Meropenem vs standard of care for treatment of neonatal late onset sepsis (NeoMero1): A randomised controlled trial.

BACKGROUND: The early use of broad-spectrum antibiotics remains the cornerstone for the treatment of neonatal late onset sepsis (LOS). However, which antibiotics should be used is still debatable, as relevant studies were conducted more than 20 years ago, recruited in single centres or countries, evaluated antibiotics not in clinical use anymore and had variable inclusion/exclusion criteria and outcome measures. Moreover, antibiotic-resistant bacteria have become a major problem in many countries worldwide. We hypothesized that efficacy of meropenem as a broad-spectrum antibiotic is superior to standard of care regimens (SOC) in empiric treatment of LOS and aimed to compare meropenem to SOC in infants aged 44 weeks meeting the Goldstein criteria of sepsis, were randomized in a 1:1 ratio to receive meropenem or one of the two SOC regimens (ampicillin+gentamicin or cefotaxime+gentamicin) chosen by each site prior to the start of the study for 8-14 days. The primary outcome was treatment success (survival, no modification of allocated therapy, resolution/improvement of clinical and laboratory markers, no need of additional antibiotics and presumed/confirmed eradication of pathogens) at test-of-cure visit (TOC) in full analysis set. Stool samples were tested at baseline and Day 28 for meropenem-resistant Gram-negative organisms (CRGNO). The primary analysis was performed in all randomised patients and in patients with culture confirmed LOS. Proportions of participants with successful outcome were compared by using a logistic regression model adjusted for the stratification factors. From September 3, 2012 to November 30th 2014, total of 136 patients (instead of planned 275) in each arm were randomized; 140 (52%) were culture positive. Successful outcome at TOC was achieved in 44/136 (32%) in the meropenem arm vs. 31/135 (23%) in the SOC arm (p = 0.087). The respective numbers in patients with positive cultures were 17/63 (27%) vs. 10/77 (13%) (p = 0.022). The main reason of failure was modification of allocated therapy. Treatment emergent adverse events occurred in 72% and serious adverse events in 17% of patients, the Day 28 mortality was 6%. Cumulative acquisition of CRGNO by Day 28 occurred in 4% of patients in the meropenem and 12% in the SOC arm (p = 0.052). CONCLUSIONS: Within this study population, we found no evidence that meropenem was superior to SOC in terms of success at TOC, short term hearing disturbances, safety or mortality were similar in both treatment arms but the study was underpowered to detect the planned effect. Meropenem treatment did not select for colonization with CRGNOs. We suggest that meropenem as broad-spectrum antibiotic should be reserved for neonates who are more likely to have Gram-negative LOS, especially in NICUs where microorganisms producing extended spectrum- and AmpC type beta-lactamases are circulating

Water-like anomalies for core-softened models of fluids: One dimension

We use a one-dimensional (1d) core-softened potential to develop a physical picture for some of the anomalies present in liquid water. The core-softened potential mimics the effect of hydrogen bonding. The interest in the 1d system stems from the facts that closed-form results are possible and that the qualitative behavior in 1d is reproduced in the liquid phase for higher dimensions. We discuss the relation between the shape of the potential and the density anomaly, and we study the entropy anomaly resulting from the density anomaly. We find that certain forms of the two-step square well potential lead to the existence at T=0 of a low-density phase favored at low pressures and of a high-density phase favored at high pressures, and to the appearance of a point $C'$ at a positive pressure, which is the analog of the T=0 ``critical point'' in the $1d$ Ising model. The existence of point $C'$ leads to anomalous behavior of the isothermal compressibility $K_T$ and the isobaric specific heat $C_P$.Comment: 22 pages, 7 figure

Scrotal calcinosis due to resorption of cyst walls: a case report

<p>Abstract</p> <p>Introduction</p> <p>Scrotal calcinosis is a rare benign entity defined as the presence of multiple calcified nodules within the scrotal skin. There are controversies about the origin of this entity. In fact, it is still debatable whether scrotal calcinosis is an idiopathic growth or dystrophic calcification of dartoic muscles. It is also unclear whether scrotal calcinosis originates from inflammation of epidermal cysts affected by mild to moderate inflammation of mononuclear cells, from foreign body granuloma formation followed by resorption of cyst walls or from eccrine epithelial cysts.</p> <p>Case presentation</p> <p>We report a 41-year-old male Turkish patient presenting with a 10-year history of scrotal tumours increasing slowly in size and number. Histopathologically, there was no epithelial lining around the calcified nodules, but there was fibrosis adjacent to atrophic stratified squamous epithelium.</p> <p>Conclusion</p> <p>Results of histopathological examinations suggested that scrotal calcinosis might have been due to resorption of cyst walls. Surgery remains the key for this problem. In cases of non-massive scrotal calcinosis, like the case presented here, excision of the nodules from the affected part of the scrotal wall and repairing the defect with horizontal stitches offer good cosmetic results without relapse.</p

Metastable liquid-liquid phase transition in a single-component system with only one crystal phase and no density anomaly

