CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors.

The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.

A Postpartum Perineal Clinic in Nova Scotia: Characteristics Associated With Attendance and Its Association With Recurrent Obstetrical Anal Sphincter Tears.

OBJECTIVES: The Healthy Recovery after Childbirth Clinic (HRCC) in Nova Scotia provides postpartum care to patients who experience obstetric anal sphincter injuries (OASIS). The purpose of this study was to describe characteristics associated with HRCC attendance, characteristics associated with a trial of labour in a subsequent delivery, and OASIS recurrence by HRCC attendance status. METHODS: A retrospective cohort study using the Atlee Perinatal Database and clinical record review included primiparous individuals who sustained an OASIS at IWK Health in Halifax between 2013 and 2020. The χ2 and Fisher exact tests were performed to compare groups. RESULTS: Of the 1041 individuals included, 67% attended HRCC. Attendance increased from 58% in 2013-2015 to 77% in 2019-2020. Younger age (<25 years) and smoking were associated with lower HRCC attendance (P = 0.07 and <0.01, respectively). Other characteristics, including area-level income and driving distance to HRCC, were not associated with attendance (P > 0.05). Of the 439 individuals who had a subsequent delivery, 92% had a trial of labour. Individuals with fourth-degree injury were less likely to attempt a trial of labour than those with third-degree injury (73% vs. 94%, P < 0.01). Of those who delivered vaginally, OASIS recurrence was similar in those who did and did not attend the HRCC (7.5% vs. 6.5%, P = 0.84). CONCLUSIONS: HRCC attendance was high, but the disparity by age and smoking status suggests some barriers to access that should be explored. Although we found no difference in OASIS recurrence by HRCC attendance, more research with larger samples with adjustment for confounders is needed.

Music therapy for supporting informal carers of adults with life-threatening illness pre- and post-bereavement; a mixed-methods systematic review.

BACKGROUND: Music therapy interventions with informal carers of individuals with life-threatening illness at pre- and post-bereavement is an increasingly important clinical area. This systematic review is the first to synthesise and critically evaluate the international evidence associated with music therapy with adult informal carers pre- and post-bereavement. Specifically, the objectives were: i) to describe the characteristics and effectiveness of music therapy interventions which aim to improve health-related outcomes for adult informal carers of adults with life-threatening illness (pre- and post-bereavement), and ii) to describe the experience of music therapy for adult informal carers of adults with life-threatening illness (pre- and post-bereavement). METHODS: Eligibility: adult informal carers of adults at end of life or bereaved; music therapy interventions for improving health-related outcomes; qualitative; mixed-method; and quantitative studies including comparators of any other intervention; published in English from 1998 onwards. Six databases were searched up to July 2022. A JBI mixed-methods systematic review approach was followed throughout, including quality appraisal, data extraction and a convergent segregated approach to synthesis and integration. RESULTS: A total of 34 studies were included, published between 2003 and 2022. Most were conducted in North America (n = 13), Australia (n = 10), or Europe (n = 8). No studies were conducted in low- and middle-income countries or in the UK. The majority were qualitative (n = 17), followed by quasi-experimental (n = 8), mixed-methods (n = 7) and two RCTs. The majority focused on carers of individuals with dementia (n = 21) or advanced cancer (n = 7). Seventeen studies were purely quantitative or included a quantitative component. During meta-synthesis, findings were aligned to core outcomes for evaluating bereavement interventions in palliative care and previously identified risk factors for complicated grief. Commonly targeted outcomes in quantitative studies included quality of life and mental wellbeing, showing equivocal effectiveness of music therapy with significant and non-significant results. Twenty-two studies either purely qualitative or with a qualitative component underwent meta synthesis and suggested a diverse range of improved pre- and post-bereavement outcomes for informal carers across all core outcomes, and across all risk and protective factors, including psychological, spiritual, emotional, and social outcomes. CONCLUSIONS: Qualitative studies provide moderate to strong evidence for improved health-related outcomes for adult informal carers of adults with life-threatening illness pre-bereavement. Limited studies including those bereaved negates conclusions for the bereavement phase. Comparisons and explanations for effectiveness across quantitative and qualitative studies are equivocal, with a high risk of bias and small samples in the limited number of quantitative studies, demonstrating a need for high-quality RCTs. SYSTEMATIC REVIEW PRE-REGISTRATION: PROSPERO [CRD42021244859].

