Emotional and effortful control abilities in 42-month-old very preterm and full-term children.

BACKGROUND: Very preterm (VP) infants are at greater risk for cognitive difficulties that may persist during school-age, adolescence and adulthood. Behavioral assessments report either effortful control (part of executive functions) or emotional reactivity/regulation impairments. AIMS: The aim of this study is to examine whether emotional recognition, reactivity, and regulation, as well as effortful control abilities are impaired in very preterm children at 42 months of age, compared with their full-term peers, and to what extent emotional and effortful control difficulties are linked. STUDY DESIGN: Children born very preterm (VP; < 29 weeks gestational age, n=41) and full-term (FT) aged-matched children (n=47) participated in a series of specific neuropsychological tests assessing their level of emotional understanding, reactivity and regulation, as well as their attentional and effortful control abilities. RESULTS: VP children exhibited higher scores of frustration and fear, and were less accurate in naming facial expressions of emotions than their aged-matched peers. However, VP children and FT children equally performed when asked to choose emotional facial expression in social context, and when we assessed their selective attention skills. VP performed significantly lower than full terms on two tasks of inhibition when correcting for verbal skills. Moreover, significant correlations between cognitive capacities (effortful control) and emotional abilities were evidenced. CONCLUSIONS: Compared to their FT peers, 42 month-olds who were born very preterm are at higher risk of exhibiting specific emotional and effortful control difficulties. The results suggest that these difficulties are linked. Ongoing behavioral and emotional impairments starting at an early age in preterms highlight the need for early interventions based on a better understanding of the relationship between emotional and cognitive difficulties.

Effects of nasal continuous airway pressure on pulmonary and systemic output in preterm infants

Objective: Respiratory assistance with nasal continuous positive airway pressure (n-CPAP) is an effective treatment in premature newborns presenting respiratory distress. The aim of the study was to depict cardiac function, systemic (Qs) and pulmonary output (Qp) by echocardiography in stable premature infants requiring prolonged n-CPAP. Our hypothesis was that n-CPAP could reduce pulmonary blood flow. Patients and methods: All premature infants < 32 weeks gestation, > 7 days-old, requiring n-CPAP without severe respiratory compromise nor need for additional oxygen were prospectively included. Every patient had a first echocardiography while on n-CPAP. N-CPAP was then discontinued for two hours and a second echocardiography was performed. Results: 17 premature infants were included. Mean gestational age was 28 ± 2 weeks and mean weight 1.1 ± 0.3 kg. Following retrieval of n-CPAP we observed an increase in Qp of 53 ml/kg/min (95% CI 19-87 ml/kg/min), but no significant change in Qs. Consecutively a significant increase in Qp/Qs ratio of 16% was found (95% CI 7-29%). Conclusions: Nasal continuous positive airway pressure has hemodynamic effects in preterm infants in stable pulmonary and cardiac conditions. It reduces pulmonary output without interference with systemic output.

Cognitive Predictors and Risk Factors of PTSD Following Stillbirth: A Short-Term Longitudinal Study.

This short-term longitudinal study investigated cognitive predictors and risk factors of posttraumatic stress disorder (PTSD) in mothers following stillbirth. After a stillbirth at ≥ 24 weeks gestational age, 65 women completed structured clinical interviews and questionnaires assessing PTSD symptoms, cognitive predictors (appraisals, dysfunctional strategies), and risk factors (perceived social support, trauma history, obstetric history) at 3 and 6 months. PTSD symptoms decreased between 3 and 6 months (Cohen's d ranged .34-.52). Regression analyses also revealed a specific positive relationship between Rumination and concurrent frequency of PTSD symptoms (β = .45). Negative Self-View and Negative World-View related positively and Self-Blame related negatively to concurrent number of PTSD symptoms (β = .48, .44, -.45, respectively). Suppression and Distraction predicted a decrease and Numbing predicted an increase in time-lagged number of PTSD symptoms (β = -.33, -.28, .30, respectively). Risk factors for PTSD symptoms were younger age (β = -.25), lower income (β = -.29), fewer previous pregnancies (β = -.31), and poorer perceived social support (β = -.26). Interventions addressing negative appraisals, dysfunctional strategies, and social support are recommended for mothers with PTSD following stillbirth. Knowledge of cognitive predictors and risk factors of PTSD may inform the development of a screening instrument.

