Widespread six degrees Celsius cooling on land during the Last Glacial Maximum.

The magnitude of global cooling during the Last Glacial Maximum (LGM, the coldest multimillennial interval of the last glacial period) is an important constraint for evaluating estimates of Earth's climate sensitivity1,2. Reliable LGM temperatures come from high-latitude ice cores3,4, but substantial disagreement exists between proxy records in the low latitudes1,5-8, where quantitative low-elevation records on land are scarce. Filling this data gap, noble gases in ancient groundwater record past land surface temperatures through a direct physical relationship that is rooted in their temperature-dependent solubility in water9,10. Dissolved noble gases are suitable tracers of LGM temperature because of their complete insensitivity to biological and chemical processes and the ubiquity of LGM-aged groundwater around the globe11,12. However, although several individual noble gas studies have found substantial tropical LGM cooling13-16, they have used different methodologies and provide limited spatial coverage. Here we use noble gases in groundwater to show that the low-altitude, low-to-mid-latitude land surface (45 degrees south to 35 degrees north) cooled by 5.8 ± 0.6 degrees Celsius (mean ± 95% confidence interval) during the LGM. Our analysis includes four decades of groundwater noble gas data from six continents, along with new records from the tropics, all of which were interpreted using the same physical framework. Our land-based result broadly supports a recent reconstruction based on marine proxy data assimilation1 that suggested greater climate sensitivity than previous estimates5-7.

CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma.

Therapeutic targeting of CDK7 has proven beneficial in preclinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in cells from patients with multiple myeloma (MM); its selective targeting counteracts E2F activity via perturbation of the cyclin-dependent kinases/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small-molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression, increasing survival in several mouse models of MM including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.

Two-million-year-old snapshots of atmospheric gases from Antarctic ice.

Over the past eight hundred thousand years, glacial-interglacial cycles oscillated with a period of one hundred thousand years ('100k world'1). Ice core and ocean sediment data have shown that atmospheric carbon dioxide, Antarctic temperature, deep ocean temperature, and global ice volume correlated strongly with each other in the 100k world2-6. Between about 2.8 and 1.2 million years ago, glacial cycles were smaller in magnitude and shorter in duration ('40k world'7). Proxy data from deep-sea sediments suggest that the variability of atmospheric carbon dioxide in the 40k world was also lower than in the 100k world8-10, but we do not have direct observations of atmospheric greenhouse gases from this period. Here we report the recovery of stratigraphically discontinuous ice more than two million years old from the Allan Hills Blue Ice Area, East Antarctica. Concentrations of carbon dioxide and methane in ice core samples older than two million years have been altered by respiration, but some younger samples are pristine. The recovered ice cores extend direct observations of atmospheric carbon dioxide, methane, and Antarctic temperature (based on the deuterium/hydrogen isotope ratio δDice, a proxy for regional temperature) into the 40k world. All climate properties before eight hundred thousand years ago fall within the envelope of observations from continuous deep Antarctic ice cores that characterize the 100k world. However, the lowest measured carbon dioxide and methane concentrations and Antarctic temperature in the 40k world are well above glacial values from the past eight hundred thousand years. Our results confirm that the amplitudes of glacial-interglacial variations in atmospheric greenhouse gases and Antarctic climate were reduced in the 40k world, and that the transition from the 40k to the 100k world was accompanied by a decline in minimum carbon dioxide concentrations during glacial maxima.

Multiple circulating forms of neprilysin detected with novel epitope-directed monoclonal antibodies.