Crude protein oscillation in diets adequate and deficient in metabolizable protein: Effects on nutrient digestibility, nitrogen balance, plasma amino acids, and greenhouse gas emissions.

Reducing dietary CP is a well-established means to improve N use efficiency. Yet, few studies have considered if transient restrictions in dietary CP could reduce the environmental footprint of late-lactation cows. We hypothesized that the effects of CP feeding pattern on digestibility and environmental outputs would be amplified at lower dietary CP. We tested CP levels below and near predicted requirements (low protein [LP], 13.8%; high protein [HP], 15.5%) offered in 2 feeding patterns: where diets alternated ±1.8 percentage units CP every 2 d (oscillating [OF]) or remained static. Our study used a 2 × 2 factorial design with 16 mid- to late-lactation Holsteins (mean = 128, SD = 12 DIM), divided into rumen-cannulated (n = 8) and noncannulated subsets (n = 8). For each 28-d experimental period, we recorded feed intake and milk production and took samples of orts (1×/d) and milk (2×/d) for 4 d. For the cannulated subset, we measured and sampled from the total mass of feces and urine production and collected plasma 2×/d across 4 d. For the noncannulated subset, we sampled carbon dioxide and methane emissions 3×/d for 4 d. For each subset, we fit linear mixed models with fixed effects for CP level, CP feeding pattern, the interaction of CP level and CP feeding pattern, period, and a random effect for cow. For plasma and urinary urea-N, we conducted time series analysis. Contrary to our hypothesis, we found no evidence that dietary CP level and CP feeding pattern interacted to influence N balance, nutrient digestibility, or gas emissions. Results showed HP resulted in similar milk N but increased manure N, reducing N use efficiency (milk true protein N/intake N) relative to LP. For OF, urea-N in urine and plasma peaked 46 to 52 h after the first higher-CP phase feeding. Nutrient digestibility and gas emissions were similar across treatments, except CO2 production was greater for OF-HP. In summary, measured variables were minimally affected by dietary CP alternating ±1.8 percentage units every 48 h, even when average dietary CP was fed below predicted requirements (LP). Although our findings suggest that mid- to late-lactation cows are resilient to oscillation in dietary CP, oscillating CP neither reduced the environmental footprint by improving nutrient use efficiencies nor reduced the potential for direct and indirect greenhouse gas emissions.

Comparing the responses of grain-fed feedlot cattle under moderate heat load and during subsequent recovery with those of feed-restricted thermoneutral counterparts: blood cells and inflammatory markers.

Given the climate projections for livestock rearing regions globally, understanding the inflammatory status of livestock under various heat loads will be informative to animal welfare and management. A survey of plasma inflammatory markers was conducted, and blood leucocyte counts followed to investigate the capacity of the ~ 500 kg grain fed Black Angus steer to respond to and recover from a moderate heat load challenge. Two sequential cohorts of 12 steers were housed in climate-controlled rooms (CCR) for 18 days. A thermally challenged (TC) group (n = 2 × 6) experienced five consecutive periods: PreChallenge, Challenge, and Recovery within the CCR, and 40 days in outdoor pens (PENS and Late PENS). PreChallenge (5 days) and Recovery (7 days) delivered thermoneutral conditions, whereas in Challenge the TC steers experienced a diurnal temperature range of 28-35 °C. A feed-restricted thermoneutral (FRTN) treatment (n = 2 × 6) was run concurrently to differentiate between responses to reduced feed intake alone and moderate heat stress. Blood neutrophil counts were particularly sensitive to moderate heat load with higher numbers during Challlenge and in PENs. The plasma concentrations of TNFα and IL-1ß were depressed in the TC group compared to the FRTN counterparts and remained so for 40 days after Challenge. Linear relationships of the concentrations of IL-1ß, IL-10, and haptoglobin with rumen temperature or dry matter intake detected in the FRTN group were altered or absent in the TC group. The findings suggest significant impacts of moderate heat load on the inflammatory status of feedlot cattle.

