Gastroesophageal reflux disease (GERD) continues to be among the most common diseases seen by gastroenterologists, surgeons, and primary care physicians. Our understanding of the varied presentations ...of GERD, enhancements in diagnostic testing, and approach to patient management have evolved. During this time, scrutiny of proton pump inhibitors (PPIs) has increased considerably. Although PPIs remain the medical treatment of choice for GERD, multiple publications have raised questions about adverse events, raising doubts about the safety of long-term use and increasing concern about overprescribing of PPIs. New data regarding the potential for surgical and endoscopic interventions have emerged. In this new document, we provide updated, evidence-based recommendations and practical guidance for the evaluation and management of GERD, including pharmacologic, lifestyle, surgical, and endoscopic management. The Grading of Recommendations, Assessment, Development, and Evaluation system was used to evaluate the evidence and the strength of recommendations. Key concepts and suggestions that as of this writing do not have sufficient evidence to grade are also provided.
The incidence of rectal cancer in the United States in young patients is considered to be low. Underestimating this incidence may result in a failure to diagnose younger patients with rectal cancer ...in a timely manner.
The authors conducted a retrospective cohort study using Surveillance, Epidemiology, and End Results (SEER) cancer registry data. A total of 7661 patients with colon, rectal, and rectosigmoid cancer who were diagnosed at age <40 years were identified between 1973 and 2005. The change in incidence over time for colon and rectal/rectosigmoid cancer was calculated and the annual percent change for anatomic subsites of colorectal cancer compared.
SEER data demonstrated an increase in the incidence of rectal cancer without any increase in colon cancer (annual percent change of 2.6% vs -0.2%). The difference was statistically significant and extended to rectosigmoid cancer, but not cancer of the sigmoid colon or descending colon (annual percent change of 2.2% vs 0.4% and -2.8%, respectively). Joinpoint analysis of the slope of the curve of rectal and rectosigmoid cancer incidence identified the beginning of the increase to be 1984. All races and both sexes demonstrated similar statistically significant increases in the incidence of rectal and rectosigmoid cancer.
The incidence of rectal and rectosigmoid cancer appears to be increasing in patients aged <40 years. Patients presenting with rectal bleeding or other alarming signs or symptoms should be evaluated with this finding in mind.
Functional luminal imaging probe (FLIP) panometry can evaluate esophageal motility in response to sustained esophageal distension at the time of sedated endoscopy. This study aimed to describe a ...classification of esophageal motility using FLIP panometry and evaluate it against high-resolution manometry (HRM) and Chicago Classification v4.0 (CCv4.0).
Five hundred thirty-nine adult patients who completed FLIP and HRM with a conclusive CCv4.0 diagnosis were included in the primary analysis. Thirty-five asymptomatic volunteers ("controls") and 148 patients with an inconclusive CCv4.0 diagnosis or systemic sclerosis were also described. Esophagogastric junction (EGJ) opening and the contractile response (CR) to distension (i.e., secondary peristalsis) were evaluated with a 16-cm FLIP during sedated endoscopy and analyzed using a customized software program. HRM was classified according to CCv4.0.
In the primary analysis, 156 patients (29%) had normal motility on FLIP panometry, defined by normal EGJ opening and a normal or borderline CR; 95% of these patients had normal motility or ineffective esophageal motility on HRM. Two hundred two patients (37%) had obstruction with weak CR, defined as reduced EGJ opening and absent CR or impaired/disordered CR, on FLIP panometry; 92% of these patients had a disorder of EGJ outflow per CCv4.0.
Classifying esophageal motility in response to sustained distension with FLIP panometry parallels the swallow-associated motility evaluation provided with HRM and CCv4.0. Thus, FLIP panometry serves as a well-tolerated method that can complement, or in some cases be an alternative to HRM, for evaluating esophageal motility disorders.
Abstract While the elements encoding enhancers and promoters have been relatively well studied, the full spectrum of insulator elements which bind the CCCTC binding factor (CTCF), is relatively ...poorly characterized. This is partly due to the genomic context of CTCF sites greatly influencing their roles and activity. Here we have developed an experimental system to determine the ability of minimal, consistently sized, individual CTCF elements to interpose between enhancers and promoters and thereby reduce gene expression during differentiation. Importantly, each element is tested in the identical location thereby minimising the effect of genomic context. We found no correlation between the ability of CTCF elements to block enhancer–promoter activity with the degree of evolutionary conservation; their resemblance to the consensus core sequences; or the number of CTCF core motifs harboured in the element. Nevertheless, we have shown that the strongest enhancer–promoter blockers include a previously described bound element lying upstream of the CTCF core motif. In addition, we found other uncharacterised DNaseI footprints located close to the core motif that may affect function. We have developed an assay of CTCF sequences which will enable researchers to sub-classify individual CTCF elements in a uniform and unbiased way.
Background & Aims
Hepatocellular carcinoma (HCC) is one of the most common human cancers. Recently, emerging evidence has suggested the role of long non‐coding RNAs (lncRNAs) in human carcinogenesis. ...In this study, we aimed to investigate the expression and functional implications of lncRNAs in human HCC.