Neprilysin (NEP) is an emerging biomarker for various diseases including heart failure (HF). However, major inter-assay inconsistency in the reported concentrations of circulating NEP and uncertainty with respect to its correlations with type and severity of disease are in part attributed to poorly characterized antibodies supplied in commercial ELISA kits. Validated antibodies with well-defined binding footprints are critical for understanding the biological and clinical context of NEP immunoassay data. To achieve this, we applied in silico epitope prediction and rational peptide selection to generate monoclonal antibodies (mAbs) against spatially distant sites on NEP. One of the selected epitopes contained published N-linked glycosylation sites at N285 and N294. The best antibody pair, mAb 17E11 and 31E1 (glycosylation-sensitive), were characterized by surface plasmon resonance, isotyping, epitope mapping, and western blotting. A validated two-site sandwich NEP ELISA with a limit of detection of 2.15 pg/ml and working range of 13.1-8000 pg/ml was developed with these mAbs. Western analysis using a validated commercial polyclonal antibody (PE pAb) and our mAbs revealed that non-HF and HF plasma NEP circulates as a heterogenous mix of moieties that possibly reflect proteolytic processing, post-translational modifications and homo-dimerization. Both our mAbs detected a ~ 33 kDa NEP fragment which was not apparent with PE pAb, as well as a common ~ 57-60 kDa moiety. These antibodies exhibit different affinities for the various NEP targets. Immunoassay results are dependent on NEP epitopes variably detected by the antibody pairs used, explaining the current discordant NEP measurements derived from different ELISA kits.

Effectiveness of low dose computed tomography to detect fractures in paediatric suspected physical abuse: a systematic review.

PURPOSE: The skeletal survey X-ray series is the current 'gold standard' when investigating suspected physical abuse (SPA) of children, in addition to a non-contrast computed tomography (CT) brain scan. This systematic literature review synthesised findings of published research to determine if low dose computed tomography (LDCT) could detect subtle fractures and therefore replace the skeletal survey X-ray series in the investigation of SPA in children aged under 3 years. METHODS: Five electronic databases and grey literature were systematically searched from their inception to 28 April 2022. Primary studies were included where the population comprised paediatric patients up to 16 years and LDCT was used to detect fractures associated with SPA. Studies involving imaging investigations of the head, standard dose CT examinations or accidental trauma were excluded. RESULTS: Three studies met the inclusion criteria, all of which were case series. These studies did not report many of the criteria required to compare the accuracy of LDCT to X-ray, i.e. they did not meet the criteria for a diagnostic accuracy test. Therefore, it is difficult to conclude from the case series if LDCT is accurate enough to replace X-rays. CONCLUSION: Due to the gap in current literature, a phantom study and subsequent post-mortem CT study are recommended as the primary investigative methods to assess the ability of low-dose CT to identify the subtle fractures associated with SPA and to calculate how low the achievable CT dose can be.

A new large-volume equilibration method for high-precision measurements of dissolved noble gas stable isotopes.

RATIONALE: Noble gases are widely used as physically based climate proxies, notably in dissolved water samples as tracers of past recharge temperature in groundwater and air-sea gas exchange processes in seawater. Recent advances in measuring large-volume samples of dissolved noble gas isotopic ratios at high precision have expanded the range of climate parameters that can be interpreted. METHODS: We build on prior methods for measuring noble gas stable isotopes at high precision with a new large-volume equilibration (LVE) method wherein sample gases are equilibrated in the sample flask between the dissolved phase and the headspace. The original dissolved gas composition is determined by measuring the headspace gases and correcting for the equilibrium dissolved gas content of the discarded water using known solubilities and fractionation factors. We evaluate the accuracy and precision of this method with air-equilibrated water standards of known noble gas composition. RESULTS: Replicate air-equilibrated water standards and field measurements demonstrate that the LVE method achieves comparable precision to prior methods, with major advantages of measuring the Ne content as a constraint on excess air and allowing for long-term sample storage. Isotope ratios measured with the LVE method in replicate samples were consistent between two laboratories, and LVE elemental noble gas abundances agreed closely with replicate samples measured using established copper-tube methods and static noble gas mass spectrometry. CONCLUSIONS: The new LVE method enables reconstruction of past water table depths at ±1 m precision along with excess air, recharge temperature, and age and hydrogeochemical indicators. It has wide application to investigating climate signals and physical gas exchange processes in groundwater and seawater.

