Longitudinal follow-up of postacute COVID-19 syndrome: DLCO, quality-of-life and MRI pulmonary gas-exchange abnormalities.

129Xe MRI red blood cell to alveolar tissue plasma ratio (RBC:TP) abnormalities have been observed in ever-hospitalised and never-hospitalised people with postacute COVID-19 syndrome (PACS). But, it is not known if such abnormalities resolve when symptoms and quality-of-life scores improve. We evaluated 21 participants with PACS, 7±4 months (baseline) and 14±4 months (follow-up) postinfection. Significantly improved diffusing capacity of the lung for carbon monoxide (DLCO, Δ=14%pred ;95%CI 7 to 21, p<0.001), postexertional dyspnoea (Δ=-0.7; 95%CI=-0.2 to -1.2, p=0.019), St George's Respiratory Questionnaire-score (SGRQ Δ=-6; 95% CI=-1 to -11, p=0.044) but not RBC:TP (Δ=0.03; 95% CI=0.01 to 0.05, p=0.051) were observed at 14 months. DLCO correlated with RBC:TP (r=0.60, 95% CI=0.22 to 0.82, p=0.004) at 7 months. While DLCO and SGRQ measurements improved, these values did not normalise 14 months post-infection. ClinicalTrials.gov NCT04584671.

Postacute COVID-19 Syndrome: 129Xe MRI Ventilation Defects and Respiratory Outcomes 1 Year Later.

Background In individuals with postacute COVID-19 syndrome (PACS) and normal pulmonary function, xenon 129 (129Xe) MRI ventilation defects, abnormal quality-of-life scores, and exercise limitation were reported 3 months after infection; the longitudinal trajectory remains unclear. Purpose To measure and compare pulmonary function, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) in individuals with PACS evaluated 3 and 15 months after COVID-19 infection. Materials and Methods In this prospective study, participants with PACS aged 18-80 years were enrolled between July 2020 and August 2021 from two quaternary care centers. 129Xe MRI VDP, diffusing capacity of lung for carbon monoxide (Dlco), spirometry, oscillometry, 6-minute walk distance (6MWD), and St George Respiratory Questionnaire (SGRQ) scores were evaluated 3 months and 15 months after COVID-19 infection. Differences between time points were evaluated using the paired t test. Multivariable models were generated to explain exercise capacity and quality-of-life improvement. Odds ratios (ORs) were used to evaluate potential treatment influences. Results Overall, 53 participants (mean age, 55 years ± 18 [SD]; 27 women) attended both 3- and 15-month visits and were included in the analysis. The mean values for 129Xe MRI VDP (5.8% and 4.2%; P = .003), forced expiratory volume in the 1st second of expiration percent predicted (84% and 90%; P = .001), Dlco percent predicted (86% and 99%; P = .002), and SGRQ score (35 and 25; P < .001) improved between the 3- and 15-month visit. VDP measured 3 months after COVID-19 infection predicted the change in 6MWD (ß = -0.643, P = .006), while treatment with respiratory medication at 3 months predicted an improved quality-of-life score at 15 months (OR, 4.0; 95% CI: 1.2, 13.8; P = .03). Conclusion Pulmonary function, gas exchange, exercise capacity, quality of life, and 129Xe MRI ventilation defect percent (VDP) improved in participants with postacute COVID-19 syndrome at 15 months compared with 3 months after infection. VDP measured at 3 months after infection correlated with improved exercise capacity, while treatment with respiratory medication was associated with an improved quality-of-life score 15 months after infection. ClinicalTrials.gov registration no. NCT05014516 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Vogel-Claussen in this issue.

Persistent 129Xe MRI Pulmonary and CT Vascular Abnormalities in Symptomatic Individuals with Post-acute COVID-19 Syndrome.