The effect of a hiding space on the behaviour and heart rate variability of dairy calves during temporary separation from the dam.

In natural settings, newborn calves hide for several days before joining the herd. It is unclear whether dairy calves housed indoors would show similar hiding behaviour. This study aimed to describe the use of an artificial hide provided to calves during temporary separation from the dam and assess the effect it has on lying and sleep-like behaviour, as well as heart rate variability (HRV). Twenty-eight cow-calf pairs were randomly assigned to having a hide (n = 14), or no hide (n = 14). Hide use (n = 14), as well as lying and sleep-like behaviour (n = 28), were recorded continuously via video camera during the first hour after the dam was removed for morning milking on day three to seven. Heart rate and R-R intervals were recorded using Polar equine monitors for a subsample of 12 calves (n = 6 per treatment) on day six. Descriptive statistics were calculated for hide use. Wilcoxon Signed Rank tests were used to evaluate whether having a hide affected lying and sleep-like behaviours as well as HRV. Hide use decreased over days and was highly variable between calves. Lying behaviour did not differ between treatments. Duration of sleep-like behaviour was higher for calves without a hide compared to those with a hide. Calves with a hide tended to show signs of higher HRV and parasympathetic activity compared to calves without a hide. Results suggest that providing a hiding space to young calves may be beneficial during periods when the cow is removed from the pen for milking.

Effectiveness of adjunctive rifampicin for treatment of Staphylococcus aureus bacteraemia: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: To assess whether the addition of rifampicin to conventional treatment of Staphylococcus aureus bacteraemia (SAB) reduces bacteriological or clinical failure or death. DATA SOURCES: PubMed, Embase and Cochrane CENTRAL databases were searched from inception to 31 December 2022. Reference lists and PubMed citations of eligible studies were checked. REVIEW METHODS: Two study authors independently identified randomized controlled trials (RCTs) involving adult participants with SAB, in which an intervention group received adjunctive rifampicin and the control group received usual care with or without a placebo. Dichotomous data (bacteriological and clinical failure and deaths) were analysed and pooled across studies using risk ratio (RR) with 95% confidence intervals (CI) using a Mantel-Haenszel random-effect model. The key variable of interest being whether rifampicin was used. RESULTS: Six RCTs including 894 participants-of which 758 (85%) were from one trial-met the inclusion criteria. The addition of rifampicin to conventional treatment of SAB significantly reduced bacteriological failure by 59% (RR 0.41, 95% CI 0.21-0.81, I2 = 0%, number need to treat 27). However, it did not reduce clinical failure (RR 0.70, 95% CI 0.47-1.03, I2 = 0%) or deaths (RR 0.96, 95% CI 0.70-1.32, I2 = 0%). Further, it did not reduce the duration of bacteraemia, or the length of hospital stay. Adjunctive rifampicin reduced SAB recurrences (1% versus 4%, P = 0.01). Emergence of rifampicin resistance during treatment was uncommon (<1%). CONCLUSION: Although adjunctive rifampicin reduced the risk of bacteriological failure and recurrences, we found no mortality benefit to support its use in SAB.

Evaluation of Radiofrequency Endometrial Ablation: A 17-year Canadian Experience.

