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Despite new combination therapies improving survival of breast cancer patients with estrogen receptor α (ER+) tumors, the molecular mechanisms for endocrine-resistant disease remain unresolved. Previously we demonstrated that expression of the RNA binding protein and N6-methyladenosine (m6A) reader HNRNPA2B1 (A2B1) is higher in LCC9 and LY2 tamoxifen (TAM)-resistant ERα breast cancer cells relative to parental TAM-sensitive MCF-7 cells. Here we report that A2B1 protein expression is higher in breast tumors than paired normal breast tissue. Modest stable overexpression of A2B1 in MCF-7 cells (MCF-7-A2B1 cells) resulted in TAM- and fulvestrant- resistance whereas knockdown of A2B1 in LCC9 and LY2 cells restored TAM and fulvestrant, endocrine-sensitivity. MCF-7-A2B1 cells gained hallmarks of TAM-resistant metastatic behavior: increased migration and invasion, clonogenicity, and soft agar colony size, which were attenuated by A2B1 knockdown in MCF-7-A2B1 and the TAM-resistant LCC9 and LY2 cells. MCF-7-A2B1, LCC9, and LY2 cells have a higher proportion of CD44+/CD24-/low cancer stem cells (CSC) compared to MCF-7 cells. MCF-7-A2B1 cells have increased ERα and reduced miR-222-3p that targets ERα. Like LCC9 cells, MCF-7-A2B1 have activated AKT and MAPK that depend on A2B1 expression and are growth inhibited by inhibitors of these pathways. These data support that targeting A2B1 could provide a complimentary therapeutic approach to reduce acquired endocrine resistance.

Background/Aims: Patients with diabetes mellitus (DM) often suffer from gastrointestinal (GI) symptoms, but these correlate poorly to established objective GI motility measures. Our aim is to perform a detailed evaluation of potential measures of gastric and small intestinal motility in patients with DM type 1 and severe GI symptoms.Methods: Twenty patients with DM and 20 healthy controls (HCs) were included. GI motility was examined with a 3-dimensional-Transit capsule, while organ volumes were determined by CT scans.Results: Patients with DM and HCs did not differ with regard to median gastric contraction frequency (DM: 3.0 contractions/minute [interquartile range {IQR}, 2.9-3.0]; HCs: 2.9 [IQR, 2.8-3.1]; P = 0.725), amplitude of gastric contractions (DM: 9 mm [IQR, 8-11]; HCs: 11 mm (IQR, 9-12); P = 0.151) or fasting volume of the stomach wall (DM: 149 cm3 [IQR, 112-187]; HCs: 132 cm3 [IQR, 107-154]; P = 0.121). Median gastric emptying time was prolonged in patients (DM: 3.3 hours [IQR, 2.6-4.6]; HCs: 2.4 hours [IQR, 1.8-2.7]; P = 0.002). No difference was found in small intestinal transit time (DM: 5 hours [IQR, 3.7-5.6]; HCs: 4.8 hours [IQR, 3.9-6.0]; P = 0.883). However, patients with DM had significantly larger volume of the small intestinal wall (DM: 623 cm3 [IQR, 487-766]; HCs: 478 cm3 [IQR, 393-589]; P = 0.003). Among patients, 13 (68%) had small intestinal wall volume and 9 (50%) had gastric emptying time above the upper 95% percentile of HCs.Conclusion: In our study, gastric emptying time and volume of the small intestinal wall appeared to be the best objective measures in patients with DM type 1 and symptoms and gastroenteropathy.

Background While commonly seen in syndromic craniosynostosis, the incidence of Chiari malformation (CM) in nonsyndromic craniosynostosis has been reported at 5% and there is a lack of understanding of the pathophysiology and management of CM in this patient population. Case Description We present a 5-year-old male patient who underwent a sagittal craniosynostosis repair at the age of 5 months and returned at the age of 5 years with daily headaches associated with behavioral changes. He was found to have pan-synostoses and radiographic evidence of increased intracranial pressure, including a Chiari malformation. Neurologic and genetic workup was unremarkable. A cranial vault reconstruction was performed, and subsequent imaging demonstrated resolution of previously noted Chiari malformation. Conclusions In our case, we provided a unique window into the underlying pathophysiology for CM in patients with concurrent nonsyndromic craniosynostosis that we hope will add to the current foundation of literature supporting the intricate relation between cranial vault compliance and Chiari malformation or hindbrain herniation. Furthermore, we provide insight into the management of acquired CM and support isolated cranial vault reconstruction in those who do not appear to have symptomatic suboccipital compression.

Aims The multi-C2 domain protein dysferlin localizes to the T-Tubule system of skeletal and heart muscles. In skeletal muscle, dysferlin is known to play a role in membrane repair and in T-tubule biogenesis and maintenance. Dysferlin deficiency manifests as muscular dystrophy of proximal and distal muscles. Cardiomyopathies have been also reported, and some dysferlinopathy mouse models develop cardiac dysfunction under stress. Generally, the role and functional relevance of dysferlin in the heart is not clear. The aim of this study was to analyse the effect of dysferlin deficiency on the transverse–axial tubule system (TATS) structure and on Ca2+ homeostasis in the heart. Methods and results We studied dysferlin localization in rat and mouse cardiomyocytes by immunofluorescence microscopy. In dysferlin-deficient ventricular mouse cardiomyocytes, we analysed the TATS by live staining and assessed Ca2+ handling by patch-clamp experiments and measurement of Ca2+ transients and Ca2+ sparks. We found increasing co-localization of dysferlin with the L-type Ca2+-channel during TATS development and show that dysferlin deficiency leads to pathological loss of transversal and increase in longitudinal elements (axialization). We detected reduced L-type Ca2+-current (ICa,L) in cardiomyocytes from dysferlin-deficient mice and increased frequency of spontaneous sarcoplasmic reticulum Ca2+ release events resulting in pro-arrhythmic contractions. Moreover, cardiomyocytes from dysferlin-deficient mice showed an impaired response to β-adrenergic receptor stimulation. Conclusions Dysferlin is required for TATS biogenesis and maintenance in the heart by controlling the ratio of transversal and axial membrane elements. Absence of dysferlin leads to defects in Ca2+ homeostasis which may contribute to contractile heart dysfunction in dysferlinopathy patients.

BACKGROUND Thermal flow evaluation (TFE) is a non-invasive method to assess ventriculoperitoneal shunt function. Flow detected by TFE is a negative predictor of the need for revision surgery. Further optimization of testing protocols, evaluation in multiple centers, and integration with clinical and imaging impressions prompted the current study. OBJECTIVE To compare the diagnostic accuracy of 2 TFE protocols, with micropumper (TFE+MP) or without (TFE-only), to neuro-imaging in patients emergently presenting with symptoms concerning for shunt malfunction. METHODS We performed a prospective multicenter operator-blinded trial of a consecutive series of patients who underwent evaluation for shunt malfunction. TFE was performed, and preimaging clinician impressions and imaging results were recorded. The primary outcome was shunt obstruction requiring neurosurgical revision within 7 d. Non-inferiority of the sensitivity of TFE vs neuro-imaging for detecting shunt obstruction was tested using a prospectively determined a priori margin of −2.5%. RESULTS We enrolled 406 patients at 10 centers. Of these, 68/348 (20%) evaluated with TFE+MP and 30/215 (14%) with TFE-only had shunt obstruction. The sensitivity for detecting obstruction was 100% (95% CI: 88%-100%) for TFE-only, 90% (95% CI: 80%-96%) for TFE+MP, 76% (95% CI: 65%-86%) for imaging in TFE+MP cohort, and 77% (95% CI: 58%-90%) for imaging in the TFE-only cohort. Difference in sensitivities between TFE methods and imaging did not exceed the non-inferiority margin. CONCLUSION TFE is non-inferior to imaging in ruling out shunt malfunction and may help avoid imaging and other steps. For this purpose, TFE only is favored over TFE+MP.