BACKGROUND: In patients with post-acute COVID-19 syndrome (PACS), abnormal gas-transfer and pulmonary vascular density have been reported, but such findings have not been related to each other or to symptoms and exercise limitation. The pathophysiologic drivers of PACS in patients previously infected with COVID-19 who were admitted to in-patient treatment in hospital (or ever-hospitalized patients) and never-hospitalized patients are not well understood. PURPOSE: To determine the relationship of persistent symptoms and exercise limitation with xenon 129 (129Xe) MRI and CT pulmonary vascular measurements in individuals with PACS. MATERIALS AND METHODS: In this prospective study, patients with PACS aged 18-80 years with a positive polymerase chain reaction COVID-19 test were recruited from a quaternary-care COVID-19 clinic between April and October 2021. Participants with PACS underwent spirometry, diffusing capacity of the lung for carbon monoxide (DLco), 129Xe MRI, and chest CT. Healthy controls had no prior history of COVID-19 and underwent spirometry, DLco, and 129Xe MRI. The 129Xe MRI red blood cell (RBC) to alveolar-barrier signal ratio, RBC area under the receiver operating characteristic curve (AUC), CT volume of pulmonary vessels with cross-sectional area 5 mm2 or smaller (BV5), and total blood volume were quantified. St George's Respiratory Questionnaire, International Physical Activity Questionnaire, and modified Borg Dyspnea Scale measured quality of life, exercise limitation, and dyspnea. Differences between groups were compared with use of Welch t-tests or Welch analysis of variance. Relationships were evaluated with use of Pearson (r) and Spearman (ρ) correlations. RESULTS: Forty participants were evaluated, including six controls (mean age ± SD, 35 years ± 15, three women) and 34 participants with PACS (mean age, 53 years ± 13, 18 women), of whom 22 were never hospitalized. The 129Xe MRI RBC:barrier ratio was lower in ever-hospitalized participants (P = .04) compared to controls. BV5 correlated with RBC AUC (ρ = .44, P = .03). The 129Xe MRI RBC:barrier ratio was related to DLco (r = .57, P = .002) and forced expiratory volume in 1 second (ρ = .35, P = .03); RBC AUC was related to dyspnea (ρ = -.35, P = .04) and International Physical Activity Questionnaire score (ρ = .45, P = .02). CONCLUSION: Xenon 129 (129Xe) MRI measurements were lower in participants previously infected with COVID-19 who were admitted to in-patient treatment in hospital with post-acute COVID-19 syndrome, 34 weeks ± 25 after infection compared to controls. The 129Xe MRI measures were associated with CT pulmonary vascular density, diffusing capacity of the lung for carbon monoxide, exercise capacity, and dyspnea. Clinical trial registration no.: NCT04584671 © RSNA, 2022 Online supplemental material is available for this article See also the editorial by Wild and Collier in this issue.

Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

All-fiber widely tunable ultrafast laser source for multimodal imaging in nonlinear microscopy.

In this Letter, we present an all-fiber, easy-to-use, wavelength-tunable, ultrafast laser, based on soliton self-frequency shifting in an Er-doped polarization-maintaining very large mode area fiber. The system is tunable over 370 nm, starting at 1620 nm, with an average power of up to 1.5 W that emits 120 fs short laser pulses directly out of the fusion-spliced fiber without using bulky pulse compression optics. The output is subsequently frequency doubled to a wavelength range covering 810 nm up to almost 1000 nm with more than 500 mW average power and 120 fs pulse width. Having a polarization extinction ratio better than 40 dB and a M2 of 1.1, the fully computer-controlled laser system presents a robust and compact laser source. These parameters make the laser perfectly suited for multimodal imaging in nonlinear microscopy.

Therapies and outcomes of congenital hyperinsulinism-induced hypoglycaemia.

Congenital hyperinsulinism is a rare disease, but is the most frequent cause of persistent and severe hypoglycaemia in early childhood. Hypoglycaemia caused by excessive and dysregulated insulin secretion (hyperinsulinism) from disordered pancreatic ß cells can often lead to irreversible brain damage with lifelong neurodisability. Although congenital hyperinsulinism has a genetic cause in a significant proportion (40%) of children, often being the result of mutations in the genes encoding the KATP channel (ABCC8 and KCNJ11), not all children have severe and persistent forms of the disease. In approximately half of those without a genetic mutation, hyperinsulinism may resolve, although timescales are unpredictable. From a histopathology perspective, congenital hyperinsulinism is broadly grouped into diffuse and focal forms, with surgical lesionectomy being the preferred choice of treatment in the latter. In contrast, in diffuse congenital hyperinsulinism, medical treatment is the best option if conservative management is safe and effective. In such cases, children receiving treatment with drugs, such as diazoxide and octreotide, should be monitored for side effects and for signs of reduction in disease severity. If hypoglycaemia is not safely managed by medical therapy, subtotal pancreatectomy may be required; however, persistent hypoglycaemia may continue after surgery and diabetes is an inevitable consequence in later life. It is important to recognize the negative cognitive impact of early-life hypoglycaemia which affects half of all children with congenital hyperinsulinism. Treatment options should be individualized to the child/young person with congenital hyperinsulinism, with full discussion regarding efficacy, side effects, outcomes and later life impact.

