Impacts of endocrine disrupting chemicals on reproduction in wildlife and humans.

Endocrine disrupting chemicals (EDCs) are ubiquitous in aquatic and terrestrial environments. The main objective of this review was to summarize the current knowledge of the impacts of EDCs on reproductive success in wildlife and humans. The examples selected often include a retrospective assessment of the knowledge of reproductive impacts over time to discern how the effects of EDCs have changed over the last several decades. Collectively, the evidence summarized here within reinforce the concept that reproduction in wildlife and humans is negatively impacted by anthropogenic chemicals, with several altering endocrine system function. These observations of chemicals interfering with different aspects of the reproductive endocrine axis are particularly pronounced for aquatic species and are often corroborated by laboratory-based experiments (i.e. fish, amphibians, birds). Noteworthy, many of these same indicators are also observed in epidemiological studies in mammalian wildlife and humans. Given the vast array of reproductive strategies used by animals, it is perhaps not surprising that no single disrupted target is predictive of reproductive effects. Nevertheless, there are some general features of the endocrine control of reproduction, and in particular, the critical role that steroid hormones play in these processes that confer a high degree of susceptibility to environmental chemicals. New research is needed on the implications of chemical exposures during development and the potential for long-term reproductive effects. Future emphasis on field-based observations that can form the basis of more deliberate, extensive, and long-term population level studies to monitor contaminant effects, including adverse effects on the endocrine system, are key to addressing these knowledge gaps.

Suitability of milk lactate dehydrogenase and serum albumin for pathogen-specific mastitis detection in automatic milking systems.

In response to intramammary infection (IMI), blood-derived leukocytes are transferred into milk, which can be measured as an increase of somatic cell count (SCC). Additionally, pathogen-dependent IgG increases in milk following infection. The IgG transfer into milk is associated with the opening of the blood-milk barrier, which is much more pronounced during gram-negative than gram-positive IMI. Thus, milk IgG concentration may help to predict the pathogen type causing IMI. Likewise, lactate dehydrogenase (LDH) and serum albumin (SA) cross the blood-milk barrier with IgG if its integrity is reduced. Because exact IgG analysis is complicated and difficult to automate, LDH activity and SA concentration aid as markers to predict the IgG transfer into milk in automatic milking systems (AMS). This study was conducted to test the hypothesis that LDH and SA in milk correlate with the IgG transfer, and in combination with SCC these factors allow the differentiation between gram-positive and gram-negative IMI or even more precisely the infection-causing pathogen. Further, the expression of these parameters in foremilk before (BME) and after (AME) milk ejection was tested. In the AMS, quarter milk samples (n = 686) from 48 Holstein-Friesian cows were collected manually BME and AME, followed by an aseptic sample for bacteriological culture. Mixed models were used to (1) predict the concentration of IgG transmitted from blood into milk based on LDH and SA; (2) use principal component analysis to evaluate joint patterns of SCC (cells/mL), IgG (mg/mL), LDH (U/L), and SA (mg/mL) and use the principal component scores to compare gram-positive, gram-negative, and control IMI types and BME versus AME samples; and (3) predict gram-positive and gram-negative IMI by inclusion of combined SCC-LDH and SCC-SA as predictors in the model. Overall, the SA and LDH had similar ability to predict IgG transmission from blood into milk. Comparing the areas under the curve (AUC) of the receiver operator characteristic curves, the SCC-LDH versus SCC-SA had lower gram-positive (AUC = 0.984 vs. 0.986) but similar gram-negative (AUC = 0.995 vs. 0.998) IMI prediction ability. The SCC, IgG, LDH, and SA were greater in gram-negative than in gram-positive IMI (BME and AME) in early lactation. All measured factors had higher values in milk samples taken BME than AME. In conclusion, LDH and SA could be used as replacement markers to indicate the presence of IgG transfer from blood into milk; in combination with SCC, both SA and LDH are suitable for differentiating IMI type, and BME is better for mastitis detection in AMS.

Anti-Ro52/TRIM21 is independently associated with pulmonary arterial hypertension and mortality in a cohort of systemic sclerosis patients.

Objective: We undertook a comprehensive cross-sectional analysis of a multicentred Australian cohort of systemic sclerosis (SSc) patients to evaluate the associations of anti-Ro52/TRIM21 with SSc pulmonary involvement.Method: The study included 596 patients from the Australian Scleroderma Cohort Study database whose anti-Ro52/TRIM21 status was known. Anti-Ro52/TRIM21 was measured via line immunoassay. Data on demographic variables, autoantibody profiles, presence of interstitial lung disease (ILD), presence of pulmonary arterial hypertension (PAH), oxygen saturation, Six-Minute Walk Test distance, Borg dyspnoea score, and lung function tests were extracted. SPSS software was used to examine associations using univariate and multivariate analyses.Results: Anti-Ro52/TRIM21 was present in 34.4% of SSc patients. In the cross-sectional analysis, anti-Ro52/TRIM21 was independently associated with PAH [odds ratio 1.75, 95% confidence interval (CI) 1.05-2.90], but not ILD or other surrogate measures of pulmonary involvement such as average patient oxygen saturation. The antibody, however, was also associated with a higher forced vital capacity/diffusing capacity of the lung for carbon monoxide ratio. Prospectively, anti-Ro52/TRIM21 was also associated with an increased risk of death in patients with SSc (hazard ratio 1.62, 95% CI 1.11-2.35), independent of confounding factors. The primary cause of death appeared to be related to PAH and/or ILD, and anti-Ro52/TRIM21 was associated with PAH-related complications.Conclusion: Anti-Ro52/TRIM21 was independently associated with PAH and mortality in SSc patients. Future longitudinal studies are recommended to investigate the timing and pathogenic mechanisms of this autoantibody in PAH.

