Complex chronic conditions among children born to women with schizophrenia.

PURPOSE: Maternal schizophrenia is linked to complications in offspring near the time of birth. Whether there is also a higher future risk of the child having a complex chronic condition (CCC) - a pediatric condition affecting any bodily system expected to last at least 12 months that is severe enough to require specialty care and/or a period of hospitalization - is not known. METHODS: In this population-based health administrative data cohort study (Ontario, Canada, 1995-2018), the risk for CCC was compared in 5066 children of women with schizophrenia (the exposed) vs. 2,939,320 unexposed children. Adjusted hazard ratios (aHR) were generated for occurrence of any CCC, by CCC category, and stratified by child sex, and child prematurity. RESULTS: CCC was more frequent in the exposed (7.7 per 1000 person-years [268 children]) than unexposed (4.2 per 100 person-years [124,452 children]) - an aHR of 1.25 (95% CI 1.10-1.41). aHRs were notably higher in 5 of 9 CCC categories: neuromuscular (1.73, 1.28-2.33), cardiovascular (1.94, 1.64-2.29), respiratory (1.83, 1.32-2.54), hematology/immunodeficiency (2.24, 1.24-4.05) and other congenital or genetic defect (1.59, 1.16-2.17). The aHR for CCC was more pronounced among boys (1.32, 1.13-1.55) than girls (1.16, 0.96-1.40), and of similar magnitude in term (1.22, 1.05-1.42) and preterm infants (1.18, 0.95-1.46). CONCLUSIONS: The risk for a CCC appears to be higher in children born to women with schizophrenia. This finding introduces opportunities for targeted preconception counselling, optimization of maternal risk factors, and intervention to support a vulnerable parent population who will experience unique challenges caring for a child with CCCs.

Efflux transporters in rat placenta and developing brain: transcriptomic and functional response to paracetamol.

Adenosine triphosphate binding cassette (ABC) transporters transfer lipid-soluble molecules across cellular interfaces either directly or after enzymatic metabolism. RNAseq analysis identified transcripts for ABC transporters and enzymes in rat E19, P5 and adult brain and choroid plexus and E19 placenta. Their functional capacity to efflux small molecules was studied by quantitative analysis of paracetamol (acetaminophen) and its metabolites using liquid scintillation counting, autoradiography and ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Animals were treated acutely (30 min) and chronically (5 days, twice daily) with paracetamol (15 mg/kg) to investigate ability of brain and placenta barriers to regulate ABC transport functionality during extended treatment. Results indicated that transcripts of many efflux-associated ABC transporters were higher in adult brain and choroid plexus than at earlier ages. Chronic treatment upregulated certain transcripts only in adult brain and altered concentrations of paracetamol metabolites in circulation of pregnant dams. Combination of changes to metabolites and transport system transcripts may explain observed changes in paracetamol entry into adult and fetal brains. Analysis of lower paracetamol dosing (3.75 mg/kg) indicated dose-dependent changes in paracetamol metabolism. Transcripts of ABC transporters and enzymes at key barriers responsible for molecular transport into the developing brain showed alterations in paracetamol pharmacokinetics in pregnancy following different treatment regimens.

HDAC7 is an actionable driver of therapeutic antibody resistance by macrophages from CLL patients.

Resistance, to therapeutic antibodies used to treat chronic lymphocytic leukemia (CLL) patients is common. Monocyte-derived macrophages (MDMs) are a major effector of antitumour responses to therapeutic antibodies and we have previously reported that resistance to therapeutic antibodies, by MDMs, increases as CLL disease progresses. In this study, we examine the effect of a Class IIa-selective HDAC inhibitor (TMP195) on the phagocytic response to opsonised tumor cells or non-opsonised targets by MDMs derived from CLL patients. We report that TMP195 enhances phagocytic responses to antibody-opsonised CLL cells and E. coli within 30 min of treatment. The enhanced response is phenocopied by knockdown of the Class IIa HDAC, HDAC7, or by low concentrations of the pan-HDAC inhibitor, vorinostat. HDAC7 knockdown and inhibition induces hyperacetylation and hyperphosphorylation of Bruton's tyrosine kinase (BTK). Moreover, BTK inhibitors abrogated the enhanced response to HDAC7 inhibition. Our data show that HDAC7 is an actionable driver of resistance to therapeutic antibodies by MDMs derived from CLL patients.

Eustachian tube balloon dilatation: a cross-sectional, survey-based study of 137 UK consultants.