Differences in Fecal Gut Microbiota, Short-Chain Fatty Acids and Bile Acids Link Colorectal Cancer Risk to Dietary Changes Associated with Urbanization Among Zimbabweans.

The incidence of colorectal cancer (CRC) is gradually rising in sub-Saharan Africa. This may be due to dietary changes associated with urbanization, which may induce tumor-promoting gut microbiota composition and function. We compared fecal microbiota composition and activity in 10 rural and 10 urban Zimbabweans for evidence of a differential CRC risk. Dietary intake was assessed by a food frequency questionnaire. Fecal microbiota composition, metabolomic profile, functional microbial genes were analyzed, and bile acids and short chain fatty acids quantified. Animal protein intake was higher among urban volunteers, but carbohydrate and fiber intake were similar. Bacteria related to Blautia obeum, Streptococcus bovis, and Subdoligranulum variabile were higher in urban residents, whereas bacteria related to Oscillospira guillermondii and Sporobacter termitidis were higher in rural volunteers. Fecal levels of primary bile acids, cholic acid, and chenodeoxycholic acid (P < 0.05), and secondary bile acids, deoxycholic acid (P < 0.05) and ursodeoxycholic acid (P < 0.001) were higher in urban residents. Fecal levels of acetate and propionate, but not butyrate, were higher in urban residents. The gut microbiota composition and activity among rural and urban Zimbabweans retain significant homogeneity (possibly due to retention of dietary fiber), but urban residents have subtle changes, which may indicate a higher CRC risk.

The enhanced recovery after surgery (ERAS) Greenie Board: a Navy-inspired quality improvement tool.

The United States Navy uses a visual feedback system for pilots, named 'the Greenie Board', to improve flight manoeuvres on aircraft carriers. Given that increased compliance with enhanced recovery after surgery protocols reduces postoperative complications, we decided to apply a similar feedback system to our institutional enhanced recovery programme. We undertook a prospective 12-month audit of 194 patients assigned to our enhanced recovery programme and evaluated adherence to the anaesthesia-related components of our protocol, before and after implementing a Greenie Board. A compliance score was calculated by summing points for adherence to: intra-operative antibiotic prophylaxis; temperature management; goal-directed intravenous fluid therapy; postoperative nausea and vomiting prophylaxis; and postoperative fluid restriction. The score for each patient was then colour-coded and anonymously displayed for each anaesthetist on a Greenie Board within the operating theatre suite. Protocol adherence improved significantly following introduction, with 'Green' scores (acceptable compliance) increasing from 33% to 72% of patients (p < 0.0001). The greatest improvement was seen with anti-emetic prophylaxis (49% to 70%, p = 0.004) with a consequent reduction in postoperative nausea and vomiting (OR 0.42, 95% CI 0.19-0.88, p = 0.021). We did not observe a decrease in other postoperative complications nor hospital length of stay. We conclude that this US Navy-inspired feedback system is an easily implemented, low-cost quality improvement tool that significantly improved adherence to intra-operative components of our enhanced recovery protocol. The system lends itself to global scaling to drive quality improvement in healthcare delivery and would be suited to institutions without electronic medical records, including low-resource countries.

Development and evaluation of an online educational resource about cancer survivorship for cancer nurses: a mixed-methods sequential study.

Cancer survivorship is recognised globally as a key issue. In spite of the key role played by nurses in survivorship care, there is an identified gap in nurse's knowledge in this area. This study reports on the development and evaluation of an educational resource for nurses working with people affected by cancer. The resource was designed using adult learning principles and includes a variety of learning materials and point of care resources. A mixed-methods sequential exploratory design was used to undertake an evaluation of the programme. This included the use of online surveys and semi-structured interviews with pilot participants. A total of 21 participants completed an online survey and 11 participants completed a telephone interview. Overall, the participants found the Cancer Survivorship resource to be engaging, practical and intuitive. A major theme emerging from the survey and interview data was that the resource was applicable to practice and useful in developing survivorship care plans. Respondents requested additional information be included on the role of various health professionals working in survivorship as well as guidelines on when to make referrals. This study provides evidence that the Cancer Survivorship tool may be a promising vehicle for delivering evidence-based education on survivorship care.