Cardiovascular diseases still account for the majority of deaths worldwide, although significant improvements in survival, after being affected by cardiovascular disease, have been achieved in the last decades. Periodontal diseases are also a common global burden. Several studies have shown a link between cardiovascular disease and periodontitis, although evidence is still lacking regarding the direct cause-effect relation. During the 2012 "Periodontitis and systemic diseases" workshop, the available evidence on the association between cardiovascular and periodontal diseases was discussed, covering biologic plausibility and clinical studies. The objective of the present narrative review was to update the previous reviews presented at the 2012 workshop, following similar methodological approaches, aiming to critically assess the available evidence. With regard to biologic plausibility, two aspects were reviewed: (a) for microbiologic mechanisms, assessing periodontal bacteria as a contributing factor to atherosclerosis based on seven "proofs," substantial evidence was found for Proofs 1 through 6, but not for Proof 7 (periodontal bacteria obtained from human atheromas can cause atherosclerosis in animal models), concluding that periodontal pathogens can contribute to atherosclerosis; (b) mechanistic studies, addressing five different inflammatory pathways that could explain the links between periodontitis and cardiovascular disease with the addition of some extra pathways , suggest an association between both entities, based on the presence of higher levels of these inflammatory markers in patients with periodontitis and cardiovascular disease, vs healthy controls, as well as on the evidence that periodontal treatment reduces serum levels of these mediators. When evidence from clinical studies was analyzed, two aspects were covered: (a) epidemiologic studies support the estimation that the incidence of atherosclerotic disease is higher in individuals with periodontitis than in individuals with no reported periodontitis, irrespective of many common risk factors, but with a substantial variability in the definitions used in reporting of exposure to periodontal diseases in different studies; (b) intervention trials have shown that periodontal therapy can reduce serum inflammatory mediators, improve the lipids profile, and induce positive changes in other cardiovascular disease surrogate measures, but no evidence is available to support that adequate periodontal therapy is able to reduce the risk for cardiovascular diseases, or the incidence of cardiovascular disease events in periodontitis patients.

Background: Groin hernia management has a significant worldwide diversity with multiple surgical techniques and variable outcomes. The International guidelines for groin hernia management serve to help in groin hernia management, but the acceptance among general surgeons remains unknown. The aim of our study was to gauge the degree of agreement with the guidelines among health care professionals worldwide. Methods: Forty-six key statements and recommendations of the International guidelines for groin hernia management were selected and presented at plenary consensus conferences at four international congresses in Europe, the America’s and Asia. Participants could cast their votes through live voting. Additionally, a web survey was sent out to all society members allowing online voting after each congress. Consensus was defined as > 70% agreement among all participants. Results: In total 822 surgeons cast their vote on the key statements and recommendations during the four plenary consensus meetings or via the web survey. Consensus was reached on 34 out of 39 (87%) recommendations, and on six out of seven (86%) statements. No consensus was reached on the use of light versus heavy-weight meshes (69%), superior cost-effectiveness of day-case laparo-endoscopic repair (69%), omitting prophylactic antibiotics in hernia repair, general or local versus regional anesthesia in elderly patients (55%) and re-operation in case of immediate postoperative pain (59%). Conclusion: Globally, there is 87% consensus regarding the diagnosis and management of groin hernias. This provides a solid basis for standardizing the care path of patients with groin hernias.

Guidelines recommend colonoscopy after an episode of diverticulitis to exclude neoplasia but the effectiveness of testing is uncertain. Patients with complicated diverticulitis may be at higher risk for neoplasia, but most patients have uncomplicated disease. We examined the incidence of colorectal cancer (CRC) and advanced adenoma (AA) in patients with diverticulitis compared with patients undergoing screening colonoscopy.CT scans from January 1, 2008, to May 1, 2013, at the University of Pittsburgh Medical Center (UPMC) were reviewed to identify those with confirmed acute diverticulitis. Subsequent surgical, colonoscopy, and pathology reports were abstracted to identify those with a diagnosis of AA and CRC. The incidence of neoplasia was compared with that reported for screening colonoscopy from a meta-analysis (n = 68,324), and from colonoscopy examinations at UPMC between 2013 and 2015 (n = 28,573).A total of 5167 abdominal/pelvic CT scan reports identified 978 patients with acute diverticulitis, among which 474 (48.5%) patients had undergone at least 1 colonoscopy or gastrointestinal surgery to April 2015. The CRC rate in patients with diverticulitis (13/474, 2.7%) was significantly higher (P .0001) compared with both the meta-analysis (0.8%) and UPMC (0.3%). The AA rate (19/474, 4.0%) was similar to the rate in the meta-analysis (5.0%, P = .39) but significantly lower than at UPMC (7.7%, P = .003). The incidence of AA or CRC in complicated diverticulitis (10/141, 7.1%) did not differ significantly (P = .85) from the incidence of AA or CRC in uncomplicated diverticulitis (22/332, 6.6%).CRC after diverticulitis was significantly higher than that observed at screening colonoscopy and was not limited to complicated disease. Colonoscopy is advisable after the diagnosis of diverticulitis.

Aim Polypropylene (PP) mesh is widely used to reinforce tissues. The foreign body reaction (FBR) to the implant is dominated by innate immune cells, especially macrophages. However, considerable numbers of adaptive immune cells have also been regularly observed, which appear to play a crucial role in the long-term host response. This study investigated the FBR to seven human PP meshes, which were removed from the abdomen for recurrence after a median of one year. Material and Methods Using immunofluorescence microscopy and distance maps, the FBR was spatially analyzed for various innate (e.g., CD68+ macrophages, CD56+ NK) and adaptive immune cells (CD3+ T, CD4+ T-helper, CD8+ cytotoxic, FoxP3+ T-regulatory, CD20+ B) as well as “conventional” immune cells (defined as cells expressing their specific immune cell marker without co-expressing CD68). Results T-helper cells (19%) and regulatory T-cells (25%) were present at comparable rates to macrophages, and clustered significantly toward the mesh fibers. For all cell types the lowest proportions of “conventional” cells (< 60%) were observed at the mesh–tissue interface, but increased considerably at about 50–100 µm, indicating reduced stimulation with rising distance to the mesh fibers. Conclusions Both innate and adaptive immune cells participate in the chronic FBR to PP meshes with T cells and macrophages being the predominant cell types, respectively. Furthermore, many cells present a “hybrid” pattern near the mesh fibers. The complexity of the local immune reaction may explain why approaches focusing on specific cell types have not been very successful in reducing the chronic FBR.

Background Inequality in preterm birth is a world-wide challenge that has proved difficult for maternity care services to meet. Reducing the inequality requires identification of pregnant women at particularly high risk of preterm birth in order to target interventions. Therefore, the aim was to estimate the risk of preterm birth in women with different combinations of socioeconomic position, mental health conditions, and age. Methods In this nationwide register-based cohort study, we included all first-time mothers that gave birth to a singleton liveborn infant in Denmark between 2000 and 2016. The absolute and relative risk of preterm birth ( Results Of the 415,523 included first-time mothers, 6.3% gave birth prematurely. The risk of preterm birth increased with decreasing educational level and increasing severity of mental health conditions in all age strata, but most in women aged ≥31 years. The highest absolute risk was 12.9% [95% CI: 11.2;14.8%] in women aged ≥31 years with low education and moderate/severe mental health conditions resulting in a relative risk of 2.23 [95% CI: 1.93–2.58] compared to the unexposed reference group in that age strata. We found positive additive interaction between low education and mental health conditions in women aged 24–30 and ≥ 31 years and between age ≥ 31 years and combinations of mental health conditions and educational levels. Conclusion The inequality in preterm birth increased with increasing age. To reduce inequality in preterm birth focused attention on women with higher age further combined with lower educational levels and mental health conditions is essential.

The impact of aspirin use after the diagnosis of colorectal cancer is unknown. Among others, PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) mutational status was proposed as a molecular biomarker for the response to adjuvant aspirin therapy. However, prognostic data on aspirin use after a colorectal cancer diagnosis in relation to KRAS mutational status is limited. In a single-center retrospective study, we obtained KRAS and PIK3CA mutational status in a cohort of 153 patients with a first diagnosis of colorectal cancer receiving tumor surgery with curative intent. PIK3CA mutational status was determined by pyrosequencing, and KRAS mutational status was determined by next-generation sequencing. Clinicopathological data and survival data were assessed using patient records and reporting registers. We observed a significant 10-year overall survival benefit in patients with aspirin use and combined wild-type PIK3CA and mutated-KRAS tumors (HR = 0.38, 95% CI = 0.17–0.87, p = 0.02), but not in patients without aspirin use. Our data indicate a benefit of aspirin usage particularly for patients with combined wild-type PIK3CA and mutated-KRAS tumor characteristics.