Population pharmacokinetic study to evaluate dosing strategies of imipenem in neonates and infants

Objective: Imipenem is a broad spectrum antibiotic used to treat severe infections in critically ill patients. Imipenem pharmacokinetics (PK) was evaluated in a cohort of neonates treated in the Neonatal Intensive Care Unit of the Lausanne University Hospital. The objective of our study was to identify key demographic and clinical factors influencing imipenem exposure in this population. Method: PK data from neonates and infants with at least one imipenem concentration measured between 2002 and 2013 were analyzed applying population PK modeling methods. Measurement of plasma concentrations were performed upon the decision of the physician within the frame of a therapeutic drug monitoring (TDM) programme. Effects of demographic (sex, body weight, gestational age, postnatal age) and clinical factors (serum creatinine as a measure of kidney function; co-administration of furosemide, spironolactone, hydrochlorothiazide, vancomycin, metronidazole and erythromycin) on imipenem PK were explored. Model-based simulations were performed (with a median creatinine value of 46 μmol/l) to compare various dosing regimens with respect to their ability to maintain drug levels above predefined minimum inhibitory concentrations (MIC) for at least 40 % of the dosing interval. Results: A total of 144 plasma samples was collected in 68 neonates and infants, predominantly preterm newborns, with median gestational age of 27 weeks (24 - 41 weeks) and postnatal age of 21 days (2 - 153 days). A two-compartment model best characterized imipenem disposition. Actual body weight exhibited the greatest impact on PK parameters, followed by age (gestational age and postnatal age) and serum creatinine on clearance. They explain 19%, 9%, 14% and 9% of the interindividual variability in clearance respectively. Model-based simulations suggested that 15 mg/kg every 12 hours maintain drug concentrations over a MIC of 2 mg/l for at least 40% of the dosing interval during the first days of life, whereas neonates older than 14 days of life required a dose of 20 mg/kg every 12 hours. Conclusion: Dosing strategies based on body weight and post-natal age are recommended for imipenem in all critically ill neonates and infants. Most current guidelines seem adequate for newborns and TDM should be restricted to some particular clinical situations.

Pregnancy outcome after TNF-α inhibitor therapy during the first trimester: a prospective multicentre cohort study.

AIMS: TNF-α inhibitors are considered relatively safe in pregnancy but experience is still limited. The aim of this study was to evaluate the risk of major birth defects, spontaneous abortion, preterm birth and reduced birth weight after first trimester exposure to TNF-α inhibitors. METHODS: Pregnancy outcomes of women on adalimumab, infliximab, etanercept, certolizumab pegol or golimumab were evaluated in a prospective observational cohort study and compared with outcomes of a non-exposed random sample. The samples were drawn from pregnancies identified by institutes collaborating in the European Network of Teratology Information Services. RESULTS: In total, 495 exposed and 1532 comparison pregnancies were contributed from nine countries. The risk of major birth defects was increased in the exposed (5.0%) compared with the non-exposed group (1.5%; adjusted odds ratio (ORadj ) 2.2, 95% CI 1.0, 4.8). The risk of preterm birth was increased (17.6%; ORadj 1.69, 95% CI 1.1, 2.5), but not the risk of spontaneous abortion (16.2%; adjusted hazard ratio [HRadj ] 1.06, 95% CI 0.7, 1.7). Birth weights adjusted for gestational age and sex were significantly lower in the exposed group compared to the non-exposed cohort (P = 0.02). As a diseased comparison group was not possible to ascertain, the influence of disease and treatment on birth weight and preterm birth could not be differentiated. CONCLUSIONS: TNF-α inhibitors may carry a risk of adverse pregnancy outcome of moderate clinical relevance. Considering the impact of insufficiently controlled autoimmune disease on the mother and the unborn child, TNF-α inhibitors may nevertheless be a treatment option in women with severe disease refractory to established immunomodulatory drugs.

