Molecular fingerprints resolve affinities of Rhynie chert organic fossils.

The affinities of extinct organisms are often difficult to resolve using morphological data alone. Chemical analysis of carbonaceous specimens can complement traditional approaches, but the search for taxon-specific signals in ancient, thermally altered organic matter is challenging and controversial, partly because suitable positive controls are lacking. Here, we show that non-destructive Fourier Transform Infrared Spectroscopy (FTIR) resolves in-situ molecular fingerprints in the famous 407 Ma Rhynie chert fossil assemblage of Aberdeenshire, Scotland, an important early terrestrial Lagerstätte. Remarkably, unsupervised clustering methods (principal components analysis and K-mean) separate the fossil spectra naturally into eukaryotes and prokaryotes (cyanobacteria). Additional multivariate statistics and machine-learning approaches also differentiate prokaryotes from eukaryotes, and discriminate eukaryotic tissue types, despite the overwhelming influence of silica. We find that these methods can clarify the affinities of morphologically ambiguous taxa; in the Rhynie chert for example, we show that the problematic "nematophytes" have a plant-like composition. Overall, we demonstrate that the famously exquisite preservation of cells, tissues and organisms in the Rhynie chert accompanies similarly impressive preservation of molecular information. These results provide a compelling positive control that validates the use of infrared spectroscopy to investigate the affinity of organic fossils in chert.

VRE acquisition in hospital and its association with hospital antimicrobial usage -a non-linear analysis of an extended time series.

BACKGROUND: Vancomycin resistant enterococci (VRE) have become endemic pathogens in many Australian hospitals causing significant morbidity. There are few observational studies that have evaluated the effect of antibiotic usage on VRE acquisition. This study examined VRE acquisition and its association with antimicrobial use. The setting was a NSW tertiary hospital with 800 beds over a 63 month period up to March 2020, straddling piperacillin-tazobactam (PT) shortages that occurred from in September 2017. METHODS: The primary outcome was monthly inpatient hospital onset Vancomycin-resistant Enterococci (VRE) acquisitions. Multivariate adaptive regression splines (MARS) were used to estimate hypothetical thresholds, where antimicrobial use above threshold is associated with increased incidence of hospital onset VRE acquisition. Specific antimicrobials and categorised usage (broad, less broad and narrow spectrum) were modelled. RESULTS: There were 846 hospital onset VRE detections over the study period. Hospital onset vanB and vanA VRE acquisitions fell significantly by 64% and 36% respectively after the PT shortage. MARS modelling indicated that PT usage was the only antibiotic found to exhibit a meaningful threshold. PT usage greater than 17.4 defined daily doses/1000 occupied bed-days (95%C I: 13.4, 20.5) was associated with higher onset of hospital VRE. CONCLUSIONS: This paper highlights the large, sustained impact that reduced broad spectrum antimicrobial use had on VRE acquisition and showed that PT use in particular was a major driver with a relatively low threshold. It raises the question as to whether hospitals should be determining local antimicrobial usage targets based on direct evidence from local data analysed with non-linear methods.

The neural correlates of working memory training in typically developing children.

Working memory training improves children's cognitive performance on untrained tasks; however, little is known about the underlying neural mechanisms. This was investigated in 32 typically developing children aged 10-14 years (19 girls and 13 boys) using a randomized controlled design and multi-modal magnetic resonance imaging (Devon, UK; 2015-2016). Training improved working memory performance and increased intrinsic functional connectivity between the bilateral intraparietal sulci. Furthermore, improvements in working memory were associated with greater recruitment of the left middle frontal gyrus on a complex span task. Repeated engagement of fronto-parietal regions during training may increase their activity and functional connectivity over time, affording greater working memory performance. The plausibility of generalizable cognitive benefits from a neurobiological perspective and implications for neurodevelopmental theory are discussed.

Osteoporosis, fracture, osteoarthritis & sarcopenia: A systematic review of circulating microRNA association.

Circulating microRNAs (c-miRs) show promise as biomarkers. This systematic review explores their potential association with age-related fracture/osteoporosis (OP), osteoarthritis (OA) and sarcopenia (SP), as well as cross-disease association. Most overlap occurred between OA and OP, suggesting potentially shared microRNA activity. There was little agreement in results across studies. Few reported receiver operating characteristic analysis (ROC) and many identified significant dysregulation in disease, but direction of effect was commonly conflicting. c-miRs with most evidence for consistency in dysregulation included miR-146a, miR-155 and miR-98 for OA (upregulated). Area under the curve (AUC) for miR-146a biomarker performance was AUC 0.92, p = 0.028. miR-125b (AUC 0.76-0.89), miR-100, miR-148a and miR-24 were consistently upregulated in OP. Insufficient evidence exists for c-miRs in SP. Study quality was typically rated intermediate/high risk of bias. Wide study heterogeneity meant meta-analysis was not possible. We provide detailed critique and recommendations for future approaches in c-miR analyses based on this review.

