Carbon dioxide levels in neonates: what are safe parameters?

There is no consensus on the optimal pCO2 levels in the newborn. We reviewed the effects of hypercapnia and hypocapnia and existing carbon dioxide thresholds in neonates. A systematic review was conducted in accordance with the PRISMA statement and MOOSE guidelines. Two hundred and ninety-nine studies were screened and 37 studies included. Covidence online software was employed to streamline relevant articles. Hypocapnia was associated with predominantly neurological side effects while hypercapnia was linked with neurological, respiratory and gastrointestinal outcomes and Retinpathy of prematurity (ROP). Permissive hypercapnia did not decrease periventricular leukomalacia (PVL), ROP, hydrocephalus or air leaks. As safe pCO2 ranges were not explicitly concluded in the studies chosen, it was indirectly extrapolated with reference to pCO2 levels that were found to increase the risk of neonatal disease. Although PaCO2 ranges were reported from 2.6 to 8.7 kPa (19.5-64.3 mmHg) in both term and preterm infants, there are little data on the safety of these ranges. For permissive hypercapnia, parameters described for bronchopulmonary dysplasia (BPD; PaCO2 6.0-7.3 kPa: 45.0-54.8 mmHg) and congenital diaphragmatic hernia (CDH; PaCO2 ≤ 8.7 kPa: ≤65.3 mmHg) were identified. Contradictory findings on the effectiveness of permissive hypercapnia highlight the need for further data on appropriate CO2 parameters and correlation with outcomes. IMPACT: There is no consensus on the optimal pCO2 levels in the newborn. There is no consensus on the effectiveness of permissive hypercapnia in neonates. A safe range of pCO2 of 5-7 kPa was inferred following systematic review.

Implantable biosensors and their contribution to the future of precision medicine.

Precision medicine can be defined as the prevention, investigation and treatment of diseases taking individual variability into account. There are multiple ways in which the field of precision medicine may be advanced; however, recent innovations in the fields of electronics and microfabrication techniques have led to an increased interest in the use of implantable biosensors in precision medicine. Implantable biosensors are an important class of biosensors because of their ability to provide continuous data on the levels of a target analyte; this enables trends and changes in analyte levels over time to be monitored without any need for intervention from either the patient or clinician. As such, implantable biosensors have great potential in the diagnosis, monitoring, management and treatment of a variety of disease conditions. In this review, we describe precision medicine and the role implantable biosensors may have in this field, along with challenges in their clinical implementation due to the host immune responses they elicit within the body.

Quality control metrics improve repeatability and reproducibility of single-nucleotide variants derived from whole-genome sequencing.

Although many quality control (QC) methods have been developed to improve the quality of single-nucleotide variants (SNVs) in SNV-calling, QC methods for use subsequent to single-nucleotide polymorphism-calling have not been reported. We developed five QC metrics to improve the quality of SNVs using the whole-genome-sequencing data of a monozygotic twin pair from the Korean Personal Genome Project. The QC metrics improved both repeatability between the monozygotic twin pair and reproducibility between SNV-calling pipelines. We demonstrated the QC metrics improve reproducibility of SNVs derived from not only whole-genome-sequencing data but also whole-exome-sequencing data. The QC metrics are calculated based on the reference genome used in the alignment without accessing the raw and intermediate data or knowing the SNV-calling details. Therefore, the QC metrics can be easily adopted in downstream association analysis.

Attitudes of parents and staff towards medical students on the paediatric wards.

This study investigates attitudes of parents and staff to medical students on paediatric wards in a Dublin teaching hospital. We invited 100 parents of patients and 30 staff involved in the care of children on the paediatric wards to participate. The majority of parents agreed or strongly agreed that they would be happy for a student to interview them (n = 87; (87%)), interview their child (80%) or examine their child (74%). Of 30 staff, 12 (40%) staff agreed that the presence of medical students on the ward increased their job satisfaction, 13 (43%) agreed or strongly agreed that medical student presence encouraged them to keep up to date with recent medical developments and 6 (20%) felt that it increased the quality of patient care. Attitudes of both parents and staff to medical students on paediatric wards are positive with both emphasising the need for professional behaviour.