Clear Cell Sarcoma of the Kidney (CCSK) With BCOR-CCNB3 Fusion: A Rare Case Report With a Brief Review of the Literature.

Pediatric renal tumors are a rare entity and majority of these tumors are accounted for by Wilms tumor. The second most common renal tumor is clear cell sarcoma of the kidney (CSSK). Most of the CSSK have either BCOR-internal tandem duplication (ITD) or YWHAE-NUTM2B/E fusion. The sarcomas with BCOR-CCNB3 fusion are well documented in soft tissue and bone tumors, but are extremely rare in the pediatric renal setting. We are reporting an extremely rare case of pediatric clear cell sarcoma of the kidney (CSSK) with BCOR-CCNB3 fusion, which was a diagnostic challenge on morphological grounds. A final diagnosis could only be reached after multiple reviews and NGS based RNA fusion testing. We have also performed a brief review of literature which revealed eight (8) other cases of this rare entity.

Primary Extradural Ectopic Orbital Meningioma in a Child.

The authors describe a rare case of primary extradural ectopic meningioma of the orbit in a 13-year-old female managed with surgical excision, adding to the very limited literature of this diagnosis in children. This is the second case to show a radiological abnormality in the gyrus rectus and olfactory bulb; however, in our case, there was no radiological evidence of connection seen.

Test-enhanced learning improves learner attendance during a laparoscopic box trainer simulation program.

BACKGROUND: Laparoscopy is the gold standard approach for many surgical procedures, but it is a complex skill to learn. Laparoscopic simulation training may help, but it is unclear how to best engage trainees in these programs. Test-enhanced learning (TEL) uses regular, well-defined assessments of performance throughout the training phase of learning. AIM: The aim of this study was to assess the effects of TEL on a laparoscopic simulation program involving a cohort of medical student volunteers. MATERIALS AND METHODS: A prospective cohort study was performed with a convenience sample of 40 medical students. Students were recruited to participate in a ten-week laparoscopic simulation program. Twenty students participated in a laparoscopic surgical program with TEL ('TEL group'), and 20 students participated in a standard laparoscopic simulation program ('control group'). RESULTS: Attendance in the TEL group was significantly higher than in the standard group (71 vs 51.5%, P = 0.03). There was no difference between groups in mean time scores. Four themes were identified in qualitative data drawn from student surveys - personal traits and motivators, training context, clear goals and feedback enabling understanding of one's own performance. CONCLUSION: Testing laparoscopic skills throughout a learning program, in conjunction with individualised feedback and tracking of learning trajectory, increases trainee attendance. Laparoscopic simulation training programs are encouraged to reflect on the pedagogic framework in which their procedural skills training operates.

Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects.

This study shows a causal association between ALDH1A2 variants and a novel, severe multiple congenital anomaly syndrome in humans that is neonatally lethal due to associated pulmonary hypoplasia and respiratory failure. In two families, exome sequencing identified compound heterozygous missense variants in ALDH1A2. ALDH1A2 is involved in the conversion of retinol (vitamin A) into retinoic acid (RA), which is an essential regulator of diaphragm and cardiovascular formation during embryogenesis. Reduced RA causes cardiovascular, diaphragmatic, and associated pulmonary defects in several animal models, matching the phenotype observed in our patients. In silico protein modeling showed probable impairment of ALDH1A2 for three of the four substitutions. In vitro studies show a reduction of RA. Few pathogenic variants in genes encoding components of the retinoic signaling pathway have been described to date, likely due to embryonic lethality. Thus, this study contributes significantly to knowledge of the role of this pathway in human diaphragm and cardiovascular development and disease. Some clinical features in our patients are also observed in Fryns syndrome (MIM# 229850), syndromic microphthalmia 9 (MIM# 601186), and DiGeorge syndrome (MIM# 188400). Patients with similar clinical features who are genetically undiagnosed should be tested for recessive ALDH1A2-deficient malformation syndrome.

