Concomitant and noncanonical JAK2 and MPL mutations in JAK2V617F‐ and MPLW515 L‐positive myelofibrosis

Sequential genotyping for phenotype‐driver mutations in JAK2 (exon 14), CALR (exon 9), and MPL (exon 10) is recommended in patients with myeloproliferative neoplasms. Yet, atypical JAK2‐ and MPL‐mutations were described in some triple‐negative patients. Whether noncanonical and/or concomitant JAK2‐ and MPL‐mutations exist in myelofibrosis (MF) regardless of phenotype‐driver mutations is not yet elucidated. For this, next‐generation sequencing (NGS) was performed using blood genomic DNA from 128 MF patients (primary MF, n = 93; post‐ET–MF, n = 18; post‐PV–MF, n = 17). While no atypical JAK2‐ or MPL‐mutations were seen in 24 CALR‐positive samples, two JAK2‐mutations [c.3323A > G, p.N1108S; c.3188G > A, p.R1063H] were detected in two of the 21 (9.5%) triple‐negative patients. Twelve of the 82 (14.6%) JAK2V617F‐positive cases had coexisting germline JAK2‐mutations [JAK2R1063H, n = 6; JAK2R893T, n = 1; JAK2T525A, n = 1] or at least one somatic MPL‐mutation [MPLY591D, n = 3; MPLW515 L, n = 2; MPLE335K, n = 1]. Overall, MPL‐mutations always coexisted with JAK2V617F and/or other MPL‐mutations. None of the JAK2V617F plus a second JAK2‐mutation carried a TET2‐mutation but all patients with JAK2V617F plus an MPL‐mutation harbored a somatic TET2‐mutation. Four genomic clusters could be identified in the JAK2V617F‐positive cohort. Cluster‐I (10%) (noncanonical JAK2_{mutated (mut)} + TET2_{wildtype (wt)}) were younger and had less proliferative disease compared with cluster‐IV (5%) (TET2_mut + MPL_mut). In conclusion, recurrent concomitant classical and/or noncanonical JAK2‐ and MPL‐mutations could be detected by NGS in 15.7% of JAK2V617F‐ and MPLW515‐positive MF patients with genotype‐phenotype associations. Many of the germline and/or somatic mutations might act as “Significantly Mutated Genes” contributing to the pathogenesis and phenotypic heterogeneity. A cost‐effective NGS‐based approach might be an important step towards patient‐tailored medicine.     

An investigation into Merseyside General Dental Practitioners' interest in primary care research, their views on research and their training needs.

OBJECTIVES: The aims of this investigation were to evaluate the interests of primary care dental practitioners within the Mersey Postgraduate Deanery in research and their views on research, their experience and research training needs. METHOD: A questionnaire was sent to all practitioners in the Mersey Deanery asking for views on dental research, whether they had been involved in any research projects or had any research training, and whether they would be interested in research training and being part of a primary dental care research network. RESULTS: A total of 192 practitioners from the 1120 in the Mersey Deanery expressed an interest in being involved in primary care research. Most believed that primary care research was very important in providing a stronger evidence-base in dentistry and improved quality of dental care. Over 50% of respondents were interested in collaborative research, provided that their income and time could be protected and it was part of the normal working day. Almost 25% had some research experience and a number had undergone research training, ranging from informal training to part of a degree. CONCLUSIONS: A number of GDPs in the Mersey Deanery are interested in primary care research. With appropriate training, support and recognition within the new Personal Dental Services (PDS) contracts, there is a golden opportunity for more primary care dentists to participate in research. This, in time, will add to the evidence base in dentistry and should improve patient care.     

Residual ridge resorption in the edentulous maxilla in patients with implant-supported mandibular overdentures: an 8-year retrospective study

PURPOSE: This retrospective study radiologically investigated alveolar bone resorption in the edentulous maxilla in patients with implant-supported mandibular overdentures. MATERIALS AND METHODS: This study consisted of 35 healthy, completely edentulous patients with a mean age of 59.7 years. They had received two implants between the mental foramina. New bar-retained mandibular overdentures and maxillary complete dentures were fabricated. Standardized panoramic radiographs taken subsequent to loading and at annual recall visits for up to 8 years were measured for alveolar bone loss in the maxilla. Bone areas and areas of reference not subject to resorption were measured with a planimetry program. The proportional value between both was expressed as a ratio (R). Bone loss was expressed as a change in R between two time points. Differences in the resorption rate between the anterior and posterior parts of the maxilla were investigated. RESULTS: Residual ridge resorption continued during the follow-up period and revealed high individual variability. With a range of 5% to 11% (median) loss in the original bone height, it was significantly (P < .031) more pronounced in the anterior than posterior maxilla (2% to 7%) from the second through eighth years. Regression analysis of the medians revealed a relatively high correlation between time and bone loss in both anterior and posterior parts of the maxilla. CONCLUSION: The anterior anchorage of mandibular overdentures by means of two implants and an ovoid bar was associated with slightly higher resorption in the anterior than in the posterior part of the edentulous maxilla.     

