Persistent osteoarticular pain in children: early clinical and laboratory findings suggestive of acute lymphoblastic leukemia (a multicenter case-control study of 147 patients).

BACKGROUND: The aim of this study was to identify early clinical and laboratory features that distinguish acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA) in children presenting with persistent bone or joint pain for at least 1 month. METHODS: We performed a multicenter case-control study and reviewed medical records of children who initially presented with bone or joint pain lasting for at least 1 month, all of whom were given a secondary diagnosis of JIA or ALL, in four French University Hospitals. Each patient with ALL was paired by age with two children with JIA. Logistic regression was used to compare clinical and laboratory data from the two groups. RESULTS: Forty-nine children with ALL and 98 with JIA were included. The single most important feature distinguishing ALL from JIA was the presence of hepatomegaly, splenomegaly or lymphadenopathy; at least one of these manifestations was present in 37 cases with ALL, but only in 2 controls with JIA, for an odds ratio (OR) of 154 [95%CI: 30-793] (regression coefficient: 5.0). If the presence of these findings is missed or disregarded, multivariate analyses showed that non-articular bone pain and/or general symptoms (asthenia, anorexia or weight loss) (regression coefficient: 4.8, OR 124 [95%CI: 11.4-236]), neutrophils < 2 × 109/L (regression coefficient: 3.9, OR 50 [95%CI: 4.3-58]), and platelets < 300 × 109/L (regression coefficient: 2.6, OR 14 [95%CI: 2.3-83.9]) were associated with the presence of ALL (area under the ROC curve: 0.96 [95%CI: 0.93-0.99]). CONCLUSIONS: Based on our findings we propose the following preliminary decision tree to be tested in prospective studies: in children presenting with at least 1 month of osteoarticular pain and no obvious ALL in peripheral smear, perform a bone marrow examination if hepatomegaly, splenomegaly or lymphadenopathy is present. If these manifestations are absent, perform a bone marrow examination if there is fever or elevated inflammatory markers associated with non-articular bone pain, general symptoms (asthenia, anorexia or weight loss), neutrophils < 2 × 109/L or platelets < 300 × 109/L.

Predictive factors associated with involved margins in breast cancer treated with neoadjuvant chemotherapy followed by breast-conserving therapy.

INTRODUCTION: This study sought to identify predictive factors of involved surgical margins in breast-conserving surgery (BCS) after neoadjuvant chemotherapy (NAC) to help guide the surgical procedure. MATERIALS AND METHODS: Retrospective study of patients who had BCS after NAC between January 2008 and December 2013. OUTCOME MEASURE: tumor-involved margin, defined by tumor cells on ink for invasive cancer and tumor-free margin < 2 mm for DCIS. RESULTS: Ninety-seven patients were included. The median age of patients was 46 years old [28-71]. The initial average tumor size was 47.8 mm [+/- 18.6]. Twelve patients (12.4%) had involved tumor margins on final histology after BCS and NAC. According to the multivariate model including only preoperative variables of positive margins, initial ultrasound tumor size ≤ 27 mm (p = 0.045) and low SBR grade (p = 0.009) were independently associated with tumor-involved margins. According to the multivariate model including pre- and postoperative variables of positive margins, ductal carcinomain situ was also independently associated with tumor-involved margins (p = 0.021). CONCLUSION: Initial ultrasound tumor size ≤ 27 mm and low SBR grade were independently associated with tumor-involved margins. These preoperative data were very helpful to guide the surgical procedure in breast cancer.

Consumption of a Carbonated Beverage with High-Intensity Sweeteners Has No Effect on Insulin Sensitivity and Secretion in Nondiabetic Adults.