A comparison of health-related quality of life in autonomic disorders: postural tachycardia syndrome versus vasovagal syncope.

PURPOSE: Postural tachycardia syndrome (POTS) and vasovagal syncope (VVS) are two disorders of orthostatic intolerance which are often misdiagnosed as the other. In each case, patients experience a reduced health-related quality of life (HRQoL) compared to healthy populations. This study was conducted to test the hypothesis that HRQoL is worse in POTS. METHODS: POTS patients were recruited from the Dysautonomia International Annual Patient and Caregiver Conference. VVS patient data came from those enrolled in the Second Prevention of Syncope Trial. Participants aged ≥ 18 years (177 POTS and 72 VVS) completed the RAND 36-Item Health Survey, a generic and coherent health-related quality of life survey. RESULTS: POTS patients reported reduced HRQoL compared to VVS patients in physical functioning (42.5 ± 1.7 vs. 76.5 ± 2.9, p < 0.001), role limitations due to physical health (11.4 ± 1.9 vs. 33.0 ± 5.0, p < 0.001), energy and fatigue (27.2 ± 1.3 vs. 50.7 ± 2.6, p < 0.001), social functioning (45.2 ± 1.8 vs. 71.2 ± 2.9, p < 0.001), pain (48.8 ± 1.9 vs. 67.7 ± 2.9, p < 0.001), and general health (31.2 ± 1.5 vs. 60.5 ± 2.6, p < 0.001) domains. Scores did not differ significantly in the role limitations due to emotional health (p = 0.052) and emotional well-being (p = 0.271) domains. Physical and general health composite scores were lower in the POTS population, while mental health composite scores were not different. CONCLUSION: Differences in HRQoL exist between these patient populations. POTS patients report lower scores in physical and general health domains than VVS patients, but emotional health domains do not differ significantly. Targeting physical functioning in these patients may help improve quality of life.

Growth hormone and targeted oncological agents: Are we stopping children with brain tumours from reaching their true height potential?

Children with low-grade gliomas have excellent long-term survival outcomes. The development of therapies targeted to the driver mutations along the Mitogen Activated Protein (MAP) kinase signalling pathway are providing long-term stability for many patients with these tumours. Given the frequency of these tumours residing within or near the suprasellar region, our patients commonly suffer from hormone deficiencies. In Australia, the Pharmaceutical Benefits Scheme currently restricts growth hormone therapy to patients who are not being actively treated for cancer, including those receiving targeted therapies. This viewpoint hopes to facilitate an important discussion amongst our colleagues as to whether this should be changed to allow growth hormone to become available to children on chronic tumour suppressive therapy.

Reduced quality of life and greater psychological distress in vasovagal syncope patients compared to healthy individuals.

BACKGROUND: Vasovagal syncope (VVS) patients have a reduced health-related quality of life (HRQoL). There are limited data comparing HRQoL and psychological profile in VVS patients and healthy individuals. We tested the hypothesis that VVS patients have greater impairment in both HRQoL and psychological profile compared to healthy nonfainting individuals, and that both outcome measures are negatively correlated for VVS patients. METHODS: The RAND 36-Item Health Survey (RAND36), global health visual analogue scale (VAS), Hospital Anxiety and Depression Scale, Anxiety Sensitivity Index, and Positive and Negative Affect Schedule - Expanded Form were completed by healthy individuals and at baseline by VVS patients enrolled in the Second Prevention of Syncope Trial, a randomized, placebo-controlled trial of fludrocortisone for VVS. RESULTS: Data were available on 76 VVS patients (34 ± 14 years; 68% F) and 85 healthy participants (35 ± 11 years; 80% F). Compared to healthy participants, VVS patients reported poorer HRQoL on all scales of the RAND36 and the VAS. VVS patients had significantly greater anxiety, depression, and anxiety sensitivity (each P < 0.001). VVS patients had more negative affect (P < 0.001) and less positive affect (P = 0.003) compared to healthy participants. Anxiety, depression, and anxiety sensitivity were negatively correlated with HRQoL for VVS patients, but not for healthy participants. CONCLUSION: In this first direct comparison, VVS patients have a significantly reduced HRQoL and more anxiety and depression compared to healthy nonfainting individuals. For VVS patients, there is a relationship between psychological distress and HRQoL, suggesting a potential benefit from more comprehensive assessment and treatment.