Cutaneous melanoma with metastasis in a cynomolgus monkey (Macaca fascicularis).

BACKGROUND: A 3.3-year-old-male cynomolgus macaque (Macaca fascicularis) showed a focally extensive soft, dark, discoid dermal mass, 0.5 cm in diameter, on the dorsal surface of the right hind foot, over the fourth and fifth metatarsal bones. METHODS AND RESULTS Microscopic examination revealed a cutaneous melanoma with local lymphatic invasion, characterized by neoplastic melanocytes within the subcapsular sinus of popliteal and inguinal lymph nodes. The diagnosis was confirmed by immunohistochemistry and transmission electron microscopy. CONCLUSIONS: To our knowledge, this is the first documented case of melanoma in a cynomolgus monkey.

Novel oblique radiographic projection of the temporomandibular articulation of horses.

A novel radiographic projection is described for assessing part of the temporomandibular articulation of horses. It minimises the superimposition of osseous structures of the cranium that limit the usefulness of conventional projections and permits improved imaging in cases of suspected disease.

Thyroid dysfunction in Down's syndrome and screening for hypothyroidism in children and adolescents using capillary TSH measurement.

UNLABELLED: Thyroid dysfunction is more common in individuals with Down's syndrome (DS) than in the general population, whose clinical features can mask the presenting signs and symptoms of hypothyroidism. Biochemical screening is necessary; however, venepuncture may be difficult. AIMS: To assess the prevalence of thyroid dysfunction in children and adolescents with DS and the feasibility of screening for hypothyroidism using capillary dried blood spot thyroid stimulating hormone (TSH) from infancy. METHODS: 394 children (217 boys, 177 girls) were clinically assessed for thyroid dysfunction and 305 children (aged 4 months to 18.9 years) were screened for hypothyroidism by capillary whole blood TSH sample. RESULTS: Thyroid dysfunction was detected in 4.6%, with 50% unscreened since neonatal screening. Parents reported minimal distress by fingerprick screening. CONCLUSION: DS is associated with an increased prevalence of thyroid dysfunction, particularly in preschool children. Biochemical screening is essential and capillary whole blood TSH sampling for hypothyroidism is feasible, less invasive and acceptable.

Visual clues act as a substitute for haptic feedback in robotic surgery.

OBJECTIVE: The lack of haptic feedback (HF) in robotic surgery is one of the major concerns of novice surgeons to that field. The superior visual appearances acquired during robotic surgery may give clues that make HF less important. METHODS: We surveyed 52 individuals on their perception of HF during robotic surgery. The first group of 34 surgically inexperienced people used the da Vinci robot for their first time (drylab). The second group included 8 laparoscopic surgeons with experience up to a fifth robotic operation. The third group included 10 surgical experts with substantial experience (150-650 robotic cases). Visual analog assessment was made of perception of HF, how much HF was missed, how much the absence of HF impaired the operators' level of comfort. Robotic experts were asked if complications have occurred as a result of a lack of HF. RESULTS: Of the first group, 50% reported the perception of HF, as did 55% of the second group and 100% of the third group (difference between group 1 and group 3: p < 0.05). The first group missed HF for 6.5; the second group for 4.3, and the third group for 4 (difference between groups 1 and 3: p < 0.05). The surgical experts claimed to have missed HF for 7.2 s when they first started robotic surgery (Difference to now: p < 0.05). The lack of HF caused discomfort for the first group of 4; for the second group of 4,4, and for the third group of 2,6. One complication was reported by the robotic experts as resulting from the lack of HF. CONCLUSIONS: The data support the conclusion that even beginners quickly experience the perception of HF when performing robotic surgery. With more experience, perception of HF and the level of comfort with robotic surgery increases significantly. This perception of HF makes "real" HF less important and demonstrates that its importance is overestimated by novices in robotic surgery.

Biological laser printing of genetically modified Escherichia coli for biosensor applications.

