A total of 25 patients (11 in the M-CSF group and 14 in the G-CSF group) were enrolled, and dose-limiting toxicity was assessed in the first 12 patients (6 in each group). The recommended doses of dinutuximab, M-CSF, and G-CSF were determined to be 17.5 mg/m2, 6.0×106 U/m2, and 5 µg/kg/d, respectively, whereas that of teceleukin was 0.75×106 IU/m2 during week 1 and 1×106 IU/m2 during week 2. The most common grade 3 or 4 adverse events in both groups were neutrophil count decreased, platelet count decreased, pyrexia, and alanine aminotransferase increased. Four patients (2 in each group) discontinued the treatment because of adverse events. At the end of the study, survival was confirmed in 22 patients (9 in the M-CSF group and 13 in the G-CSF group). From these results, we concluded that this combination regimen is a feasible treatment for Japanese patients with neuroblastoma.
Importance of Magnetic Resonance Imaging With Diffusion-weighted Imaging in Guiding Biopsy of Nodular Ganglioneuroblastoma: A Case Report
Authors: Jain Neha , Halbert Jay , Patel Premal A. , Biassoni Lorenzo , Anderson John , Sebire Neil , McHugh Kieran , Barone Giuseppe
Published: December 2019

Background:

Nodular ganglioneuroblastoma is a rare peripheral neuroblastic tumor of variable prognosis. Accurate diagnosis, staging, and risk categorization can be particularly challenging in patients with nodular ganglioneuroblastoma due to the inherent heterogeneity of these lesions.

Case Presentation:

We illustrate the use of diffusion-weighted magnetic resonance imaging to identify tumor nodules and guide tumor biopsy in an almost 5-year-old boy with a large abdominal tumor.

Conclusions:

Diffusion-weighted magnetic resonance imaging was successful in detecting and guiding biopsy of a poorly differentiated neuroblastoma nodule within the context of a well-differentiated ganglioneuroma, allowing the diagnosis and characterization of a ganglioneuroblastoma nodular, thus influencing the child’s prognosis and treatment.
Neonatal Cancer Epidemiology and Outcome: A Retrospective Study
Authors: Geurten Claire , Geurten Marie , Rigo Vincent , Dresse Marie-Françoise
Published: December 2019

Objective:

Our study aimed at describing neonatal cancer incidence, distribution by type, location, outcome, and long-term toxicity, by comparison with tumors occurring later in infancy.

Methods:

The authors led a single-center retrospective analysis of 118 cases of tumors diagnosed in the first year of life and compared tumors’ types incidence, presentation, location, and outcome according to age group at diagnosis (below or over 28 d of life).

Results:

The most frequent neonatal tumor types in our series were germ cell tumors, mainly teratoma, followed by neuroblastoma and renal tumors, whereas in children below 1 year of age, brain tumors, neuroblastoma, and leukemia were the most common types. Genetic predisposition syndromes were present in 14% of these infants and antenatal sonography enabled 68% of diagnosis for tumors presenting at birth. Other patients presented with mass syndrome, hydrops, or skin lesions. Six percent of neonates with cancer died from their malignancies, and up to 18% experienced a chronic health condition as a consequence of therapy.

Conclusions:

Tumor pattern differs in neonates and infants, with a higher percentage of benign tumors in children below 28 days of life. Yet, long-term therapy-related toxicity is significant in younger patients. Enhancing knowledge of neonatal tumors, their epidemiology, clinical presentation, genetic background, and prognosis should help promote better management and introduce follow-up programs to improve surviving rates and the quality of life of survivors.
Parental Concerns about Newborn Feeding Post Hospital Discharge
Authors: Fuhrman Lauren , Ross Erin Sundseth
Published: December 2019

Background:

Post hospital discharge newborn feeding education mostly focuses on breastfeeding and is primarily targeted at term infants. Preterm and late-preterm infants are at risk for poor feeding postdischarge, and feeding challenges are common after discharge from the neonatal intensive care unit (NICU). Families often have questions about feeding their infants after hospital discharge.

Purpose:

The goal of this project was to collect data on what questions parents have about feeding their baby after discharge and what strategies may be helpful to improve feeding experiences. These data were intended to inform plans to offer a no-cost newborn feeding clinic for all new parents after hospital discharge.

Methods:

A speech-language pathologist attended a preexisting lactation support group to meet with families and provide feeding support. The speech-language pathologist collected data on types of questions parents asked, education provided, and changes made during the visit to improve feeding experiences.

Results:

Sixty-eight families were seen in the first 6 months of the clinic. Fifty-eight were families of babies cared for in the well baby nursery; 10 were families of graduates from the NICU. Seventy-five percent of the infants were born full-term. Maternal questions focused primarily on bottles and recognizing satiety. The most commonly provided changes included trials of different bottles or positions to improve infant comfort during feedings.

Clinical Implications:

New parents often have questions about breastfeeding and bottle feedings after going home. Using these data, a decision was made to continue the no-cost infant feeding support group to address questions and provide guidance to parents after hospital discharge.
Robotic assisted fixation of sacral fractures
Authors: Weil Yoram A. , Khoury Amal , Mosheiff Rami , Kaplan Leon , Liebergall Meir , Schroeder Josh E.
Published: December 2019

Objectives:

Sacral fractures that require fixation are a challenge for the orthopaedic surgeon. Due to anatomical consideration, implant insertion is not risk free, and requires a steep learning curve. A robotic system has been successfully used in pedicle screws insertion and can be also used for iliosacral screws. The aim of the study was to demonstrate the use of the robot in the treatment of unstable sacral fractures.

Design:

Retrospective case series.

Setting:

An academic level I trauma center.

Patients:

Fourteen patients with sacral fractures were eligible for robotic assisted treatment. These included 9 high-energy fractures, 4 osteoporotic fractures, and 1 pathological fracture.

Intervention:

Fixation constructs included iliosacral screws, transiliac screws, lumbopelvic fixation, sacroplasty, or a combination of the above techniques. A Renaissance robot was mounted on a multidirectional bridge that was attached to the patients spine and implant trajectories were planned either on preoperative or intraoperative 3D scans. Guide wires were inserted percutaneously and screws were placed subsequently.

Main outcome measurements:

Accuracy of implant placement, operating room and fluoroscopy time.

Results:

Mean patient age was 36 (17–84), and number of screws, including iliosacral and pedicular ranged 1–14 per patient (average 4.25). Mean operative time was 150 minutes (range 90–300). Average fluoroscopic time was 18 seconds (7–42) for 2D and 40 seconds (12–72) for 3D imaging. All fractures healed, no hardware failure was observed. All hardware was always within bony confines, and no procedure-related neurological deficits were observed.

Conclusion:

Robotic assisted fixation of sacral fracture is a safe and reproduceable method, allowing precise and accurate implant placement.