Augmented Renal Clearance Implies a Need for Increased Amoxicillin-Clavulanic Acid Dosing in Critically Ill Children

There is little data available to guide amoxicillin-clavulanic acid dosing in critically ill children. The primary objective of this study was to investigate the pharmacokinetics of both compounds in this pediatric subpopulation. Patients admitted to the pediatric intensive care unit (ICU) in whom intravenous amoxicillin-clavulanic acid was indicated (25 to 35 mg/kg of body weight every 6 h) were enrolled. Population pharmacokinetic analysis was conducted, and the clinical outcome was documented. A total of 325 and 151 blood samples were collected from 50 patients (median age, 2.58 years; age range, 1 month to 15 years) treated with amoxicillin and clavulanic acid, respectively. A three-compartment model for amoxicillin and a two-compartment model for clavulanic acid best described the data, in which allometric weight scaling and maturation functions were added a priori to scale for size and age. In addition, plasma cystatin C and concomitant treatment with vasopressors were identified to have a significant influence on amoxicillin clearance. The typical population values of clearance for amoxicillin and clavulanic acid were 17.97 liters/h/70 kg and 12.20 liters/h/70 kg, respectively. In 32% of the treated patients, amoxicillin-clavulanic acid therapy was stopped prematurely due to clinical failure, and the patient was switched to broader-spectrum antibiotic treatment. Monte Carlo simulations demonstrated that four-hourly dosing of 25 mg/kg was required to achieve the therapeutic target for both amoxicillin and clavulanic acid. For patients with augmented renal function, a 1-h infusion was preferable to bolus dosing. Current published dosing regimens result in subtherapeutic concentrations in the early period of sepsis due to augmented renal clearance, which risks clinical failure in critically ill children, and therefore need to be updated. (This study has been registered at Clinicaltrials.gov as an observational study [{"type":"clinical-trial","attrs":{"text":"NCT02456974","term_id":"NCT02456974"}}NCT02456974].)     

Common genetic variants do not associate with CAD in familial hypercholesterolemia

In recent years, multiple loci dispersed on the genome have been shown to be associated with coronary artery disease (CAD). We investigated whether these common genetic variants also hold value for CAD prediction in a large cohort of patients with familial hypercholesterolemia (FH). We genotyped a total of 41 single-nucleotide polymorphisms (SNPs) in 1701 FH patients, of whom 482 patients (28.3%) had at least one coronary event during an average follow up of 66 years. The association of each SNP with event-free survival time was calculated with a Cox proportional hazard model. In the cardiovascular disease risk factor adjusted analysis, the most significant SNP was rs1122608:G>T in the SMARCA4 gene near the LDL-receptor (LDLR) gene, with a hazard ratio for CAD risk of 0.74 (95% CI 0.49–0.99; P-value 0.021). However, none of the SNPs reached the Bonferroni threshold. Of all the known CAD loci analyzed, the SMARCA4 locus near the LDLR had the strongest negative association with CAD in this high-risk FH cohort. The effect is contrary to what was expected. None of the other loci showed association with CAD.     

Matrix production and remodeling capacity of cardiomyocyte progenitor cells during in vitro differentiation

Cell-based therapy has emerged as a treatment modality for myocardial repair. Especially cardiac resident stem cells are considered a potential cell source since they are able to differentiate into cardiomyocytes and have improved heart function after injury in a preclinical model for myocardial infarction. To avoid or repair myocardial damage it is important not only to replace the lost cardiomyocytes, but also to remodel and replace the scar tissue by "healthy" extracellular matrix (ECM). Interestingly, the role of cardiac stem cells in this facet of cardiac repair is largely unknown. Therefore, we investigated the expression and production of ECM proteins, matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in human cardiomyocyte progenitor cells (CMPCs) undergoing differentiation towards the cardiomyogenic lineage. Our data suggest that CMPCs have the capacity to synthesize and modulate their own matrix environment, especially during differentiation towards the cardiomyogenic lineage. While undifferentiated CMPCs expressed collagen I, III, IV and fibronectin, but no elastin, during the process of differentiation the expression of collagen I, III, IV and fibronectin increased and interestingly also elastin expression was induced. Furthermore, undifferentiated CMPCs express MMP-1 -2 and -9 and upon differentiation the expression of MMP-1 decreased, while the expression of MMP-2 and MMP-9, although the latter only in the early stage of differentiation, increased. Additionally, the expression of TIMP-1, -2 and -4 was induced during differentiation. This study provides new insights into the matrix production and remodeling capacity of human CMPCs, with potential beneficial effects for the treatment of cardiac injury.     

Plant neighbor detection through touching leaf tips precedes phytochrome signals

Plants in dense vegetation compete for resources, including light, and optimize their growth based on neighbor detection cues. The best studied of such behaviors is the shade-avoidance syndrome that positions leaves in optimally lit zones of a vegetation. Although proximate vegetation is known to be sensed through a reduced ratio between red and far-red light, we show here through computational modeling and manipulative experiments that leaves of the rosette species Arabidopsis thaliana first need to move upward to generate sufficient light reflection potential for subsequent occurrence and perception of a reduced red to far-red ratio. This early hyponastic leaf growth response is not induced by known neighbor detection cues under both climate chamber and natural sunlight conditions, and we identify a unique way for plants to detect future competitors through touching of leaf tips. This signal occurs before light signals and appears to be the earliest means of above-ground plant-plant signaling in horizontally growing rosette plants.     