OBJECTIVE: To explore the opinions of the UK consultant body on endoscopic Eustachian tube balloon dilatation in the context of Eustachian tube dysfunction. METHOD: A 10-question online survey was distributed to ENT consultants currently practising in the UK (July-September 2018). RESULTS: A total of 137 ENT consultants responded. Twenty-three per cent reported experience of Eustachian tube balloon dilatation, with a further 10 per cent planning to start performing the procedure. Of those performing the procedure, 16 per cent had more than two years' experience. Thirty-two per cent were performing zero to five procedures a year. Eustachian tube balloon dilatation was primarily conducted to treat Eustachian tube dysfunction symptoms, as well as retraction pockets, baro-challenge-induced Eustachian tube dysfunction and otitis media with effusion. The most common reason for not undertaking Eustachian tube balloon dilatation was insufficient evidence of efficacy (65 per cent). Seventy-two per cent of consultants thought that creating a national database for audit and monitoring purposes would benefit the specialty. CONCLUSION: The majority of UK ENT consultants do not practise Eustachian tube balloon dilatation, citing a lack of high-level evidence to support its use. A national database for auditing and research could facilitate the creation of guidelines.

Genome-Wide Association Studies for Methane Production in Dairy Cattle.

Genomic selection has been proposed for the mitigation of methane (CH4) emissions by cattle because there is considerable variability in CH4 emissions between individuals fed on the same diet. The genome-wide association study (GWAS) represents an important tool for the detection of candidate genes, haplotypes or single nucleotide polymorphisms (SNP) markers related to characteristics of economic interest. The present study included information for 280 cows in three dairy production systems in Mexico: 1) Dual Purpose (n = 100), 2) Specialized Tropical Dairy (n = 76), 3) Familiar Production System (n = 104). Concentrations of CH4 in a breath of individual cows at the time of milking (MEIm) were estimated through a system of infrared sensors. After quality control analyses, 21,958 SNPs were included. Associations of markers were made using a linear regression model, corrected with principal component analyses. In total, 46 SNPs were identified as significant for CH4 production. Several SNPs associated with CH4 production were found at regions previously described for quantitative trait loci of composition characteristics of meat, milk fatty acids and characteristics related to feed intake. It was concluded that the SNPs identified could be used in genomic selection programs in developing countries and combined with other datasets for global selection.

Does the diurnal pattern of enteric methane emissions from dairy cows change over time?

Diet manipulation and genetic selection are two important mitigation strategies for reducing enteric methane (CH4) emissions from ruminant livestock. The aim of this study was to assess whether the diurnal pattern of CH4 emissions from individual dairy cows changes over time when cows are fed on diets varying in forage composition. Emissions of CH4 from 36 cows were measured during milking in an automatic (robotic) milking station in three consecutive feeding periods, for a total of 84 days. In Periods 1 and 2, the 36 cows were fed a high-forage partial mixed ration (PMR) containing 75% forage, with either a high grass silage or high maize silage content. In Period 3, cows were fed a commercial PMR containing 69% forage. Cows were offered PMR ad libitum plus concentrates during milking and CH4 emitted by individual cows was sampled during 8662 milkings. A linear mixed model was used to assess differences among cows, feeding periods and time of day. Considerable variation was observed among cows in daily mean and diurnal patterns of CH4 emissions. On average, cows produced less CH4 when fed on the commercial PMR in feeding Period 3 than when the same cows were fed on high-forage diets in feeding Periods 1 and 2. The average diurnal pattern for CH4 emissions did not significantly change between feeding periods and as lactation progressed. Emissions of CH4 were positively associated with dry matter (DM) intake and forage DM intake. It is concluded that if the management of feed allocation remains constant then the diurnal pattern of CH4 emissions from dairy cows will not necessarily alter over time. A change in diet composition may bring about an increase or decrease in absolute emissions over a 24-h period without significantly changing the diurnal pattern unless management of feed allocation changes. These findings are important for CH4 monitoring techniques that involve taking measurements over short periods within a day rather than complete 24-h observations.

Viral infections and breast cancer - A current perspective.

Sporadic human breast cancer is the most common cancer to afflict women. Since the discovery, decades ago, of the oncogenic mouse mammary tumour virus, there has been significant interest in the potential aetiologic role of infectious agents in sporadic human breast cancer. To address this, many studies have examined the presence of viruses (e.g. papillomaviruses, herpes viruses and retroviruses), endogenous retroviruses and more recently, microbes, as a means of implicating them in the aetiology of human breast cancer. Such studies have generated conflicting experimental and clinical reports of the role of infection in breast cancer. This review evaluates the current evidence for a productive oncogenic viral infection in human breast cancer, with a focus on the integration of sensitive and specific next generation sequencing technologies with pathogen discovery. Collectively, the majority of the recent literature using the more powerful next generation sequencing technologies fail to support an oncogenic viral infection being involved in disease causality in breast cancer. In balance, the weight of the current experimental evidence supports the conclusion that viral infection is unlikely to play a significant role in the aetiology of breast cancer.