Myocardial infarction is a frequent cause of out-of-hospital cardiac arrest. However, the benefits of early coronary angiography and revascularization in resuscitated patients without electrocardiographic evidence of ST-segment elevation are unclear.In this multicenter trial, we randomly assigned 554 patients with successfully resuscitated out-of-hospital cardiac arrest of possible coronary origin to undergo either immediate coronary angiography (immediate-angiography group) or initial intensive care assessment with delayed or selective angiography (delayed-angiography group). All the patients had no evidence of ST-segment elevation on postresuscitation electrocardiography. The primary end point was death from any cause at 30 days. Secondary end points included a composite of death from any cause or severe neurologic deficit at 30 days.A total of 530 of 554 patients (95.7%) were included in the primary analysis. At 30 days, 143 of 265 patients (54.0%) in the immediate-angiography group and 122 of 265 patients (46.0%) in the delayed-angiography group had died (hazard ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.63; P = 0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (in 164 of 255 patients [64.3%]) than in the delayed-angiography group (in 138 of 248 patients [55.6%]), for a relative risk of 1.16 (95% CI, 1.00 to 1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in the two groups.Among patients with resuscitated out-of-hospital cardiac arrest without ST-segment elevation, a strategy of performing immediate angiography provided no benefit over a delayed or selective strategy with respect to the 30-day risk of death from any cause. (Funded by the German Center for Cardiovascular Research; TOMAHAWK ClinicalTrials.gov number, NCT02750462.).

Simple Summary Estrogen receptor α (ERα) is a key driver and clinical target in breast cancer, with ~75% of women having ERα+ breast tumors at diagnosis. Endocrine therapies (tamoxifen and aromatase inhibitors) targeting ERα are the preferred treatment for ER+/HER2− breast tumors due to their efficacy and tolerance in most patients. However, patients develop resistance to these endocrine therapies and disease progression to metastasis remains a major clinical problem. There are multiple mechanisms involved in the progression to endocrine resistance, including epigenetic changes in non-coding RNAs that regulate cellular pathways leading to cancer progression and metastasis. This paper summarizes the role of long non-coding RNAs regulated by miR-29 in endocrine-resistant breast cancer. Abstract Despite improvements in the treatment of endocrine-resistant metastatic disease using combination therapies in patients with estrogen receptor α (ERα) primary tumors, the mechanisms underlying endocrine resistance remain to be elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNA) and long non-coding RNAs (lncRNA), are targets and regulators of cell signaling pathways and their exosomal transport may contribute to metastasis. Previous studies have shown that a low expression of miR-29a-3p and miR-29b-3p is associated with lower overall breast cancer survival before 150 mos. Transient, modest overexpression of miR-29b1-3p or miR-29a-3p inhibited MCF-7 tamoxifen-sensitive and LCC9 tamoxifen-resistant cell proliferation. Here, we identify miR-29b-1/a-regulated and non-regulated differentially expressed lncRNAs in MCF-7 and LCC9 cells using next-generation RNA seq. More lncRNAs were miR-29b-1/a-regulated in LCC9 cells than in MCF-7 cells, including DANCR, GAS5, DSCAM-AS1, SNHG5, and CRND. We examined the roles of miR-29-regulated and differentially expressed lncRNAs in endocrine-resistant breast cancer, including putative and proven targets and expression patterns in survival analysis using the KM Plotter and TCGA databases. This study provides new insights into lncRNAs in endocrine-resistant breast cancer.

There is initial evidence of microstructural abnormalities in the fibre-tract pathways of the cerebellum and cerebrum of individuals diagnosed with Type I Chiari malformation. However, it is unclear whether abnormal white matter architecture and macro-level morphological deviations that have been observed in Chiari translate to differences in functional connectivity. Furthermore, common symptoms of Chiari include pain and cognitive deficits, but the relationship between these symptoms and functional connectivity has not been explored in this population. Eighteen Type I Chiari patients and 18 age-, sex- and education-matched controls underwent resting-state functional MRI to measure functional connectivity. Participants also completed a neuropsychological battery and completed self-report measures of chronic pain. Group differences in functional connectivity were identified. Subsequently, pathways of significant difference were re-analyzed after controlling for the effects of attention performance and self-reported chronic pain. Chiari patients exhibited functional hypoconnectivity between areas of the cerebellum and cerebrum. Controlling for attention eliminated all deficits with the exception of that from the posterior cerebellar pathway. Similarly, controlling for pain also eliminated deficits except for those from the posterior cerebellar pathway and vermis VII. Patterns of Chiari hyperconnectivity were also found between regions of the cerebellum and cerebrum in Chiari patients. Hyperconnectivity in all regions was eliminated after controlling for attention except between left lobule VIII and the left postcentral gyrus and between vermis IX and the precuneus. Similarly, hyperconnectivity was eliminated after controlling for pain except between the default mode network and globus pallidus, left lobule VIII and the left postcentral gyrus, and Vermis IX and the precuneus. Evidence of both hyper- and hypoconnectivity were identified in Chiari, which is posited to support the hypothesis that the effect of increased pain in Chiari draws on neural resources, requiring an upregulation in inhibitory control mechanisms and resulting in cognitive dysfunction. Areas of hypoconnectivity in Chiari patients also suggest disruption in functional pathways, and potential mechanisms are discussed., Resting-state fMRI imaging was conducted on a group of Type I Chiari malformation patients and age- and education-matched controls. Analyses yielded patterns of relative hypo- and hyperconnectivity, associations between differences in functional connectivity and self-reported chronic pain, and relationships between differences in functional connectivity and attentional capacity., Graphical Abstract Graphical Abstract

Today, the world is experiencing the COVID-19 health contingency, which prevents people from being exposed to one another and restricts physical contact. Under this context, the use of technology has become an essential tool to face the challenges of daily life, and virtual reality can be an alternative in the development of solutions that effectively support the acquisition of learning skills and knowledge transmission through the execution of tasks designed by multi-disciplinary groups. In addition, it can encourage the user to continue with the acquisition of learning skills in a friendly and fun way in a health and education context. This work proposes the use of virtual reality environments as an alternative to support the learning process in children with special educational needs such as Attention Deficit Hyperactivity Disorder (ADHD) and other associated disorders that occur in basic education. These proposed reality environments are designed under the Lean UX process model and their contents are designed according to expert therapeutic guidelines. As a result of this proposal, a case study is presented in which the user experience is evaluated through the use of an interactive environment to support the special educational needs of elementary school children attending an educational institution in Mexico.

Purpose To evaluate a minimum 15-year clinical and radiographic follow-up after anteromedial tibial tubercle transfer (anteromedialization [AMZ]) for lateral and/or distal patellar facet arthrosis. Methods Patients treated from 1996 to 2000 were contacted. The inclusion criteria were a minimum of 15 years' follow-up after AMZ for isolated persistent retropatellar pain related to lateral and/or distal patellar chondrosis. The exclusion criteria were clinical patellar instability, revision, and significant medial patellar facet or adjacent compartment chondrosis. The anatomic location(s) and severity of arthrosis, as well as the degree of lateral maltracking, were documented. Follow-up data included pain, activity level, and satisfaction. Results Of 23 patients, 15 met the inclusion criteria. All were women (17 knees) followed up for a mean of 17.1 years (range, 15.4-18.8 years). The mean age at surgery was 29.5 years. Satisfactory results were reported in 94% of knees (16 of 17), based simply on patients' subjective evaluation of the degree of success perceived. An important criterion of satisfaction was that these patients stated they would opt to undergo surgery again under the same circumstances. For 35% of knees, patients reported engaging in recreational activities, whereas for 18%, patients were minimally active. The average pain score (range, 0-10) for 75% was 2.1, and most of these patients showed grade I or II arthrosis. Post-AMZ symptomatic medial patellar subluxation was corrected successfully in 2 patients. Removal of hardware was performed in 59% of knees, and additional procedures were required in 41%. No cases of postoperative lateral patellar instability or conversion to knee arthroplasty occurred. Conclusions Anteromedial tibial tubercle transfer without articular cartilage implantation is effective in patellofemoral joint preservation, ameliorating symptoms and facilitating active lifestyles for a minimum of 15 years to nearly 20 years in patients with lateral and/or distal patellofemoral arthrosis. For 94% of knees, patients would choose to undergo the procedure again under the same circumstances. Fifty-nine percent underwent screw removal, and 41% required additional procedures, mostly arthroscopic. No patients in this therapeutic case series underwent an arthroplasty procedure. Level of Evidence Level IV, therapeutic cases series.

Exposures to persistent environmental pollutants like polychlorinated biphenyls (PCBs) has been associated with liver diseases such as toxicant-associated steatohepatitis (TASH). However, previously published PCB hepatotoxicity studies evaluated mostly male animal models. Moreover, epidemiologic studies on PCB-exposed cohorts evaluating sex differences are scarce. Therefore, the objective of this study was to examine hepato-toxicological responses of PCB exposures in the context of sex-dependent outcomes. Male and female C57Bl/6 mice were exposed to Aroclor 1260 (20 mg/kg), and PCB126 (20 μg/kg), by gavage for two weeks. Female mice appeared to be more sensitive to PCB-induced hepatotoxic effects as manifested by increased liver injury markers, namely, hepatic Serpine1 expression. Additionally, compared to their male counterparts, PCB-exposed females exhibited dysregulated hepatic gene expression favoring lipid accumulation rather than lipid breakdown; accompanied by dyslipidemia. Sex differences were also observed in the expression and activation of PCB targets such as the epidermal growth factor receptor (EGFR) while PCB-induced pancreatic toxicity was similar in both sexes. Importantly, PCB exposure appeared to cause pro-androgenic, anti-estrogenic along with sex-dependent thyroid hormone effects. The overall findings demonstrated that the observed PCB-mediated hepatotoxicity was sex-dependent; confirming the existence of sex differences in environmental exposure-induced markers of TASH and warrants further investigation.