Anxiety, depression, and attachment before and after the first-trimester screening for Down syndrome: comparing couples who undergo ART with those who conceive spontaneously.

OBJECTIVES: This study's aim was to describe the emotional status of parents to be before and after the first-trimester combined prenatal screening test. METHODS: One hundred three couples participated, of which 52 had undergone an in vitro fertilization/intracytoplasmic sperm injection treatment [assisted reproductive technology (ART)] and 51 had conceived spontaneously. Participants completed the state scale of the State-trait Anxiety Inventory, the Edinburgh Depression Scale, and the Maternal and Paternal Antenatal Attachment Questionnaire before the first-trimester combined prenatal screening test at around 12 weeks of gestational age (T1) and just after receiving the results at approximately 14 weeks of gestational age (T2). RESULTS: We observed a significant decrease in anxiety and depression symptoms and a significant increase in attachment from T1 to T2. Results showed no differences between groups at either time point, which suggests that ART parents are more similar to than different from parents conceiving spontaneously. Furthermore, given the importance of anxiety during pregnancy, a subsample of women with clinical anxiety was identified. They had significantly higher rates of clinical depression and lower attachment. CONCLUSIONS: These results indicate that, regardless of whether conception was through ART or spontaneous, clinical anxiety in women over the prenatal testing period is associated with more vulnerability during pregnancy (i.e. clinical depression and less attachment to fetus). © 2015 John Wiley & Sons, Ltd.

Imaging findings in fetal diaphragmatic abnormalities.

Imaging plays a key role in the detection of a diaphragmatic pathology in utero. US is the screening method, but MRI is increasingly performed. Congenital diaphragmatic hernia is by far the most often diagnosed diaphragmatic pathology, but unilateral or bilateral eventration or paralysis can also be identified. Extralobar pulmonary sequestration can be located in the diaphragm and, exceptionally, diaphragmatic tumors or secondary infiltration of the diaphragm from tumors originating from an adjacent organ have been observed in utero. Congenital abnormalities of the diaphragm impair normal lung development. Prenatal imaging provides a detailed anatomical evaluation of the fetus and allows volumetric lung measurements. The comparison of these data with those from normal fetuses at the same gestational age provides information about the severity of pulmonary hypoplasia and improves predictions about the fetus's outcome. This information can help doctors and families to make decisions about management during pregnancy and after birth. We describe a wide spectrum of congenital pathologies of the diaphragm and analyze their embryological basis. Moreover, we describe their prenatal imaging findings with emphasis on MR studies, discuss their differential diagnosis and evaluate the limits of imaging methods in predicting postnatal outcome.

Evolution of T1 Relaxation, ADC, and Fractional Anisotropy during Early Brain Maturation: A Serial Imaging Study on Preterm Infants.

BACKGROUND AND PURPOSE: The alteration of brain maturation in preterm infants contributes to neurodevelopmental disabilities during childhood. Serial imaging allows understanding of the mechanisms leading to dysmaturation in the preterm brain. The purpose of the present study was to provide reference quantitative MR imaging measures across time in preterm infants, by using ADC, fractional anisotropy, and T1 maps obtained by using the magnetization-prepared dual rapid acquisition of gradient echo technique. MATERIALS AND METHODS: We included preterm neonates born at <30 weeks of gestational age without major brain lesions on early cranial sonography and performed 3 MRIs (3T) from birth to term-equivalent age. Multiple measurements (ADC, fractional anisotropy, and T1 relaxation) were performed on each examination in 12 defined white and gray matter ROIs. RESULTS: We acquired 107 MRIs (35 early, 33 intermediary, and 39 at term-equivalent age) in 39 cerebral low-risk preterm infants. Measures of T1 relaxation time showed a gradual and significant decrease with time in a region- and hemispheric-specific manner. ADC values showed a similar decline with time, but with more variability than T1 relaxation. An increase of fractional anisotropy values was observed in WM regions and inversely a decrease in the cortex. CONCLUSIONS: The gradual change with time reflects the progressive maturation of the cerebral microstructure in white and gray matter. Our study provides reference trajectories from 25 to 40 weeks of gestation of T1 relaxation, ADC, and fractional anisotropy values in low-risk preterm infants. We speculate that deviation thereof might reflect disturbed cerebral maturation; the correlation of this disturbed maturation with neurodevelopmental outcome remains to be addressed.