Subpolar North Atlantic western boundary density anomalies and the Meridional Overturning Circulation.

Changes in the Atlantic Meridional Overturning Circulation, which have the potential to drive societally-important climate impacts, have traditionally been linked to the strength of deep water formation in the subpolar North Atlantic. Yet there is neither clear observational evidence nor agreement among models about how changes in deep water formation influence overturning. Here, we use data from a trans-basin mooring array (OSNAP-Overturning in the Subpolar North Atlantic Program) to show that winter convection during 2014-2018 in the interior basin had minimal impact on density changes in the deep western boundary currents in the subpolar basins. Contrary to previous modeling studies, we find no discernable relationship between western boundary changes and subpolar overturning variability over the observational time scales. Our results require a reconsideration of the notion of deep western boundary changes representing overturning characteristics, with implications for constraining the source of overturning variability within and downstream of the subpolar region.

Does the source of referral affect outcomes for paediatric testicular torsion?

INTRODUCTION: This single centre study retrospectively analysed the intraoperative findings relative to source of referral for emergency scrotal explorations performed in a tertiary level paediatric surgery department. METHODS: All patients who underwent emergency scrotal exploration under the care of paediatric surgeons in our unit between April 2008 and April 2016 were identified. Clinical data were obtained from contemporaneous records. RESULTS: Over the 8-year study period, 662 boys underwent emergency scrotal exploration: 6 (1%) were internal referrals, 294 (44%) attended our emergency department (ED) directly, 271 (41%) were referred from primary care and 91 (14%) were transferred from other hospitals. Excluding procedures in neonates, testicular torsion was present in 100 cases (15%). Testicular detorsion with bilateral 3-point testicular fixation was performed in 66 (66%) and orchidectomy with contralateral fixation in 34 (34%) where the torted testis was non-viable intraoperatively. The orchidectomy rate in the presence of torsion was 23% in ED referrals (12/52), 43% in primary care referrals (12/28) and 50% for transfers (10/20). The difference in rates between ED referrals and patients transferred from other hospitals was significant (p=0.026). There was no significant difference in median age between any of the groups (p=0.10). CONCLUSIONS: Boys undergoing emergency scrotal exploration had a higher orchidectomy rate when transferred from other hospitals to our unit. This difference was statistically significant when compared with boys presenting directly to our ED. This supports advice from The Royal College of Surgeons of England for undertaking paediatric scrotal explorations in the presenting hospital when safe to do so rather than delaying the care of these patients by transferring them to a tertiary paediatric surgical unit.

Initial steps in defining the environment of the prepuce of the bull by measuring pH and temperature.

OBJECTIVE: To determine the baseline pH and temperature of the preputial cavity of bulls. METHODS: We enrolled 55 bulls ranging in age from 15 to 84 months. The preputial temperature and pH were measured by insertion of temperature and pH probes, respectively, into the preputial orifice prior to routine breeding soundness examinations. Information was obtained from owners regarding the diet of each bull and categorised as one of three categories: forage only, grain supplemented or silage supplemented. RESULTS: The average temperature of the prepuce was 37.81°C ± 1.76 and the median pH of the prepuce was 8.45 (6.35-9.46). Preputial temperatures of the bull weakly correlated with ambient temperatures (rs = -0.29, P = 0.028). The preputial pH of silage-fed bulls was significantly lower than that of bulls fed forage only (P = 0.025) or grain-supplemented diets (P = 0.002). The median preputial pH of bulls fed a silage-based diet was 7.6 (6.3-8.9) compared with a median pH 8.7 (7.8-9.1) for bulls fed forage-based diets or a median of 8.5 (7.7-9.4) for those given grain-supplemented diets. CONCLUSION: Diet and ambient temperature can, respectively, affect pH and the temperature in the prepuce. Further studies to describe and understand the microbiota of the prepuce and penis may assist in developing treatments for diseases of the genital tract in bulls.

Development and validation of a GEANT4 radiation transport code for CT dosimetry.