Blood pressure and risk of cancer incidence and mortality in the Metabolic Syndrome and Cancer Project

Observational studies have shown inconsistent results for the association between blood pressure and cancer risk. We investigated the association in 7 cohorts from Norway, Austria, and Sweden. In total, 577799 adults with a mean age of 44 years were followed for, on average, 12 years. Incident cancers were 22184 in men and 14744 in women, and cancer deaths were 8724 and 4525, respectively. Cox regression was used to calculate hazard ratios of cancer per 10-mmHg increments of midblood pressure, which corresponded with 0.7 SDs and, for example, an increment of systolic/diastolic blood pressure of 130/80 to 142/88 mmHg. All of the models used age as the time scale and were adjusted for possible confounders, including body mass index and smoking status. In men, midblood pressure was positively related to total incident cancer (hazard ratio per 10 mmHg increment: 1.07 [95% CI: 1.04-1.09]) and to cancer of the oropharynx, colon, rectum, lung, bladder, kidney, malignant melanoma, and nonmelanoma skin cancer. In women, midblood pressure was not related to total incident cancer but was positively related to cancer of the liver, pancreas, cervix, uterine corpus, and malignant melanoma. A positive association was also found for cancer mortality, with HRs per 10-mmHg increment of 1.12 (95% CI: 1.08-1.15) for men and 1.06 (95% CI: 1.02-1.11) for women. These results suggest a small increased cancer risk overall in men with elevated blood pressure level and a higher risk for cancer death in men and women.     

A SIX-CENTRE INTERNATIONAL STUDY OF THE OUTCOME OF TREATMENT IN PATIENTS WITH CLEFTS OF THE LIP AND PALATE: THE RESULTS OF A CROSS-LINGUISTIC INVESTIGATION OF CLEFT PALATE SPEECH

During the period 1964–73, 286 patients were treated for mandibular fractures. 229 patients (80%) attended the follow-up examination. The length of observation was from 1 to 9 years. The treatment and the follow-up evaluations in the 229 patients are described. Early fracture treatment has been the objective, also in patients who have undergone severe cerebral traumas. Antibiotic prophylaxis was implemented in cases of compound fractures. Preservation of teeth and tooth buds in the line of fracture was attempted. Clinical infection occurred in 0.4% of the patients. At the follow-up examination 1 patient presented with a fracture displacement outside the condylar process. Neither malocclusion nor pseudarthrosis following fracture or after treatment were seen. Permanent sensory disturbances in the innervation area of the mental nerve following fracture occurred in 8%. Radiological examination of the teeth in the line of fracture revealed unnoticed apical bone lesions in 17% of 118 patients. In a further 23% there was a negative response to the vitality test. Follow-up control of mandibular fractures is advised at 12 to 18 months after treatment.     

High‐tech AAC and severe aphasia: Candidacy for TouchSpeak (TS)

Background: Increasingly, computerised communication aids are used by people with severe, chronic aphasia. Although the candidacy for these devices is relatively unknown, it has been hypothesised that cognitive deficits have a negative impact on the functional use of Augmentative and Alternative Communication (AAC). Deficits of executive functioning are assumed to be particularly important, but other functions, such as memory and semantic processing, may also be relevant. In a previous study (van de Sandt‐Koenderman, Wiegers, Wielaert, Duivenvoorden, & Ribbers, in press van de Sandt‐Koenderman, M., Wiegers, J., Wielaert, S. M., Duivenvoorden, H. J. and Ribbers, G. M. in press. A computerised communication aid in severe aphasia: An exploratory study.. Disability and Rehabilitation,  [Google Scholar]) we reported the functional effect of TouchSpeak (TS), a computerised communication aid, in a group of stroke patients with severe aphasia. The successful participants showed different levels of proficiency. Some were able to use the system independently and creatively in many situations, some used it independently for trained situations, and others remained partner dependent in using TS.

Aims: To find factors associated with the functional success of TS in people with severe aphasia, focusing on memory, executive functioning, semantic processing, and communication skills.

Methods & Procedures: The data of 30 patients with severe aphasia were analysed retrospectively. All were trained to use TS in two self‐chosen communicative situations. Four outcome levels were differentiated: no use, dependent use, independent use, and extensive use of TS. Pre‐training assessment included memory, executive functioning, semantic processing, and communication skills. The four outcome groups were compared regarding age, time post onset, gender, and aphasia type. The role of the cognitive variables was analysed with univariate ANCOVAs with contrast analysis, with correction for age, gender, aphasia type, or time post onset in case of significant differences between the groups on these variables.

Outcomes & Results: Seven participants were classified as extensive users of TS, five were independent TS users, and five were partner dependent. In 13 cases there was no functional use of TS. Extensive users were younger than the other outcome groups. Independent of this age effect, there was an effect of semantic processing; the no‐use group scored significantly lower on semantics than all other groups.

Conclusions: Only a minority of patients with severe aphasia may be expected to become independent, flexible users of high‐tech AAC. The finding that functional success was related to semantic processing is clinically important. Prospective studies are needed to support the predictive value of semantic processing for high‐tech AAC use. The importance of intact executive functioning is not supported in this study. The broad concept of “executive functioning” needs to be studied in more detail in relation to aphasia.