Volvulus de l'intestin grêle comme cause primaire d'abdomen aigu [Volvulus of the small intestine as a cause of primary acute abdomen].

As a cause of small intestine occlusion, volvulus is often a consequence of a band or adhesions. Except in infants, it is rarely the primary cause of symptomatology. Between January 1976 and December 1992, 13 patients (7 women and 6 men, mean age of 56.8 years) were admitted in our department for an acute abdomen due to a spontaneous primary volvulus of the small bowel. Clinical examination and laboratory tests did not help in preoperative diagnosis. All patients underwent an explorative laparotomy. Six patients had had prior abdominal surgery but none of them presented adhesion or band. In 8 patients (62%), detorsion was sufficient. Resection of a segment of small bowel was necessary in 4 patients. Gangrenous of the entire bowel was observed in one patient who rapidly died. Two patients presented minor complications. One patient with Down syndrome died of bronchoaspiration. One patient has been reoperated on one year later for recurrence of the volvulus, and underwent a Noble procedure. We conclude that volvulus of the small bowel is a rare cause of acute abdomen that must be remembered. Early surgery is mandatory to reduce the risk of gangrene, which is known to double the mortality. Laparoscopy will be helpful in early diagnosis and therapy.

Reduction of small infrarenal abdominal aortic aneurysm expansion rate by statins.

BACKGROUND: To evaluate the effect of statins on the annual expansion rate (ER) of small infrarenal abdominal aortic aneurysms (AAA). PATIENTS AND METHODS: All patients under regular surveillance for small AAA between January 2000 and September 2007, in the Department of Angiology, Lausanne University Hospital, were included. Inclusion criteria were baseline abdominal aortic diameter between 25 and 55 mm, at least two measurements of AAA diameter and a minimum follow up of 6 months. Patients with Marfan disease, infectious or inflammatory AAA, and patients with prior AAA repair were excluded. The influence of statin use and other factors on ER were examined by bivariate and multivariate analysis. RESULTS: Among 589 patients who underwent an abdominal aorta evaluation, 94 patients (89 % men, mean age 69.1 years) were finally included in the analysis. Baseline AAA size was 39.9 ± 7.7 mm (mean±SE) and 48.7 ± 8.4 mm at end of follow-up. Patients had a regular aneurysm size assessment during 38.5 ± 27.7 months. Mean ER was 3.59 mm/y (± 2.81). The 50 patients who were treated with statin during the study period had a lower ER compared to the 44 controls (2.91 vs 4.37 mm/year, p = 0.01). CONCLUSIONS: This study confirms the considerable individual variations in the AAA expansion rate, and emphasizes the need for regular aortic diameter assessments. In this study, patients treated with statin demonstrate a significant decrease in the ER compared to controls. This finding need to be evaluated in prospective interventional studies powered to demonstrate the potential benefit of statin treatment.

Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n=13) or limited-stage disease (n=7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

Small Bowel Bacterial Overgrowth is found in 71% of IBS patients and associated symptoms respond wel to Rifaximin in a phase IV trial

Background: The prevalence of small intestinal bowel bacterial overgrowth (SIBO) in patients with irritable bowel syndrome (IBS) ranges from 43% to 78% as determined by the lactulose hydrogen breath (LHBT) test. Although rifaximine, a non-absorbable antibiotic, has been able to decrease global IBS symptoms as well as bloating in placebo-controlled randomized trials, these results were not repeated in phase IV studies in daily clinical practice. Aim: To assess the prevalence of SIBO in an IBS cohort and to evaluate the treatment response in the IBS cohort affected by SIBO. Methods: Enrolled patients were diagnosed with IBS using the following criteria: fulfillment of the Rome III criteria, absence of alarm symptoms (anemia, weight loss, nocturnal symptoms etc), normal fecal calproectin, normal endoscopic workup including histology. Celiac disease was excluded by serology and/or duodenal biopsy. All patients underwent lactulose hydrogen breath testing (LHBT) for SIBO diagnosis. Patients with SIBO were treated with rifaximine tablets (400mg twice daily for 14 days). Both before and at week 6 after rifaximin treatment, patients completed a questionnaire, where the following criteria were assessed individually using 11-point Likert scales: the bloating, flatulence, abdominal pain, diarrhea, and overall well-being. Results: Hundred-fifty IBS patients were enrolled (76% female, mean age 44 ± 16 years), of whom 106 (71%) were diagnosed with SIBO and consequently treated with rifaximine. Rifaximine treatment significantly reduced the following symptoms as assessed by the symptom questionnaire: bloating (5.5 ± 2.6 before vs. 3.6 ± 2.7 after treatment, p <0.001), flatulence (5 ± 2.7 vs. 4 ± 2.7, p = 0.015), diarrhea (2.9 ± 2.4 vs. 2 ± 2.4, p = 0.005), abdominal pain (4.8 ± 2.7 vs. 3.3 ± 2.5, p <0.001) and resulted in improved overall well-being (3.9 ± 2.4 vs. 2.7 ± 2.3, p <0.001). Thirteen of the 106 treated patients were lost to follow-up (12%). The LHBT was repeated 2-4 weeks after rifaximine treatment in 65/93 (70%) patients. Eradication of SIBO was documented in 85% of all patients (55/65), whereas 15% of patients (10/65) tested positive for SIBO as determined by the LHBT testing. Conclusions: The results of our phase IV trial indicate that a high proportion of IBS patients tested positive for SIBO. IBS symptoms (bloating, flatulence, diarrhea, pain, overall well-being) were significantly diminished following a 2-week treatment with rifaximine. These results support the previous findings of randomized controlled trials that the presence of SIBO is associated with symptom generation in IBS patients and that reduction and/or elimination of SIBO may help to alleviate IBSassociated symptoms.

Morbidity, survival, and site of recurrence after mediastinal lymph-node dissection versus systematic sampling after complete resection for non-small cell lung cancer

BACKGROUND: Mediastinal lymph-node dissection was compared to systematic mediastinal lymph-node sampling in patients undergoing complete resection for non-small cell lung cancer with respect to morbidity, duration of chest tube drainage and hospitalization, survival, disease-free survival, and site of recurrence. METHODS: A consecutive series of one hundred patients with non-small-cell lung cancer, clinical stage T1-3 N0-1 after standardized staging, was divided into two groups of 50 patients each, according to the technique of intraoperative mediastinal lymph-node assessment (dissection versus sampling). Mediastinal lymph-node dissection consisted of removal of all lymphatic tissues within defined anatomic landmarks of stations 2-4 and 7-9 on the right side, and stations 4-9 on the left side according to the classification of the American Thoracic Society. Systematic mediastinal lymph-node sampling consisted of harvesting of one or more representative lymph nodes from stations 2-4 and 7-9 on the right side, and stations 4-9 on the left side. RESULTS: All patients had complete resection. A mean follow-up time of 89 months was achieved in 92 patients. The two groups of patients were comparable with respect to age, gender, performance status, tumor stage, histology, extent of lung resection, and follow-up time. No significant difference was found between both groups regarding the duration of chest tube drainage, hospitalization, and morbidity. However, dissection required a longer operation time than sampling (179 +/- 38 min versus 149 +/- 37 min, p < 0.001). There was no significant difference in overall survival between the two groups; however, patients with stage I disease had a significantly longer disease-free survival after dissection than after sampling (60.2 +/- 7 versus 44.8 +/- 8 months, p < 0.03). Local recurrence was significantly higher after sampling than after dissection in patients with stage I tumor (12.5% versus 45%, p = 0.02) and in patients with nodal tumor negative mediastinum (N0/N1 disease) (46% versus 13%, p = 0.004). CONCLUSION: Our results suggest that mediastinal lymph-node dissection may provide a longer disease-free survival in stage I non-small cell lung cancer and, most importantly, a better local tumor control than mediastinal lymph-node sampling after complete resection for N0/N1 disease without leading to increased morbidity.