STUDY OBJECTIVE: The purpose of this study was to better elucidate radiofrequency endometrial ablation (REA) durability by assessing the probability of failure as defined by need for postablation hysterectomy. Age at index REA, duration from REA until hysterectomy, and REA failure (REAF) risk factors were analyzed. DESIGN: A retrospective cohort study was conducted using patient data between April 1, 2002, and March 31, 2019. REAF cases were identified using operative procedure codes. Cox proportional hazard regression assessed the effect of age at index REA on time to postablation hysterectomy. Kaplan-Meier survival curve evaluated timing of postablation hysterectomy, stratified by age at index REA. SETTING: This study was conducted at Regina General Hospital in Regina, Saskatchewan, Canada. PATIENTS: Patient population included those who were 21 years of age or older, were premenopausal, and had a history of heavy menstrual bleeding at the time of REA. INTERVENTIONS: The intervention under investigation was REA. MEASUREMENTS AND MAIN RESULTS: The overall probability of postablation hysterectomy was 22.6%. The probabilities of postablation hysterectomy were 36.1% for women younger than 30 years (n = 128), 28% for women 30 to 34.9 years old (n = 528), 29.6% for women 35 to 39.9 years old (n = 1152), and 17.6% for women 40 years and older (n = 2221). Characteristics associated with REAF included tubal occlusion, cesarean section, dysmenorrhea, and chronic pelvic pain (p <.01) among women younger than 40 years. Leiomyomas accounted for higher failure rates in women 40 years and older (p <.01). CONCLUSION: Postablation hysterectomy is more likely to occur in women younger than 40 years. REA can be considered in women aged 30 to 39.9 years old, who have no known REAF risk factors. Women younger than 40 years with REAF risk factors will experience higher rates of hysterectomy. Thus, the decision to proceed with REA should be individualized with careful consideration for the underlying causes of abnormal uterine bleeding, while respecting patient autonomy.

Comparing the responses of grain fed feedlot cattle under moderate heat load and during subsequent recovery with those of feed restricted thermoneutral counterparts: metabolic hormones.

We set out to determine the impact of moderate heat load on the plasma concentrations of a suite of hormones involved in regulating energy metabolism and feed intake. The responses of the thermally challenged (TC) feedlot steers were compared to those of feed restricted thermoneutral (FRTN) steers. Two sequential cohorts of twelve 518 ± 23 kg Black Angus steers on finisher grain ration were housed in climate-controlled rooms (CCR) for 18 days and returned to outdoor pens for 40 days. The TC group was subjected to a diurnal range of 28-35 °C for 7 days (Challenge) but held in thermoneutral conditions beforehand (PreChallenge), and in Recovery (after Challenge). The FRTN group was held in thermoneutral conditions and feed restricted throughout. Blood was collected over the three periods in CCR and two periods in outdoor pens for 40 days (PENS and Late PENS). Plasma concentrations of prolactin, thyroid stimulating hormone, insulin, leptin, adiponectin and thyroxine (T4) were determined during the five periods. Whilst the pituitary hormones were relatively stable, there were differences in plasma leptin, adiponectin and T4 between the two groups during Challenge and Recovery, and occasionally in PENS. The interaction of the plasma hormone concentrations and rumen temperature and DMI were also investigated. Whilst the positive relationship between DMI and leptin was confirmed, we found a strong negative relationship between adiponectin and rumen temperature, and a strong positive relationship between adiponectin and dry matter intake (DMI) in the TC steers only.

Contribution of the innate and adaptive immune systems to aortic dilation in murine mucopolysaccharidosis type I.

BACKGROUND: Adult immunocompetent male C57Bl/6 mucopolysaccharidosis, type I (MPSI) mice develop aortic insufficiency (AI), dilated ascending aortas and decreased cardiac function, findings not observed in immune incompetent adult male NSG MPSI mice. We sought to determine why. METHODS: Cardiac ultrasound measurements of ascending aorta and left ventricular dimensions and Doppler interrogation for AI were performed in 6-month-old male B6 MPSI (N = 12), WT (N = 6), NSG MPSI (N = 8), NSG (N = 6) mice. Urinary glycosaminoglycans, RNA sequencing with quantitative PCR were performed and aortic pathology assessed by routine and immunohistochemical staining on subsets of murine aortas. RESULTS: Ascending aortic diameters were significantly greater, left ventricular function significantly decreased, and AI significantly more frequent in B6 MPSI mice compared to NSG MPSI mice (p < 0.0001, p = 0.008 and p = 0.02, respectively); NSG and B6 WT mice showed no changes. Urinary glycosaminoglycans were significantly greater in B6 and NSG MPSI mice and both were significantly elevated compared to WT controls (p = 0.003 and p < 0.0001, respectively). By RNA sequencing, all 11 components of the inflammasome pathway were upregulated in B6 MUT, but only Aim2 and Ctsb in NSG MUT mice and none in WT controls. Both B6 and NSG MUT mice demonstrated variably-severe intramural inflammation, vacuolated cells, elastin fragmentation and disarray, and intense glycosaminoglycans on histological staining. B6 MPSI mice demonstrated numerous medial MAC2+ macrophages and adventitial CD3+ T-cells while MAC2+ macrophages were sparse and CD3+ T-cells absent in NSG MPSI mice. CONCLUSIONS: Aortic dilation, AI and decreased cardiac function occur in immunocompetent B6 MPSI male mice but not in immune incompetent NSG MPSI mice, unrelated to GAG excretion, upregulation of Ctsb, or routine histologic appearance. Upregulation of all components of the inflammasome pathway in B6 MUT, but not NSG MUT mice, and abundant medial MAC2 and adventitial CD3 infiltrates in B6, but not NSG, MPSI aortas differentiated the two strains. These results suggest that the innate and adaptive immune systems play a role in these cardiac findings which may be relevant to human MPSI.