Mesh versus non-mesh for inguinal and femoral hernia repair.

BACKGROUND: This is an update of a Cochrane Review first published in 2001.Hernias are protrusions of all or part of an organ through the body wall that normally contains it. Groin hernias include inguinal (96%) and femoral (4%) hernias, and are often symptomatic with discomfort. They are extremely common, with an estimated lifetime risk in men of 27%. Occasionally they may present as emergencies with complications such as bowel incarceration, obstruction and strangulation. The definitive treatment of all hernias is surgical repair, inguinal hernia repair being one of the most common surgical procedures performed. Mesh (hernioplasty) and the traditional non-mesh repairs (herniorrhaphy) are commonly used, with an increasing preference towards mesh repairs in high-income countries. OBJECTIVES: To evaluate the benefits and harms of different inguinal and femoral hernia repair techniques in adults, specifically comparing closure with mesh versus without mesh. Outcomes include hernia recurrence, complications (including neurovascular or visceral injury, haematoma, seroma, testicular injury, infection, postoperative pain), mortality, duration of operation, postoperative hospital stay and time to return to activities of daily living. SEARCH METHODS: We searched the following databases on 9 May 2018: Cochrane Colorectal Cancer Group Specialized Register, Cochrane Central Register of Controlled Trials (Issue 1), Ovid MEDLINE (from 1950), Ovid Embase (from 1974) and Web of Science (from 1900). Furthermore, we checked the WHO International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for trials. We applied no language or publication restrictions. We also searched the reference lists of included trials and review articles. SELECTION CRITERIA: We included randomised controlled trials of mesh compared to non-mesh inguinal or femoral hernia repairs in adults over the age of 18 years. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Where available, we collected information on adverse effects. We presented dichotomous data as risk ratios, and where possible we calculated the number needed to treat for an additional beneficial outcome (NNTB). We presented continuous data as mean difference. Analysis of missing data was based on intention-to-treat principles, and we assessed heterogeneity using an evaluation of clinical and methodological diversity, Chi2 test and I2 statistic. We used GRADE to assess the quality of evidence for each outcome. MAIN RESULTS: We included 25 studies (6293 participants) in this review. All included studies specified inguinal hernias, and two studies reported that femoral hernias were included.Mesh repair probably reduces the risk of hernia recurrence compared to non-mesh repair (21 studies, 5575 participants; RR 0.46, 95% CI 0.26 to 0.80, I2 = 44%, moderate-quality evidence). In absolute numbers, one hernia recurrence was prevented for every 46 mesh repairs compared with non-mesh repairs. Twenty-four studies (6293 participants) assessed a wide range of complications with varying follow-up times. Neurovascular and visceral injuries were more common in non-mesh repair groups (RR 0.61, 95% CI 0.49 to 0.76, I2 = 0%, NNTB = 22, high-quality evidence). Wound infection was found slightly more commonly in the mesh group (20 studies, 4540 participants; RR 1.29, 95% CI 0.89 to 1.86, I2 = 0%, NNTB = 200, low-quality evidence). Mesh repair reduced the risk of haematoma compared to non-mesh repair (15 studies, 3773 participants; RR 0.88, 95% CI 0.68 to 1.13, I2 = 0%, NNTB = 143, low-quality evidence). Seromas probably occur more frequently with mesh repair than with non-mesh repair (14 studies, 2640 participants; RR 1.63, 95% CI 1.03 to 2.59, I2 = 0%, NNTB = 72, moderate-quality evidence), as does wound swelling (two studies, 388 participants; RR 4.56, 95% CI 1.02 to 20.48, I2 = 33%, NNTB = 72, moderate-quality evidence). The comparative effect on wound dehiscence is uncertain due to wide confidence intervals (two studies, 329 participants; RR 0.55, 95% CI 0.12 to 2.48, I2 = 37% NNTB = 77, low-quality evidence). Testicular complications showed nearly equivocal results; they probably occurred slightly more often in the mesh group however the confidence interval around the effect was wide (14 studies, 3741 participants; RR 1.06, 95% CI 0.63 to 1.76, I2 = 0%, NNTB = 2000, low-quality evidence). Mesh reduced the risk of postoperative urinary retention compared to non-mesh (eight studies, 1539 participants; RR 0.53, 95% CI 0.38 to 0.73, I2 = 56%, NNTB = 16, moderate-quality evidence).Postoperative and chronic pain could not be compared due to variations in measurement methods and follow-up time (low-quality evidence).No deaths occurred during the follow-up periods reported in the seven studies (2546 participants) reporting this outcome (high-quality evidence).The average operating time was longer for non-mesh repairs by a mean of 4 minutes 22 seconds, despite wide variation across the studies regarding size and direction of effect, thus this result is uncertain (20 studies, 4148 participants; 95% CI -6.85 to -1.60, I2= 97%, very low-quality evidence). Hospital stay may be shorter with mesh repair, by 0.6 days (12 studies, 2966 participants; 95% CI -0.86 to -0.34, I2 = 98%, low-quality evidence), and participants undergoing mesh repairs may return to normal activities of daily living a mean of 2.87 days sooner than those with non-mesh repair (10 studies, 3183 participants; 95% CI -4.42 to -1.32, I2 = 96%, low-quality evidence), although the results of both these outcomes are also limited by wide variation in the size and direction of effect across the studies. AUTHORS' CONCLUSIONS: Mesh and non-mesh repairs are effective surgical approaches in treating hernias, each demonstrating benefits in different areas. Compared to non-mesh repairs, mesh repairs probably reduce the rate of hernia recurrence, and reduce visceral or neurovascular injuries, making mesh repair a common repair approach. Mesh repairs may result in a reduced length of hospital stay and time to return to activities of daily living, but these results are uncertain due to variation in the results of the studies. Non-mesh repair is less likely to cause seroma formation and has been favoured in low-income countries due to low cost and reduced availability of mesh materials. Risk of bias in the included studies was low to moderate and generally handled well by study authors, with attention to details of allocation, blinding, attrition and reporting.