Impact of a Brief Group Intervention to Enhance Parenting and the Home Learning Environment for Children Aged 6-36 Months: a Cluster Randomised Controlled Trial.

This study evaluated the effectiveness of a group parenting intervention designed to strengthen the home learning environment of children from disadvantaged families. Two cluster randomised controlled superiority trials were conducted in parallel and delivered within existing services: a 6-week parenting group (51 locations randomised; 986 parents) for parents of infants (aged 6-12 months), and a 10-week facilitated playgroup (58 locations randomised; 1200 parents) for parents of toddlers (aged 12-36 months). Each trial had three conditions: intervention (smalltalk group-only); enhanced intervention with home coaching (smalltalk plus); and 'standard'/usual practice controls. Parent-report and observational measures were collected at baseline, 12 and 32 weeks follow-up. Primary outcomes were parent verbal responsivity and home learning activities at 32 weeks. In the infant trial, there were no differences by trial arm for the primary outcomes at 32 weeks. In the toddler trial at 32-weeks, participants in the smalltalk group-only trial showed improvement compared to the standard program for parent verbal responsivity (effect size (ES) = 0.16; 95% CI 0.01, 0.36) and home learning activities (ES = 0.17; 95% CI 0.01, 0.38) but smalltalk plus did not. For the secondary outcomes in the infant trial, several initial differences favouring smalltalk plus were evident at 12 weeks, but not maintained to 32 weeks. For the toddler trial, differences in secondary outcomes favouring smalltalk plus were evident at 12 weeks and maintained to 32 weeks. These trials provide some evidence of the benefits of a parenting intervention focused on the home learning environment for parents of toddlers but not infants. TRIAL REGISTRATION: 8 September 2011; ACTRN12611000965909 .

Participation of Australian Aboriginal and Torres Strait Islander families in a parent support programme: longitudinal associations between playgroup attendance and child, parent and community outcomes.

BACKGROUND: Playgroups are a relatively unique form of family support programme that is common in Australia which has high community acceptance and significant government investment. However, limited evidence exists regarding the effectiveness of playgroups to achieve better outcomes for children and their parents. This study describes patterns of playgroup participation for Aboriginal and Torres Strait Islander families with young children and examines the extent to which participation from birth to three years is associated with subsequent child, parent and community outcomes. METHODS: This study uses three years of longitudinal data for 622 Aboriginal and Torres Strait Islander children who were participants in the Longitudinal Study of Indigenous Children (LSIC). Longitudinal associations between playgroup attendance when children were age 2 and 3 years and outcome measures for child vocabulary, motor skills, behaviour problems, prosocial development, parent home learning engagement, resilience, advice-seeking and health service use, and community trustworthiness were examined using path analysis. RESULTS: Rates of playgroup participation in this sample group were generally lower than for Australian children overall. Playgroup attendance when children were age 2 to 3 years was associated with higher parental engagement in home learning activities when children were aged 4 years which, in turn, was associated with stronger expressive vocabulary scores for children. CONCLUSION: The findings from this study suggest that playgroup participation can enhance the home learning environments for Aboriginal and Torres Strait Islander children. Playgroups as a parent support programme hold strong potential to reach and engage families, particularly in areas of high geographic isolation, which can realize improved outcomes for children, parents and communities.

Self-frequency-shifted solitons in a polarization-maintaining, very-large-mode area, Er-doped fiber amplifier.

We demonstrate soliton self-frequency-shifted, femtosecond-pulse amplification in a newly-developed, polarization-maintaining, Er-doped, very-large-mode-area fiber amplifier. The PM-VLMA Er fiber had a core diameter of 50 µm, an effective area of ~1050 µm2, and Er absorption of 50 dB/m. The measured birefringence beat length of the PM-VLMA Er fiber was 14.1 mm. The soliton wavelength could be shifted by more than 90 nm. The soliton generation process resulted in remarkably clean, 86 fs pulses with 21 nJ energy at 1650 nm and 244 kW peak power from an all-fiber, fusion spliced system without bulk-optics for pulse compression. The polarization extinction ratio of the soliton was greater than 40 dB, and the M2 was 1.1. The fully polarization-maintaining fiber laser system provides robust and stable soliton generation. Peak-to-peak variation in the soliton wavelength, measured over the course of an hour was only 0.03% and pulse energy variation was only 0.5%.