Histone Deacetylase Sirtuin 1 Promotes Loss of Primary Cilia in Cholangiocarcinoma.

BACKGROUND AND AIMS: Sirtuin 1 (SIRT1) is a complex NAD+ -dependent protein deacetylase known to act as a tumor promoter or suppressor in different cancers. Here, we describe a mechanism of SIRT1-induced destabilization of primary cilia in cholangiocarcinoma (CCA). APPROACH AND RESULTS: A significant overexpression of SIRT1 was detected in human CCA specimens and CCA cells including HuCCT1, KMCH, and WITT1 as compared with normal cholangiocytes (H69 and NHC). Small interfering RNA (siRNA)-mediated knockdown of SIRT1 in HuCCT1 cells induced cilia formation, whereas overexpression of SIRT1 in normal cholangiocytes suppressed ciliary expression. Activity of SIRT1 was regulated by presence of NAD+ in CCA cells. Inhibition of NAD -producing enzyme nicotinamide phosphoribosyl transferase increased ciliary length and frequency in CCA cells and in SIRT1-overexpressed H69 cells. Furthermore, we also noted that SIRT1 induces the proteasomal mediated degradation of ciliary proteins, including α-tubulin, ARL13B, and KIF3A. Moreover, overexpression of SIRT1 in H69 and NHC cells significantly induced cell proliferation and, conversely, SIRT1 inhibition in HuCCT1 and KMCH cells using siRNA or sirtinol reduced cell proliferation. In an orthotopic transplantation rat CCA model, the SIRT1 inhibitor sirtinol reduced tumor size and tumorigenic proteins (glioma-associated oncogene 1, phosphorylated extracellular signal-regulated kinase, and IL-6) expression. CONCLUSIONS: In conclusion, these results reveal the tumorigenic role of SIRT1 through modulation of primary cilia formation and provide the rationale for developing therapeutic approaches for CCA using SIRT1 as a target.

Meningioma with rhabdoid features: Pathologic findings in dogs.

Rhabdoid meningioma is a rare type of meningeal neoplasm in humans. This study reports the clinical, pathological, and ultrastructural features of 4 cases of canine meningioma with rhabdoid features. The cases were female and 8 to 12 years of age. Biopsies from complete surgical resections were examined for all cases. The whole brain with tumor recurrence was collected at necropsy in 2 dogs. Histologically, the tumors consisted of discohesive sheets of oval-polygonal cells with abundant eosinophilic cytoplasm and occasional paranuclear hyaline-like inclusions. Cells were intensely immunopositive for vimentin, negative for melan A and S100 protein in all cases, and showed variable immunolabeling for cytokeratin in 2 cases. Focal glial fibrillary acidic protein (GFAP)-immunopositive cells were present in 1 case. Ultrastructurally, the rhabdoid cells in case 1 contained prominent cytoplasmic whorls of intermediate filaments, recapitulating the ultrastructural features of rhabdoid meningioma in humans. In cases 2 and 3, the meningioma cells contained interdigitating cell processes folded in a maze-like fashion resembling rhabdoid-like meningioma in humans. In case 4, the voluminous cytoplasm contained many round-to-flattened mitochondria admixed with rough endoplasmic reticulum, indicating a predominant oncocytic differentiation and not the rhabdoid differentiation suggested by light microscopy. Thus, rhabdoid morphology occurs in different types of meningiomas, and ultrastructural findings are essential for a correct diagnosis.