The duality of macrophage function in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia and, in some patients, is accompanied by resistance to both chemotherapeutics and immunotherapeutics. In this review we will discuss the role of tumour associated macrophages (TAMs) in promoting CLL cell survival and resistance to immunotherapeutics. In addition, we will discuss mechanisms by which TAMs suppress T-cell mediated antitumour responses. Thus, targeting macrophages could be used to i) reduce the leukaemic burden via the induction of T-cell-mediated antitumour responses, ii) to reduce pro-survival signalling and enhance response to conventional chemotherapeutics or iii) enhance the response to therapeutic antibodies in current clinical use.

Efficacy of ACL injury risk screening methods in identifying high-risk landing patterns during a sport-specific task.

Screening methods sensitive to movement strategies that increase anterior cruciate ligament (ACL) loads are likely to be effective in identifying athletes at-risk of ACL injury. Current ACL injury risk screening methods are yet to be evaluated for their ability to identify athletes' who exhibit high-risk lower limb mechanics during sport-specific maneuvers associated with ACL injury occurrences. The purpose of this study was to examine the efficacy of two ACL injury risk screening methods in identifying high-risk lower limb mechanics during a sport-specific landing task. Thirty-two female athletes were screened using the Landing Error Scoring System (LESS) and Tuck Jump Assessment. Participants' also completed a sport-specific landing task, during which three-dimensional kinematic and kinetic data were collected. One-dimensional statistical parametric mapping was used to examine the relationships between screening method scores, and the three-dimensional hip and knee joint rotation and moment data from the sport-specific landing. Higher LESS scores were associated with reduced knee flexion from 30 to 57 ms after initial contact (P = 0.003) during the sport-specific landing; however, no additional relationships were found. These findings suggest the LESS and Tuck Jump Assessment may have minimal applicability in identifying athletes' who exhibit high-risk landing postures in the sport-specific task examined.

Identification of bacterial pathogens and antimicrobial resistance directly from clinical urines by nanopore-based metagenomic sequencing.

OBJECTIVES: The introduction of metagenomic sequencing to diagnostic microbiology has been hampered by slowness, cost and complexity. We explored whether MinION nanopore sequencing could accelerate diagnosis and resistance profiling, using complicated urinary tract infections as an exemplar. METHODS: Bacterial DNA was enriched from clinical urines (n = 10) and from healthy urines 'spiked' with multiresistant Escherichia coli (n = 5), then sequenced by MinION. Sequences were analysed using external databases and bioinformatic pipelines or, ultimately, using integrated real-time analysis applications. Results were compared with Illumina data and resistance phenotypes. RESULTS: MinION correctly identified pathogens without culture and, among 55 acquired resistance genes detected in the cultivated bacteria by Illumina sequencing, 51 were found by MinION sequencing directly from the urines; with three of the four failures in an early run with low genome coverage. Resistance-conferring mutations and allelic variants were not reliably identified. CONCLUSIONS: MinION sequencing comprehensively identified pathogens and acquired resistance genes from urine in a timeframe similar to PCR (4 h from sample to result). Bioinformatic pipeline optimization is needed to better detect resistances conferred by point mutations. Metagenomic-sequencing-based diagnosis will enable clinicians to adjust antimicrobial therapy before the second dose of a typical (i.e. every 8 h) antibiotic.

Increased FcγRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients.

Resistance to therapeutic antibodies in chronic lymphocytic leukaemia (CLL) is common. In this study, we show that therapeutic antibodies against CD62L (CD62L-Ab) or CD20 (obinutuzumab) were able to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and phagocytosis (ADP) in primary cultures of CLL cells. CLL cells derived from patients with active disease requiring treatment displayed resistance to these antibodies, whereas patients with stable disease were sensitive. Using enrichment strategies and transcriptomic analyses, we show that antibody-dependent tumour cell killing was FcγR-dependent and mediated by macrophages. Moreover, we show that resistance cannot be attributed to total numbers or established subtypes of monocytes/macrophages, or the efficiency with which they bind an immune complex. Rather, ADCC/ADP resistance was due to reduced signalling activity through the activating FcγRs resulting in the transfer of dominance to the inhibitory FcγRIIb within macrophages. Most significantly, we show that resistance is an actionable event that could be reversed using inhibitors of FcγRIIb signalling in primary cultures of CLL cells that were previously insensitive to obinutuzumab or CD62L-Ab.