Background: The effects of the regular intake of beverages containing high-intensity sweeteners on insulin sensitivity in healthy individuals remain controversial. Objective: This trial compared the effects of the consumption of a carbonated beverage containing aspartame and acesulfame K (high-intensity sweeteners beverage-HISB) with those of an unsweetened, no-calorie carbonated beverage (UB) on insulin sensitivity and secretion in nondiabetic adults. Methods: SEDULC was a randomized, double-blind, crossover study. Nondiabetic adults [mean age 31 y, 44% men, body mass index (BMI; kg/m²) 19-29] who did not consume high-intensity sweeteners were randomized 1:1 to drink 1 of the 2 carbonated beverages, 2 cans (330 mL each)/d, for 12 wk. After a 4-wk washout period, participants were switched to the opposite beverage for 12 wk. The primary outcome tested was the change in insulin sensitivity as assessed by the Matsuda Insulin Sensitivity Index (MISI) after an oral glucose load. Secondary outcomes were indexes of insulin secretion. Results: Sixty individuals were enrolled and 50 completed the study (28 nonoverweight and 22 overweight participants). The change in MISI from baseline did not significantly differ between beverages and noninferiority was demonstrated (difference = -0.23; 95% CI: -1.31, 0.85; P < 0.0001). The change in insulinogenic (means ± SEMs: 0.23 ± 0.14 for HISB compared with 0.08 ± 0.1 for UB) and disposition indexes (2.70 ± 0.99 for HISB compared with 1.62 ± 0.90 for UB) did not differ, and no differences in insulin secretion estimates were confirmed by the Stumvoll indexes. Consuming the high-intensity sweeteners did not affect body weight, self-reported dietary consumption, or self-reported physical activity. Conclusions: These findings suggest that the daily consumption of 2 cans of a beverage containing aspartame and acesulfame K over 12 wk has no significant effect on insulin sensitivity and secretion in nondiabetic adults. This trial was registered at clinicaltrials.gov as NCT02031497.

A prospective study of the frequency of severe pain and predictive factors in women undergoing first-trimester surgical abortion under local anaesthesia.

OBJECTIVE: To determine the frequency of severe pain among women and to identify the associated predictive factors during first-trimester surgical abortion under local anaesthesia (LA). STUDY DESIGN: A prospective cohort study from November 2013 to January 2014 at the Department of Gynecology and Obstetrics, Rennes, France. The study population was composed of one hundred and ninety-four patients who underwent an elective first-trimester surgical abortion under LA. In an anonymized questionnaire, the participants were asked to self-record their perceived pain level 30 min after the completion of the procedure using a 10 cm visual analogue scale (VAS). The main outcome measure was the frequency of severe pain among women, defined as VAS ≥ 7. Secondary outcome measure was the risk factor(s) for severe pain. RESULTS: Severe pain (i.e. VAS ≥ 7) was experienced by 46% (95% CI: 39%-53%) of the population. Multivariate analysis confirmed that >10 weeks of gestation (OR: 2.530 [95% CI: 1.1-5.81], p = .0287) and having 0 or 1 child (OR: 5.206 [95% CI: 1.87-14.49], p = .0016) were significant independent factors of severe pain. CONCLUSION: Nearly half of the women experienced severe pain. More than 10 weeks of gestation and parity were predictive factors of severe pain. These findings should be useful in counselling women undergoing surgical abortion under LA.

Should We Pay Attention to the Delay Before Admission to a Pediatric Intensive Care Unit for Children With Cancer? Impact on 1-Month Mortality. A Report From the French Children's Oncology Study Group, GOCE.

Acute complications requiring admission to pediatric intensive care unit (PICU) are frequent for children with cancer. Our objective was to determine early prognostic factors of mortality in a cohort of children with cancer hospitalized in PICU for acute complications and particularly to assess whether the delay before admission to a PICU is an early predictor of mortality. We conduct a retrospective multicenter analysis. All patients transferred in PICU for acute complications between January 2002 and December 2012 were included. One-month mortality of the 224 patients analyzed was 24.5%. Delay before PICU admission was a significant prognostic factor of 1-month mortality with nonsurvivors experiencing a longer median delay than survivors (24 vs. 12 h, respectively, P<0.05). Time from diagnosis to PICU admission (P<0.001), hematopoietic stem cell transplant (P<0.05), the duration of neutropenia (P<0.01), infection type (P<0.001), number of organ dysfunctions (P<0.001), and reaching any grade 4 toxicity before PICU admission (P<0.001) also affected mortality rate at 1-month post-PICU discharge. In the multivariate analysis, only reaching any grade 4 toxicity before PICU admission influenced 1-month mortality (odds ratio, 2.30; 95% confidence interval, 1.07-4.96; P<0.05). These results suggest that PICU admission before severe impairment leads to a better outcome for children with cancer.