How long will I have my ACE? The natural history of the antegrade continence enema stoma in idiopathic constipation.

PURPOSE: We aim to determine the natural history of the ACE in idiopathic constipation and factors predictive of closure. METHODS: A retrospective case-note review of all patients undergo ACE formation for idiopathic constipation Jan 2003-Mar 2016. Kaplan-Meier analysis was used to determine ACE survival and Cox's proportional hazard models to examine potential predictors of closure. RESULTS: 29/84 (35%) ACEs were closed: 21/84 due to success and 8/84 due to failure. Median age of closure was 15.5 years (3.5-23.6). Median ACE survival was 77.0 months (95% CI 58.0-96.0). An ACE survival curve was derived from which we estimate that 5-year post-ACE, one-third of patients can expect to have had their ACE closed. Younger age at ACE was predictive of earlier closure (p = 0.023) and closure for success (p < 0.001). Neither patient sex (p = 0.546) nor presence of psychological comorbidities (p = 0.769) predicted likelihood of closure. Incontinence 6-week post-ACE was also associated with increased likelihood of closure (p = 0.042). CONCLUSION: The ACE survival curve estimates the proportion of patients with idiopathic constipation who can expect closure (either due to success or failure) at certain timepoints. This may be useful for patient counseling. Younger age at ACE was associated with earlier closure (for success).

Vitamin D Levels in Infants With Biliary Atresia: Pre- and Post-Kasai Portoenterostomy.