One of the primary requirements of cell- or tissue-based sensors is the placement of cells and cellular material at or near the sensing elements of the device. The ability to achieve precise, reproducible and rapid placement of cells is the focus of this study. We have developed a technique, biological laser printing or BioLP, which satisfies these requirements and has advantages over current technologies. BioLP is capable of rapidly depositing patterns of active biomolecules and living cells onto a variety of material surfaces. Unlike ink jet or manual spotting techniques, this process delivers small volume (nl to fl) aliquots of biomaterials without the use of an orifice, thus eliminating potential clogging issues and enabling diverse classes of biomaterials to be deposited. This report describes the use of this laser-based printing method to transfer genetically-modified bacteria capable of responding to various chemical stressors onto agar-coated slides and into microtiter plates. The BioLP technology enables smaller spot sizes, increased resolution, and improved reproducibility compared to related technologies.

Mechanistic toxicogenomic analysis of WAY-144122 administration in Sprague-Dawley rats.

Application of global gene expression analysis in the study of mechanisms of toxicity could provide a more comprehensive interpretation of the molecular basis of drug action. WAY-144122 has pharmacological activity against several targets improving insulin responsiveness and favorably altering lipid profiles. Normal rats treated with suprapharmacological doses of WAY-144122 for 28 days exhibited drug-related effects in the liver and ovary. To determine the molecular mechanism underlying these effects, we employed global gene expression profiling to measure RNA levels in these target organs obtained from WAY-144122-treated rats administered test article for 1, 3, 7, and 14 days. Genes altered in expression by WAY-144122 were functionally categorized and related to their biological activity. In the liver, WAY-144122 caused a widespread up-regulation of genes involved in lipid mobilization, peroxisomal proliferation, and fatty acid beta-oxidation. In the ovary, we observed reduced expression of genes encoding luteinizing hormone receptor, follistatin, and enzymes in the estradiol synthesis pathway. Transcriptional changes in both organs precede histopathological effects. Profiling analysis allowed us to formulate hypotheses for molecular mechanisms underlying the physiological observations. In the liver, transcriptional changes suggest that WAY-144122 induced increased metabolic activity and peroxisomal proliferation resulting in increased liver weight and hepatocellular hypertrophy. We propose decreased estradiol synthesis as the underlying mechanism for the observed follicular atrophy in the ovary. Importantly, in this study, we have identified potential molecular mechanisms of drug effect in expression profiles before observation of physiological changes.

Generation of mesoscopic patterns of viable Escherichia coli by ambient laser transfer.

We have generated mesoscopic patterns of viable Escherichia coli on Si(1 1 1), glass, and nutrient agar plates by using a novel laser-based transfer process termed matrix assisted pulsed laser evaporation direct write (MAPLE DW). We observe no alterations to the E. coli induced by the laser-material interaction or the shear forces during the transfer. Transferred E. coli patterns were observed by optical and electron microscopes, and cell viability was shown through green fluorescent protein (GFP) expression and cell culturing experiments. The transfer mechanism for our approach appears remarkably gentle and suggests that active biomaterials such as proteins, DNA and antibodies could be serially deposited adjacent to viable cells. Furthermore, this technique is a direct write technology and therefore does not involve the use of masks, etching, or other lithographic tools.

Maritally violent men's heart rate reactivity to marital interactions: a failure to replicate the Gottman et al. (1995) typology.

In an attempt to replicate the J. M. Gottman et al. (1995) batterer typology, 58 men who had engaged in moderate-to-severe marital violence in the past year were studied. The sample was split into Gottman et al.'s Type 1 men (i.e., whose heart rates decreased, from baseline, during a marital conflict task) and Type 2 men (i.e., whose heart rates increased). The groups did not differ in the manner predicted on measures of marital violence, antisocial or aggressive-sadistic personality, drug dependence, criminality, general violence, childhood exposure to interparental violence, behavior during marital interactions, or relationship stability. Contrary to expectations, wives of Type 1 men rated their husband as more jealous and angry and reported more marital distress. In the only finding consistent with Gottman et al., Type 2 men scored higher on a measure of dependent personality. Implications for future research are discussed.

Heart rate reactivity in male batterers: reply to Gottman (2001) and a second look at the evidence.