ITPA deficiency and ribavirin level are still predictive of anaemia in HCV-HIV-coinfected patients receiving ribavirin combined with a first-generation DAA (ANRS HC27 study).

BACKGROUND: We aimed to determine the impact of inosine triphosphatase (ITPA) deficiency on ribavirin (RBV)-induced anaemia in HIV-HCV-coinfected patients receiving a triple therapy including the haematotoxic direct-acting antiviral agent boceprevir (BOC). METHODS: Patients of the ANRS HC27 BocepreVIH study were genotyped for two ITPA single nucleotide polymorphisms involved in ITPA deficiency. RBV trough concentration (Ctrough) was determined at week (W)4 and W8. Impact of ITPA deficiency on anaemia, RBV Ctrough, response and haematotoxicity (grade 3/4 anaemia, erythropoietin [EPO] use, RBV dose reduction or transfusion between day [D]0 and W8) was evaluated. Impact of RBV Ctrough on anaemia was also studied. RESULTS: Among the 63 genotyped patients, 33% had a predicted ITPA deficiency. ITPA deficiency was associated with a lower haemoglobin (Hb) decline both at W4 (-1.0 g/dl versus -2.1 g/dl; P=0.02) and W8 (-2.7 g/dl versus -4.1 g/dl; P=0.05). None of the patients with ITPA deficiency received EPO between D0-W8 versus 26% of patients without ITPA deficiency (P=0.01). RBV Ctrough was associated with Hb decrease both at W4 and W8 and an RBV Ctrough cutoff value of 2 µg/ml was significantly associated with a W4 Hb decline >2 g/dl. Haematotoxicity was significantly associated with a lower W4 Hb level (P=0.017), absence of ITPA deficiency (P=0.018) and higher RBV Ctrough (P=0.012). ITPA deficiency, W4 RBV Ctrough and gender were independent predictors of anaemia at W4. ITPA deficiency was not associated with virological response. CONCLUSIONS: ITPA deficiency and RBV Ctrough are still predictive of RBV-induced anaemia in HIV-HCV-coinfected patients treated with RBV combined with a first-generation direct antiviral agent.

Decline of multidrug-resistant Gram negative infections with the routine use of a multiple decontamination regimen in ICU.

OBJECTIVES: We have shown that the routine use of a multiple decontamination regimen with oropharyngeal and digestive polymyxin/tobramycin/amphotericin B plus mupirocin/chlorhexidine in intubated patients reduced all-cause acquired infections (AIs) in the intensive care unit (ICU). We now assessed the long-term impact of this strategy on AIs involving multidrug-resistant aerobic Gram negative bacilli (AGNB) and acquired episodes of extended-spectrum betalactamase (ESBL)-producing Enterobacteriaceae rectal carriage. METHODS: This was an observational single center study of all patients admitted to an ICU over 5 years (study population). Decontamination was given for the period of intubation and standard care otherwise. AIs and colonization rates were prospectively recorded. AIs rates were compared between the study period and a 1-year pre-intervention period. During study, trends were analyzed by semester using a Poisson regression model. RESULTS: The incidence rate of multidrug-resistant AGNB AIs was lower during the study (1.59 per 1000 patient-days, versus pre-intervention: 5.43‰, p < 0.001) and declined with time (adjusted OR = 0.85, 95 percent confidence interval 0.77-0.93, p < 0.001). ESBL-producing Enterobacteriaceae acquired colonization episodes (OR = 0.94 [0.88-1.00] P = 0.04) and the use of five major antibiotics (p < 0.001) also declined. CONCLUSION: A multiple decontamination regimen did not favor the emergence of multidrug-resistant AGNB. In contrast, infection and colonization rates declined with time.