Comparing the responses of grain fed feedlot cattle under moderate heat load and during subsequent recovery with those of feed restricted thermoneutral counterparts: plasma biochemistry.

Responses to heat stress in ruminants reflect the integration of local climatic conditions, environment/production system and the animal's homeostatic and homeorhetic capacities. Thus, the goal of ameliorating heat stress requires experimental settings that, within limits, closely resemble the target production system and cohort. We investigated the blood biochemical changes of two sequential cohorts of twelve 518 ± 23 kg grain fed Black Angus steers. Each cohort consisted of two treatments of 6 head/group: a thermally challenged (TC) treatment and a feed restricted thermoneutral (FRTN) treatment. Both groups were housed in climate controlled rooms for 19 days, with the TC group experiencing three distinct periods: PreChallenge, Challenge and Recovery. PreChallenge and Recovery delivered thermoneutral conditions, while Challenge consisted of 7 days of moderate diurnal heat load. The FRTN group was maintained in thermoneutral conditions at all times. Both groups were then relocated to outdoor pens for a further 40 days to detect any enduring change to metabolism as a consequence of the treatments. We compared blood biochemical responses of the treatments and inferred likely metabolic changes. Relative to the FRTN group, the TC animals experienced limited supply of triglycerides, cholesterol and glutamine during moderate heat load, suggesting constraints to energy metabolism. Lower blood urea during Recovery and in outdoor pens implied a requirement to capture N rather than allow its excretion. Altered liver enzyme profiles indicated a higher level of hepatic stress in the TC group. By the completion of feedlot finishing, the groups were not separable on most measures.

18 months on: an interrupted time series analysis investigating the effect of COVID-19 on chlamydia and gonorrhoea testing and test positivity at the Gold Coast, Australia.

BACKGROUND: STI rates have been reported as reduced during the height of the COVID-19 pandemic. Our study evaluates the number of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) infections recorded relative to the number of tests performed in 2017-2021, thus accurately depicting trends over time and evaluate the effect of COVID-19 restrictions since these were implemented in March 2020. METHODS: Data was extracted from an electronic database of pathology and clinical records used at Gold Coast Sexual Health Service (GCSHS) in Queensland, Australia from January 2017 to October 2021. Poisson regression-based interrupted time series analyses were performed for number of tests performed and test positivity over the study period. The COVID-19 period was defined as starting from March 2020 when public health directives were implemented. RESULTS: CT and NG testing dropped significantly in the month after COVID-19 restrictions were brought in, by 30% and 23% respectively. Over the 5year study period, the proportion of positive CT tests has consistently decreased by approximately 0.33% points per year (P ≤0.001). The instigation of COVID-19 restrictions had no effect on this trend. The proportion of NG positive tests remained steady prior to COVID-19 (P =0.96) at approximately 3.5%, decreased immediately at the onset of COVID-19 restrictions to approximately 2.5% (P <0.001) and has remained at this level post-COVID restrictions (P =0.54). Testing at GCSHS continued to target gay and bisexual men, accounting for ≥50% of all tests performed. CONCLUSION: Our study suggests that there has been a sustained reduction in test positivity of NG infections in the 18months since COVID-19 restrictions were implemented, and that this is not an artifact of reduced testing. It highlights the importance of maintaining health messaging including screening for sexually transmissible infections and maintaining access to services, which may include alternative models of care such as Telehealth, self-testing and collaboration between all sexual health service providers.

National Audit of Criteria For Pre-Operative Sickle Cell Screening in Children.