International audience; Background: Apathy is present in several psychiatric and neurological conditions and has been found to have a severe negative effect on disease progression. In older people, it can be a predictor of increased dementia risk. Current assessment methods lack objectivity and sensitivity, thus new diagnostic tools and broad-scale screening technologies are needed. Objective: This study is the first of its kind aiming to investigate whether automatic speech analysis could be used for characterization and detection of apathy. Methods: A group of apathetic and non-apathetic patients (n = 60) with mild to moderate neurocognitive disorder were recorded while performing two short narrative speech tasks. Paralinguistic markers relating to prosodic, formant, source, and temporal qualities of speech were automatically extracted, examined between the groups and compared to baseline assessments. Machine learning experiments were carried out to validate the diagnostic power of extracted markers.Results: Correlations between apathy sub-scales and features revealed a relation between temporal aspects of speech and the subdomains of reduction in interest and initiative, as well as between prosody features and the affective domain. Group differences were found to vary for males and females, depending on the task. Differences in temporal aspects of speech were found to be the most consistent difference between apathetic and non-apathetic patients. Machine learning models trained on speech features achieved top performances of AUC = 0.88 for males and AUC = 0.77 for females. Conclusions: These findings reinforce the usability of speech as a reliable biomarker in the detection and assessment of apathy.

Antimicrobial peptides (AMPs) are a diverse family of peptides that defend the mucosal surfaces of the oral cavity and other locations. Many AMPs have multiple functions and properties that influence aspects of innate defense and colonization by microorganisms. The human oral cavity is home to the second-most diverse microbiome, and the health of the mouth is influenced by the presence of these bacteria as well as by extrinsic factors such as periodontitis and smoking. This study hypothesized that the AMP profile is different in the presence of extrinsic factors and that this would also be reflected in the bacteria present. The AMP profile was analyzed by quantitative selected-reaction-monitoring mass spectrometry analysis and 40 bacterial species were quantified by DNA-DNA hybridization in saliva donated by 41 individuals. Periodontal status was assessed through dental examination and smoking status through medical charting. Periodontal health (in nonsmokers) was associated with a higher abundance of ribonuclease 7, protachykinin 1, β-defensin 128, lipocalin 1, bactericidal permeability-increasing protein fold-containing family B member 3, and bone-marrow proteoglycan. Nonsmoking periodontal disease was associated with an abundance of neutrophil defensin 1 and cathelicidin. However, 7 AMPs were overabundant in periodontal disease in smokers: adrenomedullin, eosinophil peroxidase, 3 different histones, myeloperoxidase, and neutrophil defensin 1. There were no differentially abundant AMPs in smokers versus nonsmokers with periodontal health. Correlation network inference of healthy nonsmokers, healthy smokers, nonsmoking periodontitis, or smoking periodontitis donors demonstrated very different networks growing in complexity with increasing numbers of stressors. The study highlights the importance of the interaction between the oral cavity and its resident microbiota and how this may be influenced by periodontal disease and smoking.

The autonomic nervous system delicately regulates the function of several target organs, including the gastrointestinal tract. Thus, nerve lesions or other nerve pathologies may cause autonomic dysfunction (AD). Some of the most common causes of AD are diabetes mellitus and α-synucleinopathies such as Parkinson’s disease. Widespread dysmotility throughout the gastrointestinal tract is a common finding in AD, but no commercially available method exists for direct verification of enteric dysfunction. Thus, assessing segmental enteric physiological function is recommended to aid diagnostics and guide treatment. Several established assessment methods exist, but disadvantages such as lack of standardization, exposure to radiation, advanced data interpretation, or high cost, limit their utility. Emerging methods, including high-resolution colonic manometry, 3D-transit, advanced imaging methods, analysis of gut biopsies, and microbiota, may all assist in the evaluation of gastroenteropathy related to AD. This review provides an overview of established and emerging assessment methods of physiological function within the gut and assessment methods of autonomic neuropathy outside the gut, especially in regards to clinical performance, strengths, and limitations for each method.

Background The current standard for open and laparoscopic repair of incisional hernia consist of an abdominal wall augmentation by mesh implantation. However, the ideal fixation method of the prothesis material remains under discussion, due to potential complications of conventional fixation methods such as chronic abdominal pain or intestinal obstruction. As the use of adhesive based mesh fixation is an option of growing interest, the aim of this experimental study was to investigate the strength and biocompatibility of two newly developed polyurethane-based adhesives in comparison to a cyanoacrylatic adhesive, which is currently in clinical use. Methods Two experimental polyurethane/urea-based adhesives (Adhesive-A and Adhesive-B) were compared to a conventional cyanoacrylatic adhesive and an untreated control group. Biomechanical testing was carried out using a pull-out test in uniaxial tensile mode, while biocompatibility assessment was performed in a rat model with 40 Sprague-Dawley rats receiving a subcutaneous implanted PVDF mesh fixed by the corresponding adhesive. Histological and immunohistochemical analysis by a Tissue FAXS system examined the tissue integration of the mesh/adhesive combination and characterized the foreign body reaction. Results Biomechanical testing of the mesh/adhesive combinations showed a minimal strength of 15.08 N without a significant difference between the groups. Cellular penetration into the mesh/adhesive interface was significantly improved after application of polyurethane adhesives and Adhesive-A showed a significantly lower migration of CD68 positive cells to the adhesive sites compared to cyanoacrylate after 7 days. Conclusion The developed polyurethane-based adhesives are a promising alternative with sufficient adhesive strength and superior short-term biocompatibility to cyanoacrylate.

Background Peanut allergy has a rising prevalence in high-income countries, affecting 0.5%-1.4% of children. This study aimed to better understand peanut anaphylaxis in comparison to anaphylaxis to other food triggers in European children and adolescents. Methods Data was sourced from the European Anaphylaxis Registry via an online questionnaire, after in-depth review of food-induced anaphylaxis cases in a tertiary paediatric allergy centre. Results 3514 cases of food anaphylaxis were reported between July 2007 - March 2018, 56% in patients younger than 18 years. Peanut anaphylaxis was recorded in 459 children and adolescents (85% of all peanut anaphylaxis cases). Previous reactions (42% vs. 38%; p = .001), asthma comorbidity (47% vs. 35%; p < .001), relevant cofactors (29% vs. 22%; p = .004) and biphasic reactions (10% vs. 4%; p = .001) were more commonly reported in peanut anaphylaxis. Most cases were labelled as severe anaphylaxis (Ring&Messmer grade III 65% vs. 56% and grade IV 1.1% vs. 0.9%; p = .001). Self-administration of intramuscular adrenaline was low (17% vs. 15%), professional adrenaline administration was higher in non-peanut food anaphylaxis (34% vs. 26%; p = .003). Hospitalization was higher for peanut anaphylaxis (67% vs. 54%; p = .004). Conclusions The European Anaphylaxis Registry data confirmed peanut as one of the major causes of severe, potentially life-threatening allergic reactions in European children, with some characteristic features e.g., presence of asthma comorbidity and increased rate of biphasic reactions. Usage of intramuscular adrenaline as first-line treatment is low and needs to be improved. The Registry, designed as the largest database on anaphylaxis, allows continuous assessment of this condition.

PLOS ONE 16(8), e0256790 (2021). doi:10.1371/journal.pone.0256790, Published by PLOS, San Francisco, California, US

BACKGROUND: Gastrointestinal (GI) symptoms are common in patients with diabetes mellitus (DM). The electromagnetic 3D-Transit system allows assessment of regional transit times and motility patterns throughout the GI tract. We aimed to compare GI transit times and detailed motility patterns of the colon in patients with DM and GI symptoms to those of healthy controls (HC). We further aimed to determine whether any abnormalities in motility were reversible by cholinergic stimulation.METHODS: We compared 18 patients with DM with 20 HC by means of the 3D-Transit system. Patients were studied before and during oral administration of 60 mg pyridostigmine.KEY RESULTS: Compared to HC, patients had prolonged gastric emptying (DM: 3.3 hours (interquartile range (IQR) 2.6-4.6); HC: 2.3 hours (IQR 1.7-2.7) (P < .01)), colonic transit time (DM: 52.6 hours (IQR 23.3-83.0); HC: 22.4 hours (IQR 18.9-43.6) (P = .02)), and whole gut transit time (DM: 69.4 hours (IQR 32.9-103.6); HC: 30.3 hours (IQR 25.2-49.9) (P < .01)). In addition, compared to HC, patients had prolonged transit time in the ascending colon (DM: 20.5 hours (IQR 11.0-44.0); HC: 8.0 hours (IQR 3.8-21.0) (P < .05)) and more slow retrograde movements in the colon (DM: 2 movements (IQR 1-4); HC: 1 movement (IQR 0-1) (P = .01)). In patients, pyridostigmine increased the number of bowel movements (P < .01) and reduced small intestine transit times (P < .05).CONCLUSIONS: Patients with DM and GI symptoms have longer than normal GI transit times. This is only partly reversible by pyridostigmine. The increased number of retrograde colonic movements in patients could potentially explain the abnormally long transit time in proximal colon.