Together, the results of 3 studies examining heart rate reactivity (HRR) in male batterers do not provide strong support for the J. M. Gottman et al. (1995) batterer typology. All research groups found similar proportions of severely violent male batterers who show heart rate increases or decreases during a marital conflict discussion, but there was inconsistent validation of this taxonomy on variables of interest. This difference was also found among less violent and nonviolent men. The authors believe HRR may be useful for differentiating batterers on the dimension of anger-hostility but are less optimistic that HRR will reliably identify psychopathic or antisocial batterers. The authors do not agree that low levels of marital interaction conflict led to their failure to replicate. Reanalysis of data from J. C. Meehan, A. Holtzworth-Munroe, and K. Herron (2001) suggests baseline artifacts may be an important determinant of HRR differences. Methodological changes may improve the reliability of HRR assessment.

Cursor orientation and computer screen positioning movements.

Implicit directional cues in arrowhead cursors could influence positioning of a cursor on the screen of the computer. Performance during cursor placement may benefit from compatibilities between cursor orientation and direction of movement. Arrowheads could also elicit illusory processes that may affect judgments of (a) the distances on the screen or (b) the location of the point of the arrowhead. To address the impact of the cursor's orientation on its positioning, we had 12 participants move cursors (crosshairs, leftward, or rightward arrow) leftward or rightward to targets (near, far) on a computer screen. Movement amplitude was more important than cursor orientation for initiation of rightward movements, whereas cursor orientation affected the duration of leftward movements and movements to farther targets. Arrowhead orientation contributed to the greater overshooting of far targets. There was little evidence that compatibility of orientation and direction of movement assisted response initiation or execution, and there was little indication that arrowhead cursors led to illusory effects that influenced cursor placement. Arrowhead cursors can provide irrelevant stimulus dimensions that distract users. This work can be applied to the design of cursors in graphical user interfaces. The use of orientation-neutral cursors or cursors whose stimulus dimensions are more relevant is recommended.

Mucopolysaccharidosis type IIIB: characterisation and expression of wild-type and mutant recombinant alpha-N-acetylglucosaminidase and relationship with sanfilippo phenotype in an attenuated patient.

Mucopolysaccharidosis type IIIB (MPS-IIB) is a lysosomal storage disorder characterised by the defective degradation of heparan sulfate due to a deficiency of alpha-N-acetylglucosaminidase (NAG). The clinical severity of MPS-IIIB ranges from an attenuated to severely affected Sanfilippo phenotype. This paper describes the expression and characterisation of wild-type recombinant NAG and the molecular characterisation of a previously identified R297X/F48L compound heterozygous MPS-IIIB patient with attenuated Sanfilippo syndrome. We have previously shown R297X to be the most common mutation in a cohort of Dutch and Australian patients, occurring at a frequency of approximately 12.5%. To date F48L has only been described in the proband. To determine the contribution of each mutation to the overall clinical phenotype of the patient, both mutant alleles were engineered into the wild-type NAG cDNA and expressed in Chinese hamster ovary cells. The wild-type NAG and F48L mutant alleles were also retrovirally expressed in MPS-IIIB skin fibroblasts. Residual NAG activity and the stability and maturation of immunoprecipitated NAG were determined for wild-type NAG and mutant NAG. The combined biochemical phenotypes of the two NAG mutant alleles demonstrated a good correspondence with the observed attenuated Sanfilippo phenotype of the patient.

Testing the Holtzworth-Munroe and Stuart (1994) batterer typology.

A. Holtzworth-Munroe and G. L. Stuart (1994) proposed that 3 subtypes (family only [FO], borderline-dysphoric [BD], and generally violent-antisocial [GVA]) would be identified using 3 descriptive dimensions (i.e., severity of marital violence, generality of violence, psychopathology) and would differ on distal and proximal correlates of violence. Maritally violent men (n = 102) and their wives were recruited from the community, as were 2 comparison groups of nonviolent couples (i.e., maritally distressed and nondistressed). Four clusters of violent men were identified. Three resembled the predicted subtypes and generally differed in the manner predicted (e.g., FO men resembled nonviolent groups: BD men scored highest on measures of dependency and jealousy; GVA men had the most involvement with delinquent peers, substance abuse, and criminal behavior; and both BD and GVA men were impulsive, accepted violence, were hostile toward women, and lacked social skills). The 4th cluster (i.e., low-level antisocial) fell between the FO and GVA clusters on many measures.