Methods
Eighty‐eight well‐annotated lncRNAs were profiled in primary HCC by quantitative RT‐PCR. Functional relevance of lncRNAs was elucidated in HCC cell lines and nude mice models. The regulatory relationship between miRNA and lncRNA was predicted in silico and further validated by luciferase reporter assay and expression analysis.
Results
In our profiling study, HOTTIP was identified as the most significantly up‐regulated lncRNA in human HCCs, even in early stage of HCC formation. Functionally, knock‐down of HOTTIP attenuated HCC cell proliferation in vitro and markedly abrogated tumourigenicity in vivo. In addition, knock‐down of HOTTIP also inhibited migratory ability of HCC cells and significantly abrogated lung metastasis in orthotopic implantation model in nude mice. HOTTIP is an antisense lncRNA mapped to the distal end of the HOXA gene cluster. Knock‐down of HOTTIP significantly suppressed the expression of a number of HOXA genes. Furthermore, we identified miR‐125b as a post‐transcriptional regulator of HOTTIP. Ectopic expression of miR‐125b reduced HOTTIP‐coupled luciferase activity and suppressed the endogenous level of HOTTIP. Moreover, in human HCCs, HOTTIP expression negatively correlated with that of miR‐125b.
Conclusions
HOTTIP is a novel oncogenic lncRNA, which negatively regulated by miR‐125b. Overexpression of HOTTIP contributes to hepatocarcinogenesis by regulating the expression of its neighbouring protein‐coding genes.
Superconducting magnets are crucial components in various scientific, industrial, and medical applications, offering unparalleled high magnetic fields and energy efficiency. However, the transition ...from the superconducting to the normal state, known as a quench, can pose significant challenges due to the sudden local release of stored energy and damage to the magnet system. Quench protection strategies have emerged as essential mechanisms to mitigate the adverse effects of quenches. One of the commonly used methods in accelerator magnets is to use strip heaters on coil surfaces. The heater element length and configuration influence the performance of the quench protection. The study of the quench protection by heaters requires the coupled modelling of the Joule heating, normal zone propagation, and transferring heat from the heaters to the cable. In this article, we present a new 2D finite element simulation model to model the increase of the cable resistance under different heater lengths in Nb 3 Sn accelerator magnets. The model allows analyzing heaters with several different lengths of heating stations along the cable. This strategy can be used to maximize the cable resistance increase at high operation current while still providing the needed normal zone propagation at lower currents. We demonstrate the model use with a high-field racetrack dipole model.
Background
Vonoprazan is a new acid-suppressing drug that received FDA approval in 2022. It reversibly inhibits gastric acid secretion by competing with the potassium ions on the luminal surface of ...the parietal cells (potassium-competitive acid blockers or P-CABs). Vonoprazan has been on the market for a short time and there are many clinical trials to support its clinical application. However, medical experience and comprehensive clinical data is still limited, especially on how and if, gastric histology is altered due to therapy.
Methods
A 12-week experiment trial with 30 Wistar rats was to assess the presence of gastrointestinal morphologic abnormalities upon administration of omeprazole and vonoprazan. At six weeks of age, rats were randomly assigned to one of 5 groups: (1) saline as negative control group, (2) oral omeprazole (40 mg/kg), as positive control group, (3) oral omeprazole (40 mg/kg) for 4 weeks, proceeded by 8 weeks off omeprazole, (4) oral vonoprazan (4 mg/kg), as positive control group, and (5) oral vonoprazan (4 mg/kg) for 4 weeks, proceeded by 8 weeks off vonoprazan.
Results
We identified non-inflammatory alterations characterized by parietal (oxyntic) cell loss and chief (zymogen) cell hyperplasia and replacement by pancreatic acinar cell metaplasia (PACM). No significant abnormalities were identified in any other tissues in the hepatobiliary and gastrointestinal tracts.
Conclusion
PACM has been reported in gastric mucosa, at the esophagogastric junction, at the distal esophagus, and in Barrett esophagus. However, the pathogenesis of this entity is still unclear. Whereas some authors have suggested that PACM is an acquired process others have raised the possibility of PACM being congenital in nature. Our results suggest that the duration of vonoprazan administration at a dose of 4 mg/kg plays an important role in the development of PACM.
The high luminosity LHC (HL-LHC) project is aimed at studying and implementing the necessary changes in the LHC to increase its luminosity by a factor of five. Among the magnets that will be upgraded ...are the 16 superconducting low-β quadrupoles placed around the two high luminosity interaction regions (ATLAS and CMS experiments). In the current baseline scenario, these quadrupole magnets will have to generate a gradient of 140 T/m in a coil aperture of 150 mm. The resulting conductor peak field of more than 12 T will require the use of Nb 3 Sn superconducting coils. We present in this paper the HL-LHC low-β quadrupole design, based on the experience gathered by the US LARP program, and, in particular, we describe the support structure components to pre-load the coils, withstand the electro-magnetic forces, provide alignment and LHe containment, and integrate the cold mass in the LHC IRs.
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