OBJECTIVES: Infants with biliary atresia (BA) are at high risk of vitamin D deficiency. We aimed to determine the prevalence and factors influencing vitamin D levels at presentation and post-Kasai portoenterostomy (KPE). METHODS: Single-centre retrospective review of infants with BA who underwent KPE. Pre- and postoperatively 25-hydroxyvitamin D (25-OHVD), liver and bone biochemistry data were collected. 25-OHVD levels <10 and 10 to 20 ng/mL were defined as vitamin D "deficiency" and "insufficiency," respectively. RESULTS: One hundred twenty-nine infants with BA (isolated n = 101, developmental n = 28, and white n = 79; non-white n = 50) were included in this study. At presentation, 75 of 92 (81%) were vitamin D deficient and only 1 infant had a level >20 ng/mL. Median 25-OHVD levels were 5(2-23), 17(2-72), 15(2-80), 17(2-69), and 23(2-98) ng/mL at pre-KPE, 1, 4, 6, and 12 months postoperation. There was no difference in 25-OHVD levels between the isolated and developmental groups with BA. Pre-KPE, white infants had significantly higher levels than non-white infants (6[2-23] vs 3[2-14] ng/mL, P = 0.01). Post-KPE 25-OHVD levels correlated well with liver and bone biochemical variables (eg, at 6 months: bilirubin rs = -0.34; P < 0.001, alkaline phosphatase rs = -0.46; P < 0.00001, and phosphate rs = 0.49; P < 0.00001). CONCLUSIONS: 25-OHVD deficiency is invariable at presentation in infants with BA, irrespective of its likely aetiology, and is more severe in non-white infants. Despite routine parenteral and enteral supplementation, low 25-OHVD levels persist post KPE especially in icteric infants. More aggressive vitamin D supplementation and monitoring in this population is paramount.

Natriuretic peptide receptor 3 (NPR3) is regulated by microRNA-100.

Natriuretic peptide receptor 3 (NPR3) is the clearance receptor for the cardiac natriuretic peptides (NPs). By modulating the level of NPs, NPR3 plays an important role in cardiovascular homeostasis. Although the physiological functions of NPR3 have been explored, little is known about its regulation in health or disease. MicroRNAs play an essential role in the post-transcriptional expression of many genes. Our aim was to investigate potential microRNA-based regulation of NPR3 in multiple models. Hypoxic challenge elevated levels of NPPB and ADM mRNA, as well as NT-proBNP and MR-proADM in human left ventricle derived cardiac cells (HCMa), and in the corresponding conditioned medium, as revealed by qRT-PCR and ELISA. NPR3 was decreased while NPR1 was increased by hypoxia at mRNA and protein levels in HCMa. Down-regulation of NPR3 mRNA was also observed in infarct and peri-infarct cardiac tissue from rats undergoing myocardial infarction. From microRNA microarray analyses and microRNA target predictive databases, miR-100 was selected as a candidate regulator of NPR3 expression. Further analyses confirmed up-regulation of miR-100 in hypoxic cells and associated conditioned media. Antagomir-based silencing of miR-100 enhanced NPR3 expression in HCMa. Furthermore, miR-100 levels were markedly up-regulated in rat hearts and in peripheral blood after myocardial infarction and in the blood from heart failure patients. Results from this study point to a role for miR-100 in the regulation of NPR3 expression, and suggest a possible therapeutic target for modulation of NP bioactivity in heart disease.

Transanal irrigation for intractable faecal incontinence and constipation: outcomes, quality of life and predicting non-adopters.