High energy, 1572.3 nm pulses for CO2 LIDAR from a polarization-maintaining, very-large-mode-area, Er-doped fiber amplifier.

We demonstrate the first polarization-maintaining, very-large-mode-area, Er-doped fiber amplifier with ~1100 µm2 effective area. The amplifier is core pumped by a Raman fiber laser and is used to generate single-frequency, one-microsecond, pulses with pulse energy of 541 µJ, peak power of 700 W, M2 of 1.1, and polarization extinction > 20 dB. The amplifier operates at 1572.3 nm, a wavelength useful for trace atmospheric CO2 detection.

Metabolic Phenotypes of Carotid Atherosclerotic Plaques Relate to Stroke Risk: An Exploratory Study.

OBJECTIVE: Stroke is a major cause of death and disability. That three-quarters of stroke patients will never have previously manifested cerebrovascular symptoms demonstrates the unmet clinical need for new biomarkers able to stratify patient risk and elucidation of the biological dysregulations. In this study, the utility of comprehensive metabolic phenotyping is assessed to provide candidate biomarkers that relate to stroke risk in stenosing carotid plaque tissue samples. METHOD: Carotid plaque tissue samples were obtained from patients with cerebrovascular symptoms of carotid origin (n = 5), and from asymptomatic patients (n = 5). Two adjacent biological replicates were obtained from each tissue. Organic and aqueous metabolite extracts were obtained separately and analysed using two ultra performance liquid chromatography coupled to mass spectrometry metabolic profiling methods. Multivariate and univariate tools were used for statistical analysis. RESULTS: The two study groups demonstrated distinct plaque phenotypes using multivariate data analysis. Univariate statistics also revealed metabolites that differentiated the two groups with a strong statistical significance (p = 10(-4)-10(-5)). Specifically, metabolites related to the eicosanoid pathway (arachidonic acid and arachidonic acid precursors), and three acylcarnitine species (butyrylcarnitine, hexanoylcarnitine, and palmitoylcarnitine), intermediates of the ß-oxidation, were detected in higher intensities in symptomatic patients. However, metabolites implicated in the process of cell death, a process known to be upregulated in the formation of the vulnerable plaque, were unaffected. CONCLUSIONS: Discrimination between symptomatic and asymptomatic carotid plaque tissue is demonstrated for the first time using metabolic profiling technologies. Two biological pathways (eicosanoid and ß-oxidation) were implicated in differentiating symptomatic from asymptomatic patients and will be further investigated. These results indicate that metabolic phenotyping should be further explored to investigate the chemistry of the unstable plaque, in the pursuit of candidate biomarkers for risk-stratification and targets for pharmacotherapeutic intervention.

Health-related impairments in young children with ADHD: a community-based study.

BACKGROUND: We aimed to examine health-related impairments in young children with attention-deficit/hyperactivity disorder (ADHD) and non-ADHD controls and explore differences in children with ADHD by gender, ADHD subtype and mental health co-morbidity status. METHODS: Children with ADHD (n = 177) and controls (n = 212) aged 6-8 years were recruited across 43 schools in Melbourne, Australia following a screening (Conners 3 ADHD Index) and case confirmation procedure (Diagnostic Interview Schedule for Children IV). Direct and blinded assessments of height and weight were used to calculate body mass index z-score and to identify overweight/obesity. Parents reported on child global health, sleep problems and physical injuries. Unadjusted and adjusted (socio-demographic factors and co-morbidities) logistic and linear regression were conducted to compare health-related impairments between (1) children with and without ADHD; (2) boys and girls with ADHD; (3) children with ADHD-inattentive and ADHD-combined types; and (4) children with ADHD by internalizing and externalizing disorder status. RESULTS: Children with ADHD had poorer global health than controls when adjusted for socio-demographic characteristics (OR: 2.0; 95% CI 1.1, 3.9); however, this attenuated after adjusting for co-morbidities. In adjusted analyses, children with ADHD had increased odds of moderate/large sleep problems (OR: 3.1; 95% CI 1.4, 6.8), compared with controls. There were no differences between children with and without ADHD in terms of physical injuries or overweight/obesity. Findings were similar when excluding children taking ADHD medication, and health-related impairments did not differ between boys and girls with ADHD. Children with ADHD-combined type had higher BMI z-scores than controls in adjusted analyses (P = 0.04). Children with ADHD and co-occurring internalizing and externalizing co-morbidities were particularly vulnerable to health-related impairments. CONCLUSION: Young children with ADHD experience a number of health-related impairments, which are exacerbated by the presence of internalizing and externalizing co-morbidities. Clinicians should consider the broader health of children with ADHD in clinical consultations.