The authors have created a radiation transport code using the GEANT4 Monte Carlo toolkit to simulate pediatric patients undergoing CT examinations. The focus of this paper is to validate their simulation with real-world physical dosimetry measurements using two independent techniques. Exposure measurements were made with a standard 100-mm CT pencil ionization chamber, and absorbed doses were also measured using optically stimulated luminescent (OSL) dosimeters. Measurements were made in air with a standard 16-cm acrylic head phantom and with a standard 32-cm acrylic body phantom. Physical dose measurements determined from the ionization chamber in air for 100 and 120 kVp beam energies were used to derive photon-fluence calibration factors. Both ion chamber and OSL measurement results provide useful comparisons in the validation of the Monte Carlo simulations. It was found that simulated and measured CTDI values were within an overall average of 6% of each other.

Synchronous laparoscopic-assisted percutaneous endoscopic gastrostomy and peritoneal dialysis catheter placement is a valid alternative to open surgery.

OBJECTIVE: Gastrostomy feeding is frequently necessary in children receiving chronic peritoneal dialysis (PD). Synchronous laparoscopic-assisted placement of percutaneous endoscopic gastrostomy (PEG) and PD catheter has many potential advantages. This study investigates whether this technique is comparable to open placement. METHODS: The notes of all patients over a 16-year time period were reviewed retrospectively. Peritonitis was defined as the presence of a white blood cell count > 100/mm(3) with at least 50% being polymorphonuclear leukocytes, and infection was defined as the presence of positive peritoneal cultures with peritonitis. RESULTS: Ten patients received primary laparoscopic-assisted PEG and PD catheter insertion (LAP) and 23 patients open gastrostomy and PD catheter (OPEN). PD catheter survival was median 12 months in the LAP group and 17 months in the OPEN group. Peritonitis and infection rates per catheter-year were 0.89 and 0.7 LAP and 0.59 and 0.5 OPEN. The risk of peritonitis and infection was not related to method of placement. CONCLUSIONS: There were no statistically significant differences in outcomes between the two groups. We conclude that laparoscopic-assisted synchronous PD and PEG catheter insertion is safe and effective.

Biological characterization of a novel class of toll-like receptor 7 agonists designed to have reduced systemic activity.

BACKGROUND AND PURPOSE Toll-like receptor 7 (TLR7) agonists have potential in the treatment of allergic diseases. However, the therapeutic utility of current low molecular weight TLR7 agonists is limited by their systemic activity, resulting in unwanted side effects. We have developed a series of TLR7-selective 'antedrugs', including SM-324405 and AZ12441970, which contain an ester group rapidly cleaved in plasma to reduce systemic exposure. EXPERIMENTAL APPROACH Agonist activity at TLR7 of the parent ester and acid metabolite was assessed in vitro in reporter cells and primary cells from a number of species. Pharmacokinetics following a dose to the lungs was assessed in mice and efficacy evaluated in vivo with a mouse allergic airway model. KEY RESULTS Compounds were selective agonists for TLR7 with no crossover to TLR8 and were metabolically unstable in plasma with the acid metabolite showing substantially reduced activity in a number of assays. The compounds inhibited IL-5 production and induced IFN-α, which mediated the inhibition of IL-5. When dosed into the lung the compounds were rapidly metabolized and short-term exposure of the 'antedrug' was sufficient to activate the IFN pathway. AZ12441970 showed efficacy in a mouse allergic airway model with minimal induction of systemic IFN-α, consistent with the low plasma levels of compound. CONCLUSIONS AND IMPLICATIONS The biological and metabolic profiles of these TLR7-selective agonist 'antedrug' compounds are consistent with a new class of compound that could be administered locally for the treatment of allergic diseases, while reducing the risk of systemic side effects. LINKED ARTICLE This article is commented on by Kaufman and Jacoby, pp. 569-572 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01758.x.

46XY girls: the importance of careful newborn examination.

STUDY OBJECTIVE: To understand the timing and factors affecting diagnosis of phenotypically female 46XY children. DESIGN, SETTING, AND PARTICIPANTS: We studied all phenotypically female 46XY children who attended our multidisciplinary disorders of sexual differentiation (DSD) clinic in Nottingham England in a 3-year period since its inception. Case notes from a prospectively maintained database were reviewed and data were analyzed on the age at presentation, family history, findings on genital examination, and underlying endocrine abnormality. RESULTS: Eleven children were studied, all of whom were being raised as girls. The median age of presentation was 18 months (range birth-15 years). Although the newborn examination detected the possibility of DSD in only 3 cases; 10 of 11 children had at least one significant abnormality in their external genitalia at presentation. CONCLUSION: Careful neonatal genital examination can identify children with DSD. However, not all children with these conditions are identified early. Early diagnosis, when possible, is important, as it has the potential to make the management of this difficult condition more straightforward.

The prevalence of osteoporosis in patients with severe hip and knee osteoarthritis awaiting joint arthroplasty.