Aim We set out to identify the current practice in the anaesthesiology departments of Ireland's public hospitals that deliver paediatric anaesthesia with regard to pre-operative screening for sickle cell disease (SCD) and Sickle cell trait (SCT). Methods The Departments of Anaesthesiology at 14 public HSE-funded hospitals that deliver paediatric anaesthesia were contacted over a three month period in 2020. Any existing policies regarding pre-operative screening of paediatric patients for Sickle cell disease or trait were sought. Comparisons were made between any screening policies in place. Results A response was received from 11 of the 14 hospitals. Three out of 11 of the Anaesthesiology Departments have formal policies in place. The ethnicities identified for pre-operative screening varied across these three hospitals. Conclusion Despite a significant increase in the number of people of African, middle Eastern & Indian descent living in Ireland in recent years, no neonatal screening programme for Sickle cell exists here, and no national policy exists with criteria to guide the practice of pre-operative screening of patients for SCD/SCT (trait). Our survey highlights a lack of standardisation in the approach to pre-operative sickle cell screening of children across Ireland's public hospital system. In view of the increasing multiculturalism in Ireland we recommend a national review of the merits of the introduction of developing a targeted national guideline for pre-operative screening for sickle cell in at-risk children.

Coexposure to Inhaled Aldehydes or Carbon Dioxide Enhances the Carcinogenic Properties of the Tobacco-Specific Nitrosamine 4-Methylnitrosamino-1-(3-pyridyl)-1-butanone in the A/J Mouse Lung.

Tobacco smoke is a complex mixture of chemicals, many of which are toxic and carcinogenic. Hazard assessments of tobacco smoke exposure have predominantly focused on either single chemical exposures or the more complex mixtures of tobacco smoke or its fractions. There are fewer studies exploring interactions between specific tobacco smoke chemicals. Aldehydes such as formaldehyde and acetaldehyde were hypothesized to enhance the carcinogenic properties of the human carcinogen, 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) through a variety of mechanisms. This hypothesis was tested in the established NNK-induced A/J mouse lung tumor model. A/J mice were exposed to NNK (intraperitoneal injection, 0, 2.5, or 7.5 µmol in saline) in the presence or absence of acetaldehyde (0 or 360 ppmv) or formaldehyde (0 or 17 ppmv) for 3 h in a nose-only inhalation chamber, and lung tumors were counted 16 weeks later. Neither aldehyde by itself induced lung tumors. However, mice receiving both NNK and acetaldehyde or formaldehyde had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that aldehydes may increase the severity of NNK-induced lung adenomas. The aldehyde coexposure did not affect the levels of NNK-derived DNA adduct levels. Similar studies tested the ability of a 3 h nose-only carbon dioxide (0, 5, 10, or 15%) coexposure to influence lung adenoma formation by NNK. While carbon dioxide alone was not carcinogenic, it significantly increased the number of NNK-derived lung adenomas without affecting NNK-derived DNA damage. These studies indicate that the chemicals in tobacco smoke work together to form a potent lung carcinogenic mixture.

Cancer spectrum in TP53-deficient golden Syrian hamsters: A new model for Li-Fraumeni syndrome.

BACKGROUND: The TP53 tumor suppressor gene is the most commonly mutated gene in human cancers. Humans who inherit mutant TP53 alleles develop a wide range of early onset cancers, a disorder called Li-Fraumeni Syndrome (LFS). Trp53-deficient mice recapitulate most but not all of the cancer phenotypes observed in TP53-deficient human cancers, indicating that new animal models may complement current mouse models and better inform on human disease development. MATERIALS AND METHODS: The recent application of CRISPR/Cas9 genetic engineering technology has permitted the emergence of golden Syrian hamsters as genetic models for wide range of diseases, including cancer. Here, the first cancer phenotype of TP53 knockout golden Syrian hamsters is described. RESULTS: Hamsters that are homozygous for TP53 mutations become moribund on average ~ 139 days of age, while hamsters that are heterozygous become moribund at ~ 286 days. TP53 homozygous knockout hamsters develop a wide range of cancers, often synchronous and metastatic to multiple tissues, including lymphomas, several sarcomas, especially hemangiosarcomas, myeloid leukemias and several carcinomas. TP53 heterozygous mutants develop a more restricted tumor spectrum, primarily lymphomas. CONCLUSIONS: Overall, hamsters may provide insights into how TP53 deficiency leads to cancer in humans and can become a new model to test novel therapies.

A Highly Efficacious PS Gene Editing System Corrects Metabolic and Neurological Complications of Mucopolysaccharidosis Type I.