OBJECTIVE The craniocervical junction (CCJ) is anatomically complex and comprises multiple joints that allow for wide head and neck movements. The thecal sac must adjust to such movements. Accordingly, the thecal sac is not rigidly attached to the bony spinal canal but instead tethered by fibrous suspension ligaments, including myodural bridges (MDBs). The authors hypothesized that pathological spinal cord motion is due to the laxity of such suspension bands in patients with connective tissue disorders, e.g., hypermobile Ehlers-Danlos syndrome (EDS). METHODS The ultrastructure of MDBs that were intraoperatively harvested from patients with Chiari malformation was investigated with transmission electron microscopy, and 8 patients with EDS were compared with 8 patients without EDS. MRI was used to exclude patients with EDS and craniocervical instability (CCI). Real-time ultrasound was used to compare the spinal cord at C1–2 of 20 patients with EDS with those of 18 healthy control participants. RESULTS The ultrastructural damage of the collagen fibrils of the MDBs was distinct in patients with EDS, indicating a pathological mechanical laxity. In patients with EDS, ultrasound revealed increased cardiac pulsatory motion and irregular displacement of the spinal cord during head movements. CONCLUSIONS Laxity of spinal cord suspension ligaments and the associated spinal cord motion disorder are possible pathogenic factors for chronic neck pain and headache in patients with EDS but without radiologically proven CCI.

In anti-glomerular basement membrane glomerulonephritis (anti-GBM GN), antibodies and T cells directed against the Goodpasture antigen, the non-collagenous domain of the α3-chain of type IV collagen (α3(IV)NC1), provoke renal inflammation resulting in rapidly progressing crescentic GN. Interleukin 6 (IL-6) is a pleiotropic cytokine with both pro- and anti-inflammatory activities, and IL-6 blockade is successfully used for treatment of diseases associated with acute and chronic inflammation. However, the role of IL-6 in anti-GBM GN is unclear. Here, we use the mouse model of experimental autoimmune glomerulonephritis (EAG) to study the role of IL-6 in anti-GBM GN. DBA/1J mice were immunized with α3(IV)NC1 and developed fatal crescentic GN. Treatment of mice with neutralizing anti-IL-6 antibodies impaired the generation of α3(VI)NC1-specific TH1 and TH17 cells. However, despite lasting reduction of the TH17 cell response, antibody treatment did not prevent crescentic GN. Antibody treatment was also ineffective in a therapeutic setting with pre-existing autoantibodies and T cells. In conclusion, our results indicate that although the blockade of IL-6 impairs the development of autoimmunity against α3(VI)NC1, this treatment does not ameliorate crescentic GN both in a preemptive and a therapeutic approach.

Although it is well established that microbial infections predispose to autoimmune diseases, the underlying mechanisms remain poorly understood. After infection, tissue-resident memory T (TRM) cells persist in peripheral organs and provide immune protection against reinfection. However, whether TRM cells participate in responses unrelated to the primary infection, such as autoimmune inflammation, is unknown. By using high-dimensional single-cell analysis, we identified CD4+ TRM cells with a TH17 signature (termed TRM17 cells) in kidneys of patients with ANCA-associated glomerulonephritis. Experimental models demonstrated that renal TRM17 cells were induced by pathogens infecting the kidney, such as Staphylococcus aureus, Candida albicans, and uropathogenic Escherichia coli, and persisted after the clearance of infections. Upon induction of experimental glomerulonephritis, these kidney TRM17 cells rapidly responded to local proinflammatory cytokines by producing IL-17A and thereby exacerbate renal pathology. Thus, our data show that pathogen-induced TRM17 cells have a previously unrecognized function in aggravating autoimmune disease.

Objectives The current COVID‐19 outbreak in conjunction with the need to provide safe dental treatments and the limited knowledge on the efficacy of protective measures has posed dentists into a challenging situation. Therefore, the present article aimed at collecting experiences and recommendations of frontline clinical experts on critical aspects of dental treatment provision during pandemic. Material & Methods From a total of 32 European countries, one leading academic expert in Oral and Maxillofacial Surgery or Oral Surgery per country was asked to participate in an anonymous online 10‐item survey on COVID‐19 covering the topics of safety of dental settings, personal protective equipment (PPE), and patient‐related measures to reduce transmission risk. Data collection took place from April 12th to May 22nd, 2020. Results A total of 27 experts from different European countries completed the survey. The transmission risk of SARS‐CoV‐2 in dental settings for aerosol‐generating procedures was considered high by all experts except two. For aerosol‐free and aerosol‐generating procedures, more than 80% of the experts recommended face protection and caps for every single treatment. For aerosol‐generating procedures, additional measures (FFP2/FFP3 masks and gowns) were suggested by the vast majority of the experts. To reduce transmission risk, all experts recommended limiting aerosol‐generating procedures and reducing the number of patients in waiting areas as well as hand hygiene for the patients. Conclusion The limitation of aerosol‐generating procedures along with the usage of adequate personal protection equipment was considered to be crucial to protect dental healthcare providers and patients, thus reducing the transmission risk of COVID‐19.

Background Knowledge of unplanned readmission rates and prognostic factors for readmission among older people after early discharge from emergency departments is sparse. The aims of this study were to examine the unplanned readmission rate among older patients after short-term admission, and to examine risk factors for readmission including demographic factors, comorbidity and admission diagnoses. Methods This cohort study included all medical patients aged ≥65 years acutely admitted to Danish hospitals between 1 January 2013 and 30 June 2014 and surviving a hospital stay of ≤24 h. Data on readmission within 30 days, comorbidity, demographic factors, discharge diagnoses and mortality were obtained from the Danish National Registry of Patients and the Danish Civil Registration System. We examined risk factors for readmission using a multivariable Cox regression to estimate adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for readmission. Results A total of 93,306 patients with a median age of 75 years were acutely admitted and discharged within 24 h, and 18,958 (20.3%; 95% CI 20.1 - 20.6%) were readmitted with a median time to readmission of 8 days (IQR 3 - 16 days). The majority were readmitted with a new diagnosis. Male sex (aHR 1.15; 1.11 - 1.18) and a Charlson Comorbidity Index ≥3 (aHR 2.28; 2.20 - 2.37) were associated with an increased risk of readmission. Discharge diagnoses associated with increased risk of readmission were heart failure (aHR 1.26; 1.12 - 1.41), chronic obstructive pulmonary disease (aHR 1.33; 1.25 - 1.43), dehydration (aHR 1.28; 1.17 - 1.39), constipation (aHR 1.26; 1.14 - 1.39), anemia (aHR 1.45; 1.38 - 1.54), pneumonia (aHR 1.15; 1.06 - 1.25), urinary tract infection (aHR 1.15; 1.07 - 1.24), suspicion of malignancy (aHR 1.51; 1.37 - 1.66), fever (aHR 1.52; 1.33 - 1.73) and abdominal pain (aHR 1.12; 1.05 - 1.19). Conclusions One fifth of acutely admitted medical patients aged ≥65 were readmitted within 30 days after early discharge. Male gender, the burden of comorbidity and several primary discharge diagnoses were risk factors for readmission.