Keep in Mind Quality of Life: Outcome of a Ten-Year Series of Post-Transplantation Early Relapses in Childhood Acute Lymphoblastic Leukemia-A Report from the Grand Ouest Oncology Study Group for Children in France.

Relapses of acute lymphoblastic leukemia (ALL) early after hematopoietic stem cell transplantations in children are uncommon but associated with a very poor prognosis. Whereas there are no current recommendations for the management of these relapses, the children's quality of life is an important issue. We studied the outcomes, including 1-year overall survival, complete remission, and quality of life, of 19 children with ALL who relapsed within the first year after their transplantation treated in the 5 participating centers between 2000 and 2011 Patients were distributed as follows: supportive care only (group A), outpatient treatment (mainly steroid and vincristine, group B), or intensive inpatient treatment (group C). There were no significant differences in 1-year overall survival (31.5% for the entire cohort) or remission rate for time between transplantation and relapse (< 6 months or 6 to 12 months), transplantation or disease characteristics, or treatment group. However, time spent in hospital (for treatment and complications) significantly differed between treatment groups B and C (20.8% ± 13.0 versus 59.1% ± 32.9, respectively; P < .05). No differences in organ toxicities, school attendance, or Lansky scores were found between treatment groups. Our sample size-limited data indicate, in a prepersonalized medicine era, that children treated with steroid and vincristine have the same prognosis as those treated with intensive therapy, but they may benefit from improved quality of life. Nevertheless, new therapeutic strategies are required and future prospective trials would help to establish recommendations.

Effects of TRP channel agonist ingestion on metabolism and autonomic nervous system in a randomized clinical trial of healthy subjects.

Various lines of published evidence have already demonstrated the impact of TRPV1 agonists on energetic metabolism through the stimulation of the sympathetic nervous system (SNS). This study presents a trial investigating if stimulation of the two related sensory receptors TRPA1 and TRPM8 could also stimulate the SNS and impact the energetic metabolism of healthy subjects. The trial was designed to be double-blinded, randomized, cross-over, placebo-controlled with healthy subjects and the impact on the energetic metabolism and the autonomic nervous system (ANS) of cinnamaldehyde, capsaicin and a cooling flavor was measured during the 90 min after ingestion. Energy expenditure and substrate oxidation were measured by indirect calorimetry. An exploratory method to measure ANS activity was by facial thermography and power spectral analysis of heart rate variability using ECG was also used. Following cinnamaldehyde ingestion, energy expenditure was increased as compared to placebo. Furthermore, postprandial fat oxidation was maintained higher compared to placebo after cinnamaldehyde and capsaicin ingestion. Similar peripheral thermoregulation was observed after capsaicin and cinnamaldehyde ingestion. Unlike capsaicin, the dose of cinnamaldehyde was not judged to be sensorially 'too intense' by participants suggesting that Cinnamaldehyde would be a more tolerable solution to improve thermogenesis via spicy ingredients as compared to capsaicin.

Autism as a disorder of biological and behavioral rhythms: toward new therapeutic perspectives.

There is a growing interest in the role of biological and behavioral rhythms in typical and atypical development. Recent studies in cognitive and developmental psychology have highlighted the importance of rhythmicity and synchrony of motor, emotional, and interpersonal rhythms in early development of social communication. The synchronization of rhythms allows tuning and adaptation to the external environment. The role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of the circadian clocks network suggests that this hormone might be also involved in the synchrony of motor, emotional, and interpersonal rhythms. Autism provides a challenging model of physiological and behavioral rhythm disturbances and their possible effects on the development of social communication impairments and repetitive behaviors and interests. This article situates autism as a disorder of biological and behavioral rhythms and reviews the recent literature on the role of rhythmicity and synchrony of rhythms in child development. Finally, the hypothesis is developed that an integrated approach focusing on biological, motor, emotional, and interpersonal rhythms may open interesting therapeutic perspectives for children with autism. More specifically, promising avenues are discussed for potential therapeutic benefits in autism spectrum disorder of melatonin combined with developmental behavioral interventions that emphasize synchrony, such as the Early Start Denver Model.