Antibacterial effects of conventional glass ionomer cement.

OBJECTIVES: The antibacterial activity of conventional glass ionomer cement against three different microorganism strains alone and following incorporation of 1, 2 and 3% Benzalkonium Chloride and Cetylpyridinium Chloride was evaluated. METHODS: Agar diffusion method was used to determine the inhibitory effect of the conventional glass ionomer cement ChemFlex on Streptococcus mutans, Lactobacillus casei and Actinomyces viscosus. Bacterial strains were inoculated into BHIB, and incubated in an anaerobic atmosphere (37 °C). From the bacteria grown in the liquid medium, the density of the inoculum was set to be equivalent to McFarland 2 standard. In Shaedler agar, 350 µL of the bacterial suspension were equally spread. Specimens (4 mm × 6 mm) were prepared from the cement without and with addition of 1, 2 and 3% Benzalkonium Chloride and Cetylpyridinium Chloride. The inhibition zones were determined after 48 hours, after 2, 7 and 21 days of incubation. RESULTS: The combination ChemFlex + Benzalkonium Chloride has the best effect on the three analysed bacteria. The Benzalkonium Chloride antibacterial compound has a stronger antibacterial effect than Cetylpyridinium Chloride. CONCLUSIONS: Glass ionomer cements can potentially be used as a medium for slow release of active antimicrobial components, and they have the potential to improve clinical outcomes of the cements (Tab. 3, Fig. 3, Ref. 31).

Metabolic phenotype-microRNA data fusion analysis of the systemic consequences of Roux-en-Y gastric bypass surgery.

BACKGROUND/OBJECTIVES: Bariatric surgery offers sustained marked weight loss and often remission of type 2 diabetes, yet the mechanisms of establishment of these health benefits are not clear. SUBJECTS/METHODS: We mapped the coordinated systemic responses of gut hormones, the circulating miRNAome and the metabolome in a rat model of Roux-en-Y gastric bypass (RYGB) surgery. RESULTS: The response of circulating microRNAs (miRNAs) to RYGB was striking and selective. Analysis of 14 significantly altered circulating miRNAs within a pathway context was suggestive of modulation of signaling pathways including G protein signaling, neurodegeneration, inflammation, and growth and apoptosis responses. Concomitant alterations in the metabolome indicated increased glucose transport, accelerated glycolysis and inhibited gluconeogenesis in the liver. Of particular significance, we show significantly decreased circulating miRNA-122 levels and a more modest decline in hepatic levels, following surgery. In mechanistic studies, manipulation of miRNA-122 levels in a cell model induced changes in the activity of key enzymes involved in hepatic energy metabolism, glucose transport, glycolysis, tricarboxylic acid cycle, pentose phosphate shunt, fatty-acid oxidation and gluconeogenesis, consistent with the findings of the in vivo surgery-mediated responses, indicating the powerful homeostatic activity of the miRNAs. CONCLUSIONS: The close association between energy metabolism, neuronal signaling and gut microbial metabolites derived from the circulating miRNA, plasma, urine and liver metabolite and gut hormone correlations further supports an enhanced gut-brain signaling, which we suggest is hormonally mediated by both traditional gut hormones and miRNAs. This transomic approach to map the crosstalk between the circulating miRNAome and metabolome offers opportunities to understand complex systems biology within a disease and interventional treatment setting.

Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy.