Validation of a cataplexy questionnaire in 983 sleep-disorders patients.

Our goal was to validate a self-administered narcolepsy questionnaire focusing on cataplexy. Nine hundred and eight three consecutive subjects entering the Stanford Sleep Disorder Clinic completed the questionnaire. Clinic physicians reported on the presence or absence of "clear-cut" cataplexy. Responses to 51 cataplexy-related questionnaire items were compared between subjects with clear-cut cataplexy (n = 63) and all other patients (n = 920). As previously reported, a large portion of the non-narcoleptic population was found to experience muscle weakness with various intense emotions (1.8% to 18.0%) or athletic activities (26.2% to 28.8%). Factor analysis and Receiver Operating Characteristic Curve (ROC) analysis were used to determine the most predictive items for clear-cut cataplexy. Most strikingly, cataplexy was best differentiated from other types of muscle weakness when triggered by only three typical situations: "when hearing and telling a joke," "while laughing," or "when angry." Face or neck, rather than limbs, were also more specifically involved in clear-cut cataplexy. Other items, such as length of attacks, bilaterality, and alteration in consciousness, were poorly predictive. A simple decision tree was constructed to isolate high-(91.7%) and low-(0.6%) risk groups for cataplexy. This questionnaire will be used to increase diagnostic consistency across clinical centers, thus providing more homogenous subject pools for clinical and basic research studies.

Heavy long-term ethanol consumption induces an alpha- to beta-myosin heavy chain isoform transition in rat.

Alcoholic heart muscle disease is characterized by structural changes which include chamber dilation, ventricular hypertrophy, and myocyte damage. These effects often lead to contractile dysfunction and ultimately to heart failure if alcohol consumption is not terminated. In rat models for heart failure in which heart failure is induced by pressure or volume overload, there is a shift in the myosin heavy chain (MHC) isoforms, from alpha to beta. As a result of this MHC transition, there is typically a decrease in myosin ATPase activity. We utilized a rat model of chronic alcohol consumption in order to determine if alcohol causes a similar shift in MHC isoforms and changes in myosin ATPase activity. A liquid diet containing 9% ethanol (46% of daily calories; 11.8 g/kg/day) was administered to adult rats for a period of 60 or 90 days. This heavy consumption of ethanol resulted in an average blood ethanol content of 150 mg %. The relative abundance of beta-MHC isoform protein increased from a control level of 9.7% to 35.1% in hearts of ethanol-fed rats, following 90 days of ethanol consumption. In a separate set of experiments, the levels of alpha-MHC and beta-MHC mRNA were demonstrated to increase by 150% and 230%, respectively. Following a 60 day treatment, there was a significant reduction in the actomyosin Mg2+ -ATPase activity in the myofibrillar preparations from hearts of ethanol-fed rats compared to hearts from control-fed rats. In addition, the myosin Ca2+ -ATPase activity was decreased 17% and 30% after 60 and 90 days of ethanol consumption, respectively. The present study demonstrates that chronic ethanol consumption induces an increase in the proportion of the total MHC content composed of the beta-isoform. This isoform transition is accompanied by an accumulation of beta-MHC mRNA, suggesting that the switch is organized pretranslationally. A functional consequence of this transition in MHC phenotype is demonstrated by significant decreases in the myofibrillar and myosin ATPase activities.

Ocular vergence measurement in projected and collimated simulator displays.

The purpose of this study was to investigate electrooculography (EOG) as a measurement of ocular vergence in both collimated and projected simulator environments. The task required participants to shift their gaze between a central fixation point and a target appearing at one of three eccentricities. EOG was effective in recording ocular vergence. The EOG results were similar between collimated and projected displays, except for differences in vergence changes during lateral movement of the eyes, and ocular excursions downward elicited a greater EOG response than the reverse upward movement. The computer-based technique of recording vergence was found to produce measurable traces from a majority of participants. The technique has potential for further development as a tool for measuring ocular vergence in virtual environments where methods that require the wearing of head-mounted apparatus to track ocular structures (e.g., the pupil), which cannot be worn at the same time as a flight or flight-simulator helmet, are unsuitable.