Significance Progress in studying the androgen receptor (AR), the primary drug target in prostate cancer, has been hampered by challenges in expressing and purifying active multidomain AR for use in cell-free biochemical reconstitution assays. Here we successfully express full-length and truncated AR variants and demonstrate that the oncogenic ETS protein ERG, responsible for half of all prostate cancers, enhances the ability of AR to bind DNA through direct interaction with AR. In addition to providing a biochemical system to evaluate AR activity on different DNA templates, our findings provide insight into why ERG-positive prostate cancers have an expanded AR cistrome., The androgen receptor (AR) is a type I nuclear hormone receptor and the primary drug target in prostate cancer due to its role as a lineage survival factor in prostate luminal epithelium. In prostate cancer, the AR cistrome is reprogrammed relative to normal prostate epithelium and particularly in cancers driven by oncogenic ETS fusion genes. The molecular basis for this change has remained elusive. Using purified proteins, we report a minimal cell-free system that demonstrates interdomain cooperativity between the ligand (LBD) and DNA binding domains (DBD) of AR, and its autoinhibition by the N terminus of AR. Furthermore, we identify ERG as a cofactor that activates AR’s ability to bind DNA in both high and lower affinity contexts through direct interaction within a newly identified AR-interacting motif (AIM) in the ETS domain, independent of ERG’s own DNA binding ability. Finally, we present evidence that this interaction is conserved among ETS factors whose expression is altered in prostate cancer. Our work highlights, at a biochemical level, how tumor-initiating ETS translocations result in reprogramming of the AR cistrome.

Extracellular matrix (ECM) remodeling is a hallmark of the pathology of gastrointestinal disorders. Collagen type VI (COL6) is produced by fibroblasts, and the COL6 α3-chain has shown to be elevated in patients with ulcerative colitis (UC), Crohn’s disease (CD) and colorectal cancer (CRC). Measuring COL6α3 in serum may therefore have potential as a biomarker for gastrointestinal disorders. The aims of this study were to develop and validate a competitive ELISA targeting a specific neo-epitope of COL6α3 and evaluate its associations with the gastrointestinal disorders UC, CD and CRC, in comparison to healthy controls. A monoclonal antibody was raised against a matrix metalloproteinase-2 and -9 specific cleavage site of COL6α3 (C6Mα3) and employed in a competitive enzyme-linked immunosorbent assay (ELISA). The assay was developed and technically validated. Levels of C6Mα3 were measured in serum from patients with UC (n = 58), CD (n = 44) and CRC (n = 39) and compared to healthy controls (n = 32). The levels of C6Mα3 were elevated in patients with UC, CD and CRC patients compared to healthy controls (all p

Background The incidence of incisional hernia is with up to 30% one of the frequent long-term complication after laparotomy. After establishing minimal invasive operations, the laparoscopic intraperitoneal onlay mesh technique (lap. IPOM) was first described in 1993. Little is known about the foreign body reaction of IPOM-meshes, which covered a defect of the parietal peritoneum. This is becoming more important, since IPOM procedure with peritoneal-sac resection and hernia port closing (IPOM plus) is more frequently used. Methods In 18 female minipigs, two out of three Polyvinylidene-fluoride (PVDF) -meshes (I: standard IPOM; II: IPOM with modified structure [bigger pores]; III: IPOM with the same structure as IPOM II + degradable hydrogel-coating) were placed in a laparoscopic IPOM procedure. Before mesh placement, a 2x2cm peritoneal defect was created. After 30 days, animals were euthanized, adhesions were evaluated by re-laparoscopy and mesh samples were explanted for histological and immunohistochemichal investigations. Results All animals recovered after implantation and had no complications during the follow-up period. Analysing foreign body reaction, the IPOM II mesh had a significant smaller inner granuloma, compared to the other meshes (IPOM II: 8.4 µm ± 1.3 vs. IPOM I 9.1 µm ± 1.3, p Conclusion A peritoneal defect covered by IPOM prostheses leads to an increased foreign body reaction compared to intact peritoneum. Whenever feasible, a peritoneal defect should be closed accurately before placing an IPOM-mesh to avoid an excessive foreign body reaction and therefore inferior biomaterial properties of the prosthesis.

An 8-week-old infant was admitted to the hospital after an initially normal postpartum course with pronounced shortness of breath. Progressive hypoxia and a loss of consciousness occurred during the computer tomography examination, whereby the massively increased airway resistance hardly allowed ventilation. During a emergency thoracotomy, a bronchogenic cyst which had compressed the left main bronchus, was successfully extirpated.

Summary In vitro allergy diagnostics are currently based on the detection of specific IgE binding on intact allergens or a mixture thereof. This approach has drawbacks as it may yield false‐negative and/or false‐positive results. Thus, we reviewed the impact of known B‐cell epitopes of food allergens to predict transience or persistence, tolerance or allergy and the severity of an allergic reaction and to examine new epitope mapping strategies meant to improve serum‐based allergy diagnostics. Recent epitope mapping approaches have been worthwhile in epitope identification and may increase the specificity of allergy diagnostics by using epitopes predominately recognized by allergic patients in some cases. However, these approaches did not lead to discrimination between clinically relevant and irrelevant epitopes so far, since the polyclonal serum IgE‐binding epitope spectrum seems to be too individual, independent of the disease status of the patients. New epitope mapping strategies are necessary to overcome these obstacles. The use of patient‐derived monoclonal antibodies instead of patient sera for functional characterization of clinically relevant and irrelevant epitope combinations, distinguished by their ability to induce degranulation, might be a promising approach to gain more insight into the allergic reaction and to improve serum‐based allergy diagnostics.

Today the use of textile meshes has become a standard for the treatment of abdominal wall hernias and for the reinforcement of any tissue repair as the strength of the implant decreases the recurrence rates. With increasing use, side effects of the textile implants became apparent, as well.Based on publications in Medline over the past decade, general and specific benefits, as well as risks, are discussed with the challenge to define individual risk-benefit ratios. For meshes, certain high-risk or low-risk conditions can be defined. In an attempt to eliminate mesh-related risks, quality control for medical devices has meanwhile been revised. In both the USA and the EU post-market surveillance studies are required to keep medical devices approved.The impact of material on the complication rate will vary depending on the patient's co-morbidity or the risks of the procedure. Even the best material can end up with disappointing results in case of poor healing or poor surgery. On the other hand, when using high-risk devices, most of the complications after excellent surgery with excellent indication can be supposed to be mesh-related. Thus, the use of low-risk devices is recommended even though its advantage may not be demonstrable in clinical studies.

Altered extracellular matrix (ECM) remodeling is an important part of the pathology of gastrointestinal (GI) disorders. In the intestine, type XVI collagen (col-16) plays a role in pathogenesis by affecting ECM architecture and induce cell invasion. Measuring col-16 in serum may therefore have biomarker potential in GI disorders such as colorectal cancer (CRC) and ulcerative colitis (UC). The aim of this study was to determine whether col-16 can serve as a biomarker for altered ECM remodeling in patients with CRC and UC. A monoclonal antibody was raised against the C-terminal end of col-16 (PRO-C16), and a competitive enzyme-linked immunosorbent assay (ELISA) was developed and technically validated. Levels of PRO-C16 were measured in serum from patients with CRC (before (n = 50) and 3 months after (n = 23) tumor resections), UC (n = 39) and healthy controls (n = 50). The PRO-C16 ELISA was specific toward the C-terminal of col-16. PRO-C16 was significantly elevated both in serum from patients with CRC (P = 0.0026) and UC (P P > 0.999). Levels of PRO-C16 identified patients with a GI disorder with a positive predictive value of 0.9 and an odds ratio of 12 (95%CI = 4.5-29.5, P

We are grateful for the interest in our article (1) and the well-taken question raised by Li et al. (2). In previous reports from our group (3,4) we underlined that classification as impaired fasting glucose (IFG) will miss a large proportion of patients with dysglycemia (impaired …

Cardiovascular disease is a common cause of morbidity and premature mortality. Cardiovascular disease can be prevented when risk factors are identified early. Calcified carotid artery atheromas (CCAAs), detected in panoramic radiographs, and periodontitis have both been associated with increased risk of cardiovascular disease. This case-control study aimed to 1) investigate associations between periodontitis and CCAA detected in panoramic radiographs and 2) determine the risk of future myocardial infarctions due to CCAA combined with periodontitis. We evaluated 1,482 participants (738 cases and 744 controls) with periodontitis and CCAAs recruited from the PAROKRANK study (Periodontitis and Its Relation to Coronary Artery Disease). Participants were examined with panoramic radiographs, including the carotid regions. Associations between myocardial infarction and periodontitis combined with CCAA were evaluated in 696 cases and 696 age-, sex-, and residential area–matched controls. Periodontitis was evaluated radiographically (as degree of bone loss) and with a clinical periodontal disease index score (from clinical and radiographic assessments). We found associations between CCAA and clinical periodontal disease index score among cases (odds ratio [OR], 1.51; 95% CI, 1.09 to 2.10; P = 0.02) and controls (OR, 1.70; 95% CI, 1.22 to 2.38; P < 0.01), although not between CCAA and the degree of bone loss. In a multivariable model, myocardial infarction was associated with CCAA combined with periodontitis, as assessed by degree of bone loss (OR, 1.75; 95% CI, 1.11 to 2.74; P = 0.01). When the cohort was stratified by sex, only men showed a significant association between myocardial infarction and CCAA combined with periodontitis. Participants with clinically diagnosed periodontitis exhibited CCAA in panoramic radiographs more often than those without periodontitis, irrespective of the presence of a recent myocardial infarction. Participants with combined periodontitis and CCAA had a higher risk of having had myocardial infarction as compared with participants with either condition alone. These findings implied that patients in dental care might benefit from dentists assessing panoramic radiographs for CCAA—particularly, patients with periodontitis who have not received any preventive measures for cardiovascular disease.