OBJECTIVE: To characterize deficits in burrowing behavior - an ethologically-relevant rodent behavior - in the monosodium iodoacetate (MIA) rat model of osteoarthritis (OA), and the sensitivity of these deficits to reversal by analgesic drugs of both prototypical and novel mechanisms of action. A second objective was to compare the burrowing assay to a spontaneous locomotor activity (sLA) assay. METHOD: Male Wistar Han rats (200-220 g) received intrarticular (i.a.) injections of MIA or saline for sham animals. A deficit in the amount of sand burrowed from steel tubes filled with 2.5 kg of sand was used as a measure of pain-related behavior, and sensitivity to reversal of these deficits by analgesic drugs was assessed in bilaterally MIA-injected rats. RESULTS: Bilateral MIA injections induced a significant impairment of burrowing behavior, which was concentration-dependent. The temporal pattern of the deficits was biphasic: a large deficit at 3 days post-injection, resolving by day 14 and returning at the 21 and 28 day time points. At the 3 day time point ibuprofen, celecoxib and an anti-nerve growth factor (NGF) monoclonal antibody (mAb) were able to significantly reinstate burrowing behavior, whereas the fatty acid amide hydrolase (FAAH) inhibitor PF-04457845 and morphine displayed no reversal effect. Morphine impaired burrowing behavior at 3 mg/kg in sham animals. Deficits in rearing frequency in the locomotor activity assay proved irreversible by analgesics. CONCLUSION: Burrowing behavior provides an objective, non-reflexive read-out for pain-related behavior in the MIA model that has predictive validity in detecting analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and an anti-NGF mAb.

Axicons for mode conversion in high peak power, higher-order mode, fiber amplifiers.

Higher-order mode fiber amplifiers have demonstrated effective areas as large as 6000 µm2, allowing for high pulse energy and peak power amplification. Long-period gratings are used to convert the fundamental mode to the higher-order mode at the entrance to the amplifier, and reconvert back to the fundamental at the exit, to achieve a diffraction limited beam. However, long period gratings are susceptible to nonlinearity at high peak power. In this work, we propose and demonstrate axicons for linear bulk-optic mode conversion at the output of higher order mode amplifiers. We achieve an M2 of less than 1.25 for 80% mode conversion efficiency. Experiments with pulsed amplifiers confirm that the mode conversion is free from nonlinearity. Furthermore, chirp pulse amplifier experiments confirm that HOM amplifiers plus axicon mode convertors provide energy scalability in femtosecond pulses, compared to smaller effective area, fundamental mode fiber amplifiers. We also propose and demonstrate a route towards fiber integration of the axicon mode convertor by fabricating axicons directly on the tip of the fiber amplifier end-cap.

The association between the regular use of preventive labour induction and improved term birth outcomes: findings of a systematic review and meta-analysis.

BACKGROUND: Despite a lack of high-quality evidence, the use of 'non-indicated' term labour induction is increasingly restricted throughout the world. OBJECTIVES: To assess published associations between the regular use of modelled risk-based 'non-indicated' term labour induction (hereinafter 'preventive induction') and rates of common adverse birth outcomes. SEARCH STRATEGY: MEDLINE and PUBMED databases were searched electronically. SELECTION CRITERIA: Studies were identified that compared term birth outcomes following either the current standard approach with its emphasis on the expectant management of intermediate-level risk or the regular use of preventive induction. DATA COLLECTION AND ANALYSIS: Four studies from four unique databases were identified. A meta-analysis was performed using STATA IC12. MAIN RESULTS: Pregnancies exposed to the regular use of preventive induction (n = 1153), as compared with pregnancies receiving the current standard approach (n = 1865), experienced a lower caesarean delivery rate (5.7% versus 14.4%; relative risk 0.39, 95% CI 0.31-0.50; I(2) P = 0.21), a lower neonatal intensive care unit admission rate (2.9% versus 6.5%; relative risk 0.45, 95% CI 0.31-0.65; I(2) P = 0.57), and a lower weighted adverse outcome index score (2.8 versus 6.1). CONCLUSIONS: The regular use of preventive induction, as compared with the current standard approach, was associated with a more favourable pattern of birth outcomes. Other recently published meta-analyses have also determined that certain types of 'non-indicated' labour induction are beneficial. Accordingly, the current broad restrictions on 'non-indicated' labour induction should be reconsidered. Adequately powered multi-site randomised clinical trials are needed to definitively study the risks and benefits of modelled risk-based 'non-indicated' (i.e. 'preventive') term labour induction.