Our previous study delivered zinc finger nucleases to treat mice with mucopolysaccharidosis type I (MPS I), resulting in a phase I/II clinical trial (ClinicalTrials.gov: NCT02702115). However, in the clinical trial, the efficacy needs to be improved due to the low transgene expression level. To this end, we designed a proprietary system (PS) gene editing approach with CRISPR to insert a promoterless α-l-iduronidase (IDUA) cDNA sequence into the albumin locus of hepatocytes. In this study, adeno-associated virus 8 (AAV8) vectors delivering the PS gene editing system were injected into neonatal and adult MPS I mice. IDUA enzyme activity in the brain significantly increased, while storage levels were normalized. Neurobehavioral tests showed that treated mice had better memory and learning ability. Also, histological analysis showed efficacy reflected by the absence of foam cells in the liver and vacuolation in neuronal cells. No vector-associated toxicity or increased tumorigenesis risk was observed. Moreover, no off-target effects were detected through the unbiased genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) analysis. In summary, these results showed the safety and efficacy of the PS in treating MPS I and paved the way for clinical studies. Additionally, as a therapeutic platform, the PS has the potential to treat other lysosomal diseases.

Prognostic histopathologic features of canine glial tumors.

Gliomas are relatively common tumors in aged dogs (especially brachycephalic breeds), and the dog is proving to be useful as a translational model for humans with brain tumors. Hitherto, there is relatively little prognostic data for canine gliomas and none on outcome related to specific histological features. Histologic sections of tumor biopsies from 33 dogs with glioma treated with surgical resection and immunotherapy and 21 whole brains obtained postmortem were reviewed. Tumors were diagnosed as astrocytic, oligodendroglial, or undefined glioma using Comparative Brain Tumor Consortium criteria. Putative features of malignancy were evaluated, namely, mitotic counts, glomeruloid vascularization, and necrosis. For biopsies, dogs with astrocytic tumors lived longer than those with oligodendroglial or undefined tumor types (median survival 743, 205, and 144 days, respectively). Dogs with low-grade gliomas lived longer than those with high-grade gliomas (median survival 734 and 194 days, respectively). Based on analysis of tumor biopsies, low mitotic counts, absence of glomeruloid vascularization, and absence of necrosis correlated with increased survival (median 293, 223, and 220 days, respectively), whereas high mitotic counts, glomeruloid vascularization, and necrosis correlated with poor survival (median 190, 170, and 154 days, respectively). Mitotic count was the only histological feature in biopsy samples that significantly correlated with survival (P < .05). Whole-brain analyses for those same histologic features had similar and more robust correlations, and were statistically significant for all features (P < .05). The small size of biopsy samples may explain differences between biopsy and whole-brain tumor data. These findings will allow more accurate prognosis for gliomas.

Effect of bovine feeding system (pasture or concentrate) on the oxidative and sensory shelf life of whole milk powder.

Correlating volatile compounds with the sensory attributes of whole milk powder (WMP) is fundamental for appreciating the effect of lipid oxidation (LO) on sensory perception. LO compounds can adversely affect the sensory perception of WMP by imparting rancid, metallic, and painty notes. Whole milk powders derived from milk produced by cows maintained on a pasture diet (grass and grass-clover mix) versus a nonpasture diet [total mixed ration (TMR); concentrates and silage] were stored at room temperature 21°C (ambient storage) and 37°C (accelerated storage) and analyzed for volatile compounds and sensory attributes every 2 mo for a total of 6 mo. Thirteen volatile compounds originating from LO were chosen to track the volatile profile of the WMP during storage. Color, composition, total fatty acid, and free fatty acid profiling were also carried out. Significant variations in the concentrations of 14 fatty acids were observed in WMP based on diet. Concentrations of free fatty acids increased in all sample types during storage. Similar trends in sensory attributes were observed with an increase in painty attributes, corresponding to an increase in hexanal. Buttery/toffee attributes were found to be more closely correlated with TMR WMP. Those WMP derived from pasture diets were found to be more susceptible to LO from a volatile perspective, particularly in relation to aldehyde development, which is likely due to increased concentrations of conjugated linoleic acid and α-linolenic acid found in these samples.