BACKGROUND: the presence of osteoporosis in patients with hip and knee osteoarthritis (OA) has important implications for understanding disease progression and providing optimal surgical and medical management. OBJECTIVE: to determine the prevalence of osteoporosis among patients with osteoarthritis awaiting total knee arthroplasty or total hip arthroplasty aged between 65 and 80 years. DESIGN: cross-sectional observational study. SETTING: tertiary referral centre in Newcastle upon Tyne, UK. SUBJECTS: patients with osteoarthritis awaiting total knee hip arthroplasty aged between 65 and 80 years. METHODS: lumbar spine, bilateral femoral and forearm bone mineral density (BMD) measurements were obtained using dual-energy X-ray absorptiometry. RESULTS: the cohort consisted of 199 patients with a mean age of 72 years (SD 4), and 113 (57%) were women. The overall rate of osteoporosis at any site was 23% (46/199) and a further 43% (85/199) of patients would have been classified as osteopaenic according to World Health Organization criteria. Osteoporosis was more commonly detected in the forearm (14%) than the lumbar spine (8.5%) and proximal femur of the index side (8.2%). CONCLUSIONS: in summary, a significant proportion of patients with end-stage OA have osteoporosis but this diagnosis may be missed unless BMD measurements are performed at sites distant from joints affected by OA.

Long-term AAV vector gene and protein expression in mouse brain from a small pan-cellular promoter is similar to neural cell promoters.

The neurogenetic, lysosomal enzyme (LSE) deficiency diseases are characterized by storage lesions throughout the brain; therefore, gene transfer needs to provide widespread distribution of the normal enzyme. Adeno-associated virus (AAV) vectors can be effective in the brain despite limited transduction because LSEs are exported to neighboring cells (cross-correction) to reverse the metabolic deficit. The extent of correction is determined by a combination of the total amount of LSE produced by a vector and the spatial distribution of the vector within the brain. Neuron-specific promoters have been used in the brain because AAV predominantly transduces neurons. However, these promoters are large, using up a substantial amount of the limited cloning capacity of AAV vector genomes. A small promoter that is active in all cells, from the LSE beta-glucuronidase (GUSB), has been used for long-term expression in AAV vectors in the brain but the natural promoter is expressed at very low levels. The amount of LSE exported from a cell is proportional to the level of transcription, thus more active promoters would export more LSE for cross-correction, but direct comparisons have not been reported. In this study, we show that in long-term experiments (>6 months) the GUSB minimal promoter (hGBp) expresses the hGUSB enzyme in brain at similar levels as the neuron-specific enolase promoter or the promoter from the latency-associated transcript of herpes simplex virus. The hGBp minimal promoter thus may be useful for long-term expression in the central nervous system of large cDNAs, bicitronic transcription units, self-complimentary or other designs with size constraints in the AAV vector system.

Research in hand osteoarthritis: time for reappraisal and demand for new strategies. An opinion paper.

BACKGROUND: Osteoarthritis of the hands is a prevalent musculoskeletal disease with a considerable effect on patients' lives, but knowledge and research results in the field of hand osteoarthritis are limited. Therefore, the Disease Characteristics in Hand OA (DICHOA) initiative was founded in early 2005 with the aim of addressing key issues and facilitating research into hand osteoarthritis. OBJECTIVE: To review and discuss current knowledge on hand osteoarthritis with regard to aetiopathogenesis, diagnostic criteria, biomarkers and clinical outcome measures. METHODS: Recommendations were made based on a literature review. RESULTS: Outcomes of hand osteoarthritis should be explored, including patient perspective on the separate components of disease activity, damage and functioning. All imaging techniques should be cross-validated for hand osteoarthritis with clinical status, including disease activity, function and performance, biomarkers and long-term outcome. New imaging modalities are available and need scoring systems and validation. The role of biomarkers in hand osteoarthritis has to be defined. CONCLUSION: Future research in hand osteoarthritis is warranted.

Is regional anaesthesia better than general anaesthesia for caesarean section?

The Royal College of Anaesthetists have set the standard that 85% of emergency caesarean sections should be carried out under regional anaesthesia. Reducing the frequency of caesarean sections carried out under general anaesthesia may serve to reduce maternal morbidity and mortality, which has been shown over recent years. A retrospective audit was carried out at a tertiary referral centre investigating the mode of anaesthesia and fetal outcome after emergency caesarean section. The proportion carried out under regional anaesthesia was less than recommended. Despite a longer time taken to induce anaesthesia there was no increase in adverse fetal outcome, supporting the use of regional anaesthesia wherever possible to keep maternal complications to a minimum.