Response to glucose tolerance testing and solid high carbohydrate challenge: comparison between Roux-en-Y gastric bypass, vertical sleeve gastrectomy, and duodenal switch

Background

Hyperinsulinemic hypoglycemia is common after Roux-en-Y gastric bypass (RYGB) and may result in weight regain. The purpose of our investigation was to compare the effect of RYGB, vertical sleeve gastrectomy (VSG), and duodenal switch (DS) on insulin and glucose response to carbohydrate challenge.

Methods

Patients meeting National Institutes of Health criteria for bariatric surgery selected their bariatric procedure after evaluation and education in this prospective nonrandomized study. Preoperatively and at 6, 9, and 12 months’ follow-up, patients underwent blood draw to determine levels of fasting glucose, fasting insulin, glycated hemoglobin (HbA1c), C-peptide, and 2-h oral glucose challenge test. Homoeostatic Model Assessment (HOMA)-IR, fasting to 1-h and 1- to 2-h ratios of glucose and insulin, were calculated. Statistical analysis was performed using ANOVA and Student’s paired t test. All procedures were performed via a laparoscopic technique at a single institution.

Results

Data from a total of 38 patients (13 RYGB, 12 VSG, 13 DS) were available for analysis. At baseline, all groups were similar; the only statistically significant difference was that DS patients had a higher preoperative weight and body mass index (BMI). All operations caused weight loss (BMI 47.7 ± 10–30.7 ± 6.4 kg/m² in RYGB; 45.7 ± 8.5–31.1 ± 5.5 kg/m² in VSG; 55.9 ± 11.4–27.5 ± 5.6 kg/m² in DS), reduction of fasting glucose, and improved insulin sensitivity. RYGB patients had a rapid rise in glucose with an accompanying rise in 1-h insulin to a level that exceeded preoperative levels. This was followed by a rapid decrease in glucose level. In comparison, DS patients had a lower increase in glucose and 1-h insulin, and the lowest HbA1c. These differences were statistically significant at various data points. For VSG, the results were intermediary.

Conclusions

Compared to gastric bypass, DS results in greater weight loss and improves insulin sensitivity and glucose homeostasis without causing a hyperinsulinemic response. Because the response to challenge after VSG is intermediary, pyloric preservation alone cannot account for this difference.     

A Better Landmark for Positioning a Central Venous Catheter

Background.Improper positioning of central venous catheters (CVCs) can lead to erosion through the superior vena cava (SVC) or right atrium (RA) and pericardial tamponade. It is widely recommended that the tip of CVCs be placed above the heart or the pericardial reflection. The purpose of this study was to identify an easily recognized landmark to allow identification of the proximal extent of the pericardial reflection on a routine chest radiograph (CXR). Methods.We analyzed the computerized tomograms of the chest from 97 adults to evaluate the relationship between the pericardial reflection, SVC, carina, and right mainstem bronchus. Correlations between demographic data and length of SVC or pericardial reflection were sought. Results.The mean length of the SVC was 6.5 cm. The pericardial reflection covered an average of 3.6 cm of the distal SVC. The carina was a mean of 1.3 cm below the mid-point of the SVC and 0.7 cm below the pericardial reflection. There was no significant correlation between SVC or pericardial length and either age, height, or weight. Conclusions.The distal half of the SVC lies within the pericardial reflection, and the upper limit of the pericardial reflection is slightly above the level of the carina. These landmarks are useful for determining proper position of the tip of a CVC on CXR.     

Weight-adjusted resting energy expenditure is not constant in critically ill patients

Objective In critically ill patients, energy requirements are frequently calculated as a multiple of total body weight presuming a linear relationship between total body weight and resting energy expenditure (REE); however, it is doubtful if this estimation of energy needs should be applied to all patients, particularly to overweight patients, since adipose tissue has a low contribution to REE. This study was undertaken to test the hypothesis that REE adjusted for total body weight decreases with increasing body mass index in critically ill patients. Additionally, measured REE was compared with three predictive equations. Design and Setting Clinical study in a university hospital intensive care unit. Patients One hundred critically ill patients admitted to the intensive care unit. Measurements and results Patients were included into four groups according to their body mass index (normal weight, pre-obese, obese, and morbidly obese). Measured REE was assessed using indirect calorimetry. Energy needs were calculated using the basal metabolic rate, the Consensus Statement of the American College of Chest Physicians (REEacs), and 25 kcal/kg of ideal body weight (REEibw). Adjusted REE was 24.8 ± 5.5 kcal/kg in normal weight, 22.0 ± 3.7 kcal/kg in pre-obese, 20.4 ± 2.6 kcal/kg in obese, and 16.3 ± 2.3 kcal/kg in morbidly obese patients (p < 0.01). Basal metabolic rate underestimated measured REE in normal weight and pre-obese patients. REEacs and REEibw over- and underestimated measured REE in overweight patients, respectively. Conclusions Predictive equations were not able to estimate measured REE adequately in all the patients. Adjusted REE decreased with increasing body mass index; thus, a body mass index group-specific adaptation for the estimation of energy needs should be applied.