We investigate the phase behavior of a single-component system in 3 dimensions with spherically-symmetric, pairwise-additive, soft-core interactions with an attractive well at a long distance, a repulsive soft-core shoulder at an intermediate distance, and a hard-core repulsion at a short distance, similar to potentials used to describe liquid systems such as colloids, protein solutions, or liquid metals. We showed [Nature {\bf 409}, 692 (2001)] that, even with no evidences of the density anomaly, the phase diagram has two first-order fluid-fluid phase transitions, one ending in a gas--low-density liquid (LDL) critical point, and the other in a gas--high-density liquid (HDL) critical point, with a LDL-HDL phase transition at low temperatures. Here we use integral equation calculations to explore the 3-parameter space of the soft-core potential and we perform molecular dynamics simulations in the interesting region of parameters. For the equilibrium phase diagram we analyze the structure of the crystal phase and find that, within the considered range of densities, the structure is independent of the density. Then, we analyze in detail the fluid metastable phases and, by explicit thermodynamic calculation in the supercooled phase, we show the absence of the density anomaly. We suggest that this absence is related to the presence of only one stable crystal structure.Comment: 15 pages, 21 figure

Carotid artery plaque in women with rheumatoid arthritis and low estimated cardiovascular disease risk: a cross-sectional study

INTRODUCTION: We previously reported that most patients with rheumatoid arthritis (RA) and moderate cardiovascular disease (CVD) risk according to the Systematic COronary Evaluation score (SCORE) experience carotid artery plaque. In this study, we aimed to identify patient characteristics that can potentially predict carotid plaque presence in women with RA and a concurrent low CVD risk according to the SCORE. METHODS: A cohort of 144 women with an evaluated low risk of CVD (SCORE value of zero) was assembled amongst 550 consecutive patients with RA that underwent CVD risk factor recording and carotid artery ultrasound. Participants had no established CVD, moderate or severe chronic kidney disease, or diabetes. We assessed carotid plaque(s) presence and its associated patient characteristics. RESULTS: Carotid artery plaque was present in 35 (24.3%) of women with RA. Age, the number of synthetic disease-modifying agents (DMARDs) and total cholesterol concentrations were independently associated with plaque in multivariable stepwise backward regression analysis (odds ratio (95% confidence interval)=1.15 (1.07 to 1.24), P49.5 years or/and total cholesterol concentration of >5.4 mmol/l, respectively, compared to only 7.8% in those (n=64; 44.4%) with age≤49.5 years or/and total cholesterol concentration of ≤5.4 mmol/l, respectively. CONCLUSIONS: Approximately one-third of women with RA who experience a low SCORE value and are aged >49.5 years or/and have a total cholesterol concentration of >5.4 mmol/l, experience high-risk atherosclerosis, which requires intensive CVD risk management

Analysis of metallothionein and vimentin immunoreactivity in pharyngeal squamous cell carcinoma and its microenvironment

Metallothionein (MT) has been shown to have pro-proliferative anti-apoptotic activity and to be involved in microenvironment remodeling. The aim of this study has been to determine whether the changes in MT and vimentin immunoreactivity observed in cancer and its microenvironment are related to the local spread of the disease. The immunoreactivity levels of both MT and vimentin were evaluated together with CD56 and CD57 antigens in 49 tissue samples taken from patients with squamous cell carcinoma originating from the palatine tonsils and in 20 tissue samples derived from patients with chronic tonsillitis (the reference group). MT immunoreactivity levels were statistically significantly higher in the tissue samples from squamous cell carcinoma than in those of the reference group and also higher in the squamous cell carcinoma samples compared with the stromal samples. Moreover, stromal fibroblasts exhibited high vimentin and MT immunoreactivity levels. Statistically significantly higher MT immunoreactivity levels within the tumor cells were identified in patients with the presence of lymph node metastases in contrast to those patients without such metastases. Vimentin was detected in both the tumor and the stromal tissue samples and presented an interesting pattern of staining strongly expressed within the stroma and the septal architecture of the tumor. The number of CD56- and CD57-positive lymphocytes identified in tissue samples both from squamous cell carcinoma and from the stroma was statistically significantly lower than that in the reference group. MT expression by tumor cells is thus associated with an aggressive phenotype of the tumor and the ability to create metastases

Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease

Carotid ultrasound is useful for the cardiovascular risk stratification in patients with hidradenitis suppurativa

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disease which has been associated with an increased risk of adverse cardiovascular (CV) outcomes. Adequate stratification of the CV risk is an issue of major importance in patients with HS. To analyze the usefulness of carotid ultrasound (US) assessment for the CV disease risk stratification compared with a traditional score, the Framingham risk score (FRS), in a series of patients with HS. METHODS: Cross-sectional study of 60 patients with HS without history of CV events, diabetes mellitus or chronic kidney disease. Information on CV risk factors was collected and the FRS was calculated. Thus, the patients were classified into low, intermediate and high-CV disease risk categories based on FRS. Carotid US was performed in all participants, and the presence of atherosclerotic plaques was considered as a marker of high CV risk. RESULTS: HS patients had a mean age of 45.1±10.2 years, and 55% were female. The median FRS was 5.7 (IQR: 3.1-14.7). Twenty-four (40%) of the patients were classified into the low risk group, 28 (46.7%) in the intermediate risk group, and 8 (13.3%) into the FRS-high risk category. Noteworthy, carotid US revealed that about one-third of the patients (17/52; 32.6%) in the FRS-based low and intermediate risk categories had carotid plaques, and, therefore, they were reclassified into a high-risk category. CONCLUSION: CV risk in HS patients may be underestimated by using the FRS. Carotid US may be useful to improve the CV risk stratification of patients with HS.This study was funded through an unrestricted grant provided by AbbVie to MGL. AbbVie has not played any role in study design, data collection and analysis, decision to publish or preparation of the manuscript