Transcriptomic analysis of monocytes and macrophages derived from CLL patients which display differing abilities to respond to therapeutic antibody immune complexes.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. While therapeutic antibodies show clinical activity in CLL patients, resistance inevitably develops resulting in treatment failure. Identifying mechanisms of antibody resistance and methods to reduce resistance would be valuable in managing CLL. Monocyte derived cells (MDCs), also known as nurse like cells (NLCs) in CLL [1], [2], are known to be crucial components of the CLL microenvironment network and following "maturation" in in vitro culture systems are able to provide support for the survival of the malignant B cells from CLL patients. In addition to their protective role, MDCs are key effector cells in mediating responses to therapeutic antibody therapies [3]. We have determined that macrophages from patients with early stable CLL are able to elicit superior cytotoxic response to therapeutic antibodies than macrophages derived from patients with progressive CLL. We have exploited this unique finding to gain insight into antibody resistance. Thus, we have profiled monocytes on day 0 and MDCs on day 7 from antibody sensitive and antibody resistant CLL patients (GEO accession number GEO: GSE71409). We show that there are no significant differences in transcriptomes from the monocytes or MDCs derived from sensitive or resistant patient samples. However, we show that MDCs acquire an M2-like macrophage transcriptomic signature following 7 days culture regardless of whether they were derived from sensitive or resistant patient samples.

The BDNF Val66Met polymorphism moderates the relationship between cognitive reserve and executive function.

The concept of cognitive reserve (CR) has been proposed to account for observed discrepancies between pathology and its clinical manifestation due to underlying differences in brain structure and function. In 433 healthy older adults participating in the Tasmanian Healthy Brain Project, we investigated whether common polymorphic variations in apolipoprotein E (APOE) or brain-derived neurotrophic factor (BDNF) influenced the association between CR contributors and cognitive function in older adults. We show that BDNF Val66Met moderates the association between CR and executive function. CR accounted for 8.5% of the variance in executive function in BDNF Val homozygotes, but CR was a nonsignificant predictor in BDNF Met carriers. APOE polymorphisms were not linked to the influence of CR on cognitive function. This result implicates BDNF in having an important role in capacity for building or accessing CR.

Methane emissions among individual dairy cows during milking quantified by eructation peaks or ratio with carbon dioxide.

The aims of this study were to compare methods for examining measurements of CH4 and CO2 emissions of dairy cows during milking and to assess repeatability and variation of CH4 emissions among individual dairy cows. Measurements of CH4 and CO2 emissions from 36 cows were collected in 3 consecutive feeding periods. In the first period, cows were fed a commercial partial mixed ration (PMR) containing 69% forage. In the second and third periods, the same 36 cows were fed a high-forage PMR ration containing 75% forage, with either a high grass silage or high maize silage content. Emissions of CH4 during each milking were examined using 2 methods. First, peaks in CH4 concentration due to eructations during milking were quantified. Second, ratios of CH4 and CO2 average concentrations during milking were calculated. A linear mixed model was used to assess differences between PMR. Variation in CH4 emissions was observed among cows after adjusting for effects of lactation number, week of lactation, diet, individual cow, and feeding period, with coefficients of variation estimated from variance components ranging from 11 to 14% across diets and methods of quantifying emissions. No significant difference was detected between the 3 PMR in CH4 emissions estimated by either method. Emissions of CH4 calculated from eructation peaks or as CH4 to CO2 ratio were positively associated with forage dry matter intake. Ranking of cows according to CH4 emissions on different diets was correlated for both methods, although rank correlations and repeatability were greater for CH4 concentration from eructation peaks than for CH4-to-CO2 ratio. We conclude that quantifying enteric CH4 emissions either using eructation peaks in concentration or as CH4-to-CO2 ratio can provide highly repeatable phenotypes for ranking cows on CH4 output.

Variation in enteric methane emissions among cows on commercial dairy farms.

Methane (CH4) emissions by dairy cows vary with feed intake and diet composition. Even when fed on the same diet at the same intake, however, variation between cows in CH4 emissions can be substantial. The extent of variation in CH4 emissions among dairy cows on commercial farms is unknown, but developments in methodology now permit quantification of CH4 emissions by individual cows under commercial conditions. The aim of this research was to assess variation among cows in emissions of eructed CH4 during milking on commercial dairy farms. Enteric CH4 emissions from 1964 individual cows across 21 farms were measured for at least 7 days/cow using CH4 analysers at robotic milking stations. Cows were predominantly of Holstein Friesian breed and remained on the same feeding systems during sampling. Effects of explanatory variables on average CH4 emissions per individual cow were assessed by fitting a linear mixed model. Significant effects were found for week of lactation, daily milk yield and farm. The effect of milk yield on CH4 emissions varied among farms. Considerable variation in CH4 emissions was observed among cows after adjusting for fixed and random effects, with the CV ranging from 22% to 67% within farms. This study confirms that enteric CH4 emissions vary among cows on commercial farms, suggesting that there is considerable scope for selecting individual cows and management systems with reduced emissions.