PurposePostoperative recovery following colorectal surgery remains impaired by severe complications including postoperative ileus (POI). Human studies of POI have been limited by a lack of safe and easy-to-use objective methods. Motilis 3D-transit is a completely ambulatory, minimally invasive system whereby electromagnetic capsules are followed by external sensors during their passage of the gastrointestinal (GI) tract. The aim of this study was to evaluate the applicability of the 3D-transit system in a surgical setting.MethodWe included 12 patients as a substudy of the randomised double blind controlled Stimulation of the Autonomic Nervous System In Colorectal Surgery by perioperative nutrition (SANICS)-II trial undergoing elective segmental colonic resection with primary anastomosis at Aarhus University Hospital and Randers Regional Hospital, Denmark. To study region-specific motility, three electromagnetic capsules were administered. One was taken 3 hours before surgery, the next was taken 1 hour before surgery, while the third was placed distal to the anastomosis during surgery. Total and regional GI transit times as well as time until first propulsive colonic contraction were determined.ResultsAll patients tolerated the setup well with no adverse events related to the 3D-transit system. Large variations were found in total GI transit time (26.7–127.6 hours), gastric emptying (0.07–>106.9 hours), small intestinal (1.2–58.4 hours) and colorectal transit time (14.3–>118.1 hours). Time from end of surgery to first propulsive movement in the colon varied from 3.9 to 85 hours. No correlation was found between parameters of GI motility and tolerance of an oral diet or recovery of bowel function.ConclusionThe 3D-transit system allows safe assessment of GI motility in patients operated with segmental colonic resections and primary anastomosis for colorectal cancer. Postsurgical motility varies significantly between patients.

Background: Kidney disease has been reported in adults with inflammatory bowel disease (IBD) and is regarded an extraintestinal manifestation or more rarely a side effect of the medical treatment.Methods: In this cross-sectional study we describe the extent of kidney pathology in a cohort of 56 children with IBD. Blood and urine samples were analyzed for markers of kidney disease and ultrasonography was performed to evaluate pole-to-pole kidney length.Results: We found that 25% of the patients had either previously reported kidney disease or ultrasonographic signs of chronic kidney disease. The median kidney size compared with normal children was significantly reduced. In a multivariate linear mixed model, small kidneys significantly correlated with the use of infliximab, whereas the use of enteral nutritional therapy was associated with larger kidneys.Conclusion : Children with IBD are at risk of chronic kidney disease, and the risk seems to be increased with the severity of the disease.

Background Dysregulation of microRNA (miRNA) expression is associated with hallmarks of aggressive tumor phenotypes, e.g., enhanced cell growth, proliferation, invasion, and anchorage independent growth in prostate cancer (PCa). Methods Serum-based miRNA profiling involved 15 men diagnosed with non-metastatic (stage I, III) and metastatic (stage IV) PCa and five age-matched disease-free men using miRNA arrays with select targets confirmed by quantitative real-time PCR (qRT-PCR). The effect of miR-186-5p inhibition or ectopic expression on cellular behavior of PCa cells (i.e., PC-3, MDA-PCa-2b, and LNCaP) involved the use bromodeoxyuridine (BrdU) incorporation, invasion, and colony formation assays. Assessment of the impact of miR-186-5p inhibition or overexpression on selected targets entailed microarray analysis, qRT-PCR, and/or western blots. Statistical evaluation used the modified t-test and ANOVA analysis. Results MiR-186-5p was upregulated in serum from PCa patients and metastatic PCa cell lines (i.e., PC-3, MDA-PCa-2b, LNCaP) compared to serum from disease-free individuals or a normal prostate epithelial cell line (RWPE1), respectively. Inhibition of miR-186-5p reduced cell proliferation, invasion, and anchorage-independent growth of PC-3 and/or MDA-PCa-2b PCa cells. AKAP12, a tumor suppressor target of miR-186-5p, was upregulated in PC-3 and MDA-PCa-2b cells transfected with a miR-186-5p inhibitor. Conversely, ectopic miR-186-5p expression in HEK 293 T cells decreased AKAP12 expression by 30%. Both pAKT and β-catenin levels were down-regulated in miR-186-5p inhibited PCa cells. Conclusions Our findings suggest miR-186-5p plays an oncogenic role in PCa. Inhibition of miR-186-5p reduced PCa cell proliferation and invasion as well as increased AKAP12 expression. Future studies should explore whether miR-186-5p may serve as a candidate prognostic indicator and a therapeutic target for the treatment of aggressive prostate cancer. Electronic supplementary material The online version of this article (10.1186/s12885-018-4258-0) contains supplementary material, which is available to authorized users.

PURPOSE OF REVIEW: The treatment of pain in patients with cirrhosis is complicated by unpredictable hepatic drug metabolism and a higher risk of adverse drug reactions. We aimed to conduct a scoping review regarding pain management in cirrhosis. RECENT FINDINGS: Despite the high prevalence of pain in patients with cirrhosis, there is little literature to guide the management of pain in this population. Complex pain syndromes and disease-specific pain etiologies exist are common in patients with cirrhosis. There are numerous contraindications and limitations when considering pharmacotherapy for analgesia in cirrhosis, specifically with non-steroidal anti-inflammatory drugs (NSAIDS) and opioid medications. Non-pharmacologic therapies for pain have not been specifically assessed in this population. SUMMARY: As with other populations, a multi-dimensional treatment approach to pain with a focus on physical, behavioral, procedural and pharmacologic treatment is recommended when caring for patients with cirrhosis and pain. However, more research is needed to evaluate opioid-sparing and non-pharmacologic analgesia in this population.

Background: Abdominal adhesions are one of the most common complications after abdominal surgery, and fibrin is suspected to be a crucial component. The aim of the current study was an in vivo evaluation of a new recombinant fibrinogenase (AK03) in two animal models.Methods: Sixty-four rats were randomly divided into four groups (sodium chloride [NaCl], icodextrin, AK03 low dose, and AK03 high dose) and evaluated at two time endpoints. Adhesion model comprised both a visceral defect (terminal ileum) and parietal defect. Test (AK03) and control substances (NaCl and icodextrin) were administered intraperitoneally after setting the intraabdominal defects. A second dose was administered 24 h after surgery. Plasma fibrinogen values were taken at baseline and after 7 and 21 d, respectively. Rats were sacrificed after 7 or 21 d for macroscopic (Diamond score) and immunohistochemical investigations.Results: After 7 and 21 d, the Diamond score of postsurgical adhesions were significantly lower in both AK03-treated groups compared with NaCl control group (P = 0.02). There were no unspecific systemic side effects in both treatment groups and no decrease in plasma fibrinogen concentration. In none of the four groups was there any evidence for impaired wound repair. Microscopically in the area of the parietal defect, we saw less cluster of differentiation 3(+) T-lymphocytes and cluster of differentiation 68(+) macrophages in both groups receiving AK03 compared with the NaCl and icodextrin control groups.Conclusions: The results of this study indicate that the new recombinant fibrinogenase AK03 effectively prevents peritoneal adhesions without causing side effects, notably systemic fibrinogen depletion, bleeding, or impaired wound repair. Due to these results, future clinical studies may be promising. (C) 2017 Elsevier Inc. All rights reserved.