Allelic variation in the VMD2 gene in best disease and age-related macular degeneration.

PURPOSE: To assess the allelic variation of the VMD2 gene in patients with Best disease and age-related macular degeneration (AMD). METHODS: Three hundred twenty-one AMD patients, 192 ethnically similar control subjects, 39 unrelated probands with familial Best disease, and 57 unrelated probands with the ophthalmoscopic findings of Best disease but no family history were screened for sequence variations in the VMD2 gene by single-strand conformation polymorphism (SSCP) analysis. Amplimers showing a bandshift were reamplified and sequenced bidirectionally. In addition, the coding regions of the VMD2 gene were completely sequenced in six probands with familial Best disease who showed no SSCP shift. RESULTS: Forty different probable or possible disease-causing mutations were found in one or more Best disease or AMD patients. Twenty-nine of these variations are novel. Of the 39 probands with familial Best disease, mutations were detected in all 39 (33 by SSCP and 6 by DNA sequencing). SSCP screening of the 57 probands with a clinical diagnosis of Best disease but no family history revealed 16 with mutations. Mutations were found in 5 of 321 AMD patients (1.5%), a fraction that was not significantly greater than in control individuals (0/192, 0%). CONCLUSIONS: Patients with the clinical diagnosis of Best disease are significantly more likely to have a mutation in the VMD2 gene if they also have a positive family history. These findings suggest that a small fraction of patients with the clinical diagnosis of AMD may actually have a late-onset variant of Best disease, whereas at the same time, a considerable fraction of isolated patients with the ophthalmoscopic features of Best disease are probably affected with some other macular disease.

Small vascular and Alzheimer disease-related pathologic determinants of dementia in the oldest-old.

The relative contributions of Alzheimer disease (AD) and vascular lesion burden to the occurrence of cognitive decline are more difficult to define in the oldest-old than they are in younger cohorts. To address this issue, we examined 93 prospectively documented autopsy cases from 90 to 103 years with various degrees of AD lesions, lacunes, and microvascular pathology. Cognitive assessment was performed prospectively using the Clinical Dementia Rating scale. Neuropathologic evaluation included the Braak neurofibrillary tangle (NFT) and β-amyloid (Aβ) protein deposition staging and bilateral semiquantitative assessment of vascular lesions. Statistics included regression models and receiver operating characteristic analyses. Braak NFTs, Aβ deposition, and cortical microinfarcts (CMIs) predicted 30% of Clinical Dementia Rating variability and 49% of the presence of dementia. Braak NFT and CMI thresholds yielded 0.82 sensitivity, 0.91 specificity, and 0.84 correct classification rates for dementia. Using these threshold values, we could distinguish 3 groups of demented cases and propose criteria for neuropathologic definition of mixed dementia, pure vascular dementia, and AD in very old age. Braak NFT staging and severity of CMI allow for defining most of demented cases in the oldest-old. Most importantly, single cutoff scores for these variables that could be used in the future to formulate neuropathologic criteria for mixed dementia in this age group were identified.