PURPOSE: Intractable faecal incontinence (FI) and constipation is a challenging condition to manage in children. Transanal irrigation (TAI) is a non-operative treatment option. This study presents our experience with TAI with the aim of finding predictive factors of non-compliance. METHODS: This is an outcome and quality of life (QoL) study of a prospectively maintained database of patients < 17 years old commenced on TAI for intractable FI/constipation between 2008 and 2014. Outcome measures were: (1) compliance-classified as non-adopter (use of TAI stopped within 1 month after commencement) or adopter; (2) functional outcome-classified as responder (totally continent or occasional soiling) or non-responder; (3) Rintala score; and (4) QoL score (PedsQL™ 4.0 Generic Core Scale). Analysis to determine predictive factors was also performed. RESULTS: 42 patients were started on TAI [74% male, median age of commencement was 7 (3-16) years]. Underlying diagnoses were: idiopathic constipation (62%), anorectal malformation (26%), Hirschsprung disease (5%), spina bifida (5%) and gastroschisis (2%). Median follow-up period was 14 (3-78) months. 24% were non-adopters. 84% of the adopters responded to treatment. Rintala scores (mean ± SD) pre- and post-TAI were 6.7 ± 3.5 and 11.2 ± 4.8, respectively (P < 0.001). QoL scores pre- and post-TAI were 55.6 ± 24.1 and 65.5 ± 23.7, respectively (P < 0.001). Median age at which TAI was commenced in the non-adopter and adopter group were 6 (IQR 4.5-8.25) and 8 (IQR 7-12), respectively (P = 0.008). CONCLUSION: TAI is a safe and effective treatment for intractable constipation/FI in children. If tolerated, it can significantly improve quality of life. Age and underlying diagnosis are important factors when recommending TAI to children with intractable FI/constipation.

Can celiac serology alone be used as a marker of duodenal mucosal recovery in children with celiac disease on a gluten-free diet?

OBJECTIVES: Assessment of treatment response in children with celiac disease (CD) after commencing a strict gluten-free diet (GFD) is generally based on the resolution of clinical features and normalization of serology. Recent adult studies have shown that serologic markers do not correlate with mucosal recovery. We aimed (i) to determine whether anti-tissue transglutaminase immunoglobulin (Ig)A (tTG) and anti-deamidated gliadin peptide IgG (DGP) antibodies are sensitive and specific markers of mucosal recovery in children with CD on a GFD for at least 12 months, and (ii) to determine whether a validated dietary questionnaire of compliance can identify patients with mucosal recovery. METHODS: A total of 150 children with biopsy-proven CD were prospectively evaluated with duodenal biopsies at ≥12 months on GFD, paired with repeat tTG and DGP serology. The biopsies were reviewed in a blinded manner by two histopathologists and graded by Marsh criteria. A validated questionnaire of dietary compliance was also administered. RESULTS: Of 150 children recruited, 27 (18%) had positive serology, 97 (65%) had negative serology, and 26 (17%) had equivocal serology. Of the 97 children with negative serology, none had Marsh type 3 enteropathy. Of the 27 patients with positive serology, only 6 had Marsh type 3 changes. The sensitivity and specificity of serology as a marker of significant mucosal pathology was 75 and 85%, respectively, with a positive predictive value of 22% but a negative predictive value of 98%. Of the 129 (86%) questionnaires completed, 88% reported good or excellent compliance with a GFD (negative predictive value 97%). CONCLUSIONS: This study suggests that follow-up using two serological tests in children with CD on a GFD may obviate the need for repeat mucosal biopsy in the majority of patients. A standardized dietary questionnaire may be useful in identifying patients who require further evaluation.

A Rare Case Report of Granular Cell Tumour of the Abdominal Wall and a Review of the Literature.

Granular cell tumours (GCTs) are rare soft tissue tumours of neural origin. They have been reported in multiple anatomical sites. However, only 14 cases worldwide have been reported arising from the abdominal wall. While they can clinically manifest in a variety of ways, often they present as a small, slow-growing nodule with benign features. They can, however, be malignant, and in rare cases, they have been reported to metastasise. Here, we present a case of a rare abdominal wall GCT, which was managed with local excision. The purpose of this paper is to report the patient's clinical history, presentation, and surgical management, as well as to review the current literature to highlight the existence of this rare entity and the possibility that this may occur and should be considered a differential diagnosis in clinical practice.