With rising rates of obesity in the United States, the burden of knee dislocations in this population remains unknown. This national epidemiologic study was designed to analyze the association of obesity with closed knee dislocation and vascular complications.Retrospective cohort study.The deidentified Nationwide Inpatient Sample database was used to access the US inpatient data from 2000 to 2012.Patients with noncongenital closed knee dislocations were included. Examined variables included patient age, sex, vascular injury, and obesity status.Outcome measures included hospital length of stay, amputation, and inpatient hospitalization charge.From 2000 to 2012, a total of 19,087 knee dislocations were identified, including 2265 in overweight/obese patients (11.9%). The annual incidence of knee dislocations reported in patients diagnosed as either obese or morbidly obese increased over the 13-year period (P0.0001). The overall average rate of vascular injury requiring intervention was 5.63%, whereas 7.2% of obese patients and 11.3% of morbidly obese patients with knee dislocations (P0.0001) sustained a vascular injury requiring intervention. The average length of stay and amputation rate for obese and morbidly obese patients who sustained a knee dislocation was not statistically different from nonobese patients when vascular injury was controlled. When patients with a vascular injury were excluded, obese and morbidly obese patients who sustained a knee dislocation had higher average cost of hospital stay than nonobese patients (P = 0.0262).This study demonstrates significant increases in costs of stay with obese patients sustaining knee dislocations when compared with normal weight knee dislocation patients. Vascular injuries were found to be far more common in obese and morbidly obese patient groups than nonobese patients. Providers should be on high alert when managing knee dislocations in obese patients because a significant number require prompt vascular intervention.Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Therapies targeting estrogen receptor α (ERα) including tamoxifen, a selective estrogen receptor modulator (SERM) and aromatase inhibitors (AI), e.g., letrozole, have proven successful in reducing the death rate for breast cancer patients whose initial tumors express ERα. However, about 40% of patients develop acquired resistance to these endocrine treatments. There is a critical need to develop sensitive circulating biomarkers that accurately identify signaling pathways altered in breast cancer patients resistant to endocrine therapies. Serum miRNAs have the potential to serve as biomarkers of the progression of endocrine-resistant breast cancer due to their cancer-specific expression and stability. Exosomal transfer of miRNAs has been implicated in metastasis and endocrine-resistance. This review focuses on miRNAs in breast tumors and in serum, including exosomes, from breast cancer patients that are associated with resistance to tamoxifen since it is best-studied.

Background Intradural spinal lipomas without an associated dysraphism, represent a fraction of an already-rare entity. These lesions often present with progressive neurologic deficits. The underlying pathophysiology of these lesions is poorly understood as are the underlying factors that predispose these masses to grow. Case description We present two cases: an 11-year-old female and a 56-year-old female, each with a cervical spinal intramedullary lipoma presenting with slowly worsening neurological deficits. Each of these lesions were microsurgically debulked and underwent a duraplasty with an Alloderm® patch (Allergan) with rapidly improving symptoms postoperatively. Conclusions Subpial lipomas, without associated spinal dysraphism, are a rare entity, and both its pathogenesis and the techniques used in management remain uncertain. In our patients, resection of the lipoma with exposure of the lipoma spinal cord interface was performed to a variable degree, while respecting the transiting nerve roots and spinal cord anatomy, with immediate postoperative improvement in function. This reaffirms the benefit of mass reduction and supports a limited decompression. Even the use of a duraplasty to decompress the spinal cord and restore the spinal CSF circulation can greatly impact the postoperative course. Our patients support the relationship between hormonal flux, weight gain, and the onset of symptoms.

Background:Epidemiologic studies have demonstrated a link between periodontitis (PD) and rheumatoid arthritis (RA), specifically RA characterized by anti-citrullinated protein antibodies (ACPA). The keystone pathogen driving PD, Porphyromonas gingivalis (Pg), is the only pathogen known to express peptidylarginine deiminase (PAD), a citrullinating enzyme. Hence, Pg has been proposed to be involved in triggering the ACPA response, by generating citrullinated antigens in an inflammatory milieu(1). Another major virulence factor of Pg is arginine gingipain B (RgpB), a proteinase which cleaves proteins so that P.PAD can access the site where citrullination takes place. We have previously shown elevated anti-RgpB IgG levels in ACPA+ RA patients, even before clinical onset(2, 3), and we hypothesize that anti-RgpB IgG could serve as a serological marker to identify PD patients with increased risk of developing ACPA+ RA.Objectives:Based on this hypothesis, we set out to investigate whether anti-RgpB IgG was associated with PD, PD severity, autoimmunity in general, and the ACPA response in particular.Methods:Anti-RgpB IgG, as well as RA- and systemic lupus erythematosus (SLE)-related autoantibodies targeting cyclic citrullinated peptide(s) (CCP2), rheumatoid factor (RF), dsDNA, cardiolipin, and β2 glycoprotein, were measured by ELISA in serum samples from the ParoKrank study, which is a well-characterized cohort of 805 patients with a first myocardial infarction and 805 matched controls, where periodontal status has been determined by dentists(4). In this study, individuals with PD (n=941) were compared to individuals without PD (n=557).Results:We detected significantly elevated (pConclusion:Our data demonstrates a specific association between severe PD, elevated anti-RgpB IgG levels and RA-related autoantibodies, supporting a role for Pg in linking PD to ACPA+ RA. Further investigation will be needed to confirm whether anti-RgpB IgG can be used as a serological marker to identify PD patients with increased risk of developing ACPA+ RA.References:[1]Rosenstein ED, Greenwald RA, Kushner LJ, Weissmann G. Hypothesis: the humoral immune response to oral bacteria provides a stimulus for the development of rheumatoid arthritis. Inflammation. 2004;28(6):311-8.[2]Kharlamova N, Jiang X, Sherina N, Potempa B, Israelsson L, Quirke AM, et al. Antibodies to Porphyromonas gingivalis Indicate Interaction Between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology. Arthritis Rheumatol. 2016;68(3):604-13.[3]Johansson L, Sherina N, Kharlamova N, Potempa B, Larsson B, Israelsson L, et al. Concentration of antibodies against Porphyromonas gingivalis is increased before the onset of symptoms of rheumatoid arthritis. Arthritis Res Ther. 2016;18(1):201.[4]Rydén L, Buhlin K, Ekstrand E, Faire Ud, Gustafsson A, Holmer J, et al. Periodontitis Increases the Risk of a First Myocardial Infarction. Circulation. 2016;133(6):576-83.Disclosure of Interests:None declared

While normal-pressure hydrocephalus (NPH) is most commonly diagnosed in older adulthood, a significant body of literature has accumulated over half a century documenting the clinical phenomenon of an NPH-like syndrome in pediatric patients. As in adult NPH, it is likely that pediatric NPH occurs due to a heterogeneous array of developmental, structural, and neurodegenerative pathologies, ultimately resulting in aberrant cerebrospinal fluid (CSF) flow and distribution within and around the brain. In this review, we aimed to systematically survey the existing clinical evidence supporting the existence of a pediatric form of NPH, dating back to the original recognition of NPH as a clinically significant subtype of communicating hydrocephalus. Leveraging emergent trends from the old and more recent published literature, we then present a modern characterization of pediatric NPH as a disorder firmly within the same disease spectrum as adult NPH, likely with overlapping etiology and pathophysiological mechanisms. Exemplary cases consistent with the diagnosis of pediatric NPH selected from the senior author’s neurosurgical practice are then presented alongside the systematic review to aid in discussion of the typical clinical and radiographic manifestations of pediatric NPH. Common co-morbidities and modern surgical treatment options are also described.

// Shuguang Leng 1 , Guodong Wu 1 , Donna M. Klinge 1 , Cynthia L. Thomas 1 , Elia Casas 1 , Maria A. Picchi 1 , Christine A. Stidley 2 , Sandra J. Lee 3 , Seena Aisner 4 , Jill M. Siegfried 5 , Suresh Ramalingam 6 , Fadlo R. Khuri 6 , Daniel D. Karp 7 and Steven A. Belinsky 1 1 Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, NM, USA 2 Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA 3 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA 4 Rutgers New Jersey Medical School, Newark, NJ, USA 5 Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA 6 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA 7 MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Steven A. Belinsky, email: sbelinsk@LRRI.org Keywords: gene methylation, lung cancer risk, biomarker, CT screening Received: March 14, 2017 Accepted: June 05, 2017 Published: July 15, 2017 ABSTRACT CT screening for lung cancer reduces mortality, but will cost Medicare ~2 billion dollars due in part to high false positive rates. Molecular biomarkers could augment current risk stratification used to select smokers for screening. Gene methylation in sputum reflects lung field cancerization that remains in lung cancer patients post-resection. This population was used in conjunction with cancer-free smokers to evaluate classification accuracy of a validated eight-gene methylation panel in sputum for cancer risk. Sputum from resected lung cancer patients (n=487) and smokers from Lovelace (n=1380) and PLuSS (n=718) cohorts was studied for methylation of an 8-gene panel. Area under a receiver operating characteristic curve was calculated to assess the prediction performance in logistic regressions with different sets of variables. The prevalence for methylation of all genes was significantly increased in the ECOG-ACRIN patients compared to cancer-free smokers as evident by elevated odds ratios that ranged from 1.6 to 8.9. The gene methylation panel showed lung cancer prediction accuracy of 82–86% and with addition of clinical variables improved to 87–90%. With sensitivity at 95%, specificity increased from 25% to 54% comparing clinical variables alone to their inclusion with methylation. The addition of methylation biomarkers to clinical variables would reduce false positive screens by ruling out one-third of smokers eligible for CT screening and could increase cancer detection rates through expanding risk assessment criteria.