A validation study on the use of intra-operative video recording as an objective assessment tool for core ENT surgery.

OBJECTIVES: To investigate the reliability and validity of remote scoring a video assessment of a core ENT surgical procedure (myringotomy and grommet insertion) and its suitability as an objective tool for assessing the technical skills of ENT surgeons. DESIGN: Single-blinded (raters) video assessment. SETTING: Tertiary Care University Hospital. PARTICIPANTS: Consultant and trainee [Specialty Registrar (StR) and Core Trainee (CT)] ENT surgeons performing a total of 30 consecutive index procedures. MAIN OUTCOME MEASURES: To determine the construct validity and the reliability of video assessment scoring of myringotomy and grommet insertion by two raters at ENT Consultant level with a subspecialty interest in Otology. To measure the performance (by rating) of participants compared to operative time. RESULTS: A strong correlation between scores by the two blinded raters was demonstrated (ρ = 0.748; P < 0.001). Median scores (/45) for each group were as follows: CT 25.5 (IQR 21.13-31.25), StR 33 (IQR 24.88-35) and Consultant 40 (IQR 35.38-42.63). Kruskal-Wallis test analysis showed statistically significant mean rank scores between the three different levels of experience (H = 12.77, P = 0.002). Multiple group comparisons indicated a significant difference between CT and Consultant groups (P < 0.001) and StR and Consultant groups (P = 0.007). Analysis of the time taken between the experience groups demonstrated a difference (H = 8.689, P = 0.013) although individual intergroup comparisons indicated this was only significant between CT and Consultant groups (P = 0.004). There was a significant negative correlation (ρ = -0.842; P < 0.001) between time taken for procedure and score achieved. CONCLUSIONS: Video assessment of myringotomy and ventilation tube insertion may represent a valid, feasible tool for use in summative and formative assessments of trainee ENT surgeons. Remote scoring of assessment procedures minimises bias and enables blinding of raters. ENT is well positioned to benefit from video assessment due to the high number of surgical procedures within the specialty that are performed utilising digital technology.

Palm cooling does not improve running performance.

The aim of this study was to test the efficacy of the BEX Runner palm cooling device during a combination of exercise and environmental heat stress. Twelve subjects completed two randomly ordered time-to-exhaustion runs at 75% VO2max, 30 °C, and 50% relative humidity with and without palm cooling. Time to exhaustion runs started once the warm-up had elicited a core temperature of 37.5 °C. Heart rate, Rating of Perceived Exertion, Feeling Scale, and core temperature were recorded at 2-min intervals during each run. Time to exhaustion was longer in control than treatment (46.7±31.1 vs. 41.3±26.3 min, respectively, p<0.05); however, when warm-up time was included in analysis, there was no difference between trials for total exercise time (52.5±24.2 vs. 54.5±31.4 min, respectively). The rate-of-rise of core temperature was not different between control and treatment (0.047 vs. 0.048 °C · min-1, respectively). The use of the BEX Runner palm cooling device during a run in hot conditions did not eliminate or even attenuate the rise in core temperature. Exercise time in hot conditions did not increase with the use of the palm cooling device and time to exhaustion was reduced.

Figure skater level moderates balance training.

It was suggested that baseline levels of postural control in figure skaters might influence the effectiveness of neuromuscular training. The aims of the present study were to investigate the baseline association of skater skill level with standard center of pressure metrics and time to stabilization, and to determine if skill level influenced the effectiveness of a 6-week neuromuscular training program. There was no main effect of skill level for any baseline center of pressure metric for either test. There was no main effect of skill level on the percent change in any metric for the single leg stance following training. However, skill level did influence landing test outcome measures. The difference in percent change of root mean squared was evident for the mediolateral (low: 24.5±16.50% vs. high: 2.42±14.99%) and anterior-posterior (low: 6.66±9.21% vs. high: - 4.03±5.91%) axes. Percent change in anterior-posterior time to stabilization also differed by skill level (low: - 0.73%±4.74 vs. high: - 5.61%±2.76). Note that this study was underpowered with 26 subjects and 14 subjects contributing to baseline and post-training assessments, respectively. Though no baseline differences in postural control were observed, compared with low skill levels, high skill levels benefitted more from training.