Ultrasound evaluation of cervical regeneration after LLETZ for cervical intraepithelial neoplasia: a prospective observational study.

OBJECTIVES: To assess cervical regeneration after large loop excision of the transformation zone (LLETZ) by ultrasound (US) measurements of cervical length (CL) before conization as well as in the postoperative short- and long-term and to identify factors affecting regeneration. PATIENTS AND METHODS: This was a prospective observational study including patients under 45 years of age treated by LLETZ for Cervical Intraepithelial Neoplasia (CIN) with repeated measurements of CL by transvaginal US before and just after LLETZ, at 1 and 6 months postoperatively. RESULTS: A total of 83 patients were enrolled, out of which 53 were included in the study. The mean CL was 28.6 mm (±5.7) preoperatively versus 18.3 mm (±4.2) after surgery; 21.8 mm (±4.4) at 1 month and 25.5 mm (±4.9) at 6 months. The mean cone length estimated by US was 10.3 mm (±3.4). The differences in CL before/after conization and CL after conization/at 6 months were statistically significant (p<0.0001). Cervical regeneration at 6 months was 71% (±20), statistically greater than regeneration at 1 month (32%, ±16) (p<0.0001). DISCUSSION: Post-conization cervical tissue regeneration occurred with almost three quarters of the initial cervical length restored at 6 months. Further studies evaluating obstetric outcomes after LLETZ according to cervical regeneration might subsequently be used in clinical practice to identify high-risk pregnancies by pre- and postoperative US measurements of the cervical length. A rigorous assessment of CIN treatment risks and benefits remains essential when considering treating patients of childbearing age given a potential obstetric risk from conization.

Effects of pre-exercise sucralose ingestion on carbohydrate oxidation during exercise.

Recent studies have demonstrated a direct link between increased exogenous CHO oxidation (CHOexog) and enhanced performance. The limiting factor for CHOexog appears to be at the level of intestinal transporters, with sodium/glucose cotransporter 1 (SGLT1) and glucose transporter Type 5 (GLUT5) responsible for glucose and fructose transport, respectively. Studies in animal models have shown that SGLT1 and intestinal glucose uptake are up-regulated by high carbohydrate diets or noncaloric sweeteners. The aim of this study was to determine the effect of preexercise ingestion of noncaloric sweeteners on CHOexog during exercise in athletes. In a randomized, crossover, double-blind fashion twenty-three healthy male cyclists (age = 29 ± 7 yrs, mass = 73.6 ± 7.4 kg, VO2peak = 68.3 ± 9.3 ml/kg/min) consumed 8 × 50 ml doses of either placebo (CON) or 1mM sucralose (SUCRA) every 15 min starting 120 min before the onset of exercise. This was followed by 2h of cycling at 48.5 ± 8.6% of VO2peak with continual ingestion of a maltodextrin drink (1.2 g/min; 828 ml/ hr). Average CHOexog during the first hour of exercise did not differ between SUCRA and CON conditions (0.226 ± 0.081 g/min vs. 0.212 ± 0.076 g/min, Δ =0.015 g/min, 95% CI -0.008 g/min, 0.038 g/min, p = .178). Blood glucose, plasma insulin and lactate, CHO and fat substrate utilization, heart rate, ratings of perceived exertion, and gastrointestinal symptoms did not differ between conditions. Our data suggest that consumption of noncaloric sweeteners in the immediate period before exercise does not lead to a significant increase in CHOexog during exercise.