Early-Cannulation Arteriovenous Grafts Are Safe and Effective in Avoiding Recurrent Tunneled Central Catheter Infection.

OBJECTIVES: Tunneled central venous catheter infection (TCVCi) is a common complication that often necessitates removal of the TCVC and replacement by a further TCVC. Theoretically, insertion of an early - cannulation graft (ecAVG) early after TCVC infection is possible but not widely practiced with concerns over safety and infection in the ecAVG. With 8 years of ecAVG experience, the aim of this study was to compare the outcomes following TCVC infection, comparing replacement with TCVC (TCVCr) versus immediate ecAVG (ecAVGr). DESIGN: Retrospective comparison of 2 cohorts, who underwent replacement of an infected TCVC either by an early cannulation graft (n = 18) or by a further central catheter (n = 39). METHODS: Data were abstracted from a prospectively completed electronic patient record and collected on patient demographics, TCVC insertion, duration and infection, including culture proven bacteriaemia and subsequent access interventions. RESULTS: Eighteen of 299 patients identified from 2012 to 2020 had an ecAVG implanted as treatment for a TCVCi. In a 1-year time-period (January 1, 2015-December 31, 2015) out of 222 TCVC inserted, 39 were as a replacement following a TCVCi. No patient with an ecAVGr developed an immediate infection, nor complication from the procedure. The rate of subsequent vascular access infection was significantly more frequent for those with a TCVCr than with an ecAVGr (0.6 vs. 0.1/patient/1000 HD days, P< 0.000). The number of further TCVC required was significantly higher in the TCVCr group (7.1 vs. 0.4/patient/1000 HD days, P= 0.000). CONCLUSIONS: An ecAVG early following a TCVC infection is safe, reduces the incidence of subsequent infectious complications and reduces the number of TCVC required, with a better functional patency.

SNP discovery and population structure analysis in Lassi and Marecha camel breeds using a genotyping by sequencing method.

Pakistani camels have been classified socio-geographically into 20 breeds, but they have not yet been subjected to substantial selective pressures and the genetic basis for these breeds is not understood. However, it should be possible to distinguish them by use of molecular data. This study investigated the genetic diversity and population structure within and between two major Pakistani camel breeds, Marecha and Lassi. As no SNP array is currently available, we first identified 63 619 SNPs using a genotyping by sequencing approach. After quality control, a panel of 36 926 SNPs was used in the analysis. Population structure was investigated with a principal coordinate analysis as well as a cluster analysis using NetView, and multilocus heterozygosity analysis to explore between- and within-breed genetic variation. In addition, between-breed variation was explored using the fixation index, FST . We also compared relationship matrices computed using the VanRaden SNP-based method and a method developed specifically for genotyping by sequencing data. Among the two camel breeds, Lassi showed a lower level of genetic diversity whereas Marecha showed a higher level. As a genotyping platform has not yet been developed for the camel, the SNPs discovered in this study will be useful in future genetic studies in camels.

Transitioning from conventional to automatic milking: Effects on the human-animal relationship.

There are several differences in how an automatic milking system (AMS; milking equipment not requiring human intervention for the milk harvesting process) and a conventional milking system (CMS) are managed, where the effect of milking system type on the human-animal relationship has remained unexplored. A survey and observations from 5 Australian dairy farms transitioning from CMS to AMS were taken twice, 1 yr apart, before and after transition to an AMS. The farmers completed a survey and had all farmer-cow interactions documented for 3 d. In addition, a random selection of lactating cows had their avoidance distance (the distance at which they move away from an approaching person) recorded and were involved in a handling test during both visits. The survey findings indicated that basic management practices remained mostly unchanged, whereas records of farmer-cow interactions showed 4 out of 5 farms had less interaction time after AMS transition. This was caused by a reduction in milk harvesting tasks, where a small portion of this time was re-invested into time that farmers spent around the cows without directly interacting with them and into tasks involving close cow contact. Overall, an approximate 27% decline was observed in avoidance distances of cows from an AMS compared with the CMS. A handling test was performed on 4 of the 5 farms before and after AMS transition, where the farmers were asked to move a selection of cows through a gate one at a time. In the AMS more vocal effort was required to move the cows, and the cows responded with a reduced occurrence of running past the farmer and reduced occurrence of slipping in an attempt to avoid the farmers compared with the CMS. Overall, results show that farmers spent less time interacting with cows in the AMS, and that cows were less fearful around people as seen by reduced avoidance distances and reduced stress responses to close handling.

Rare disruptive variants in the DISC1 Interactome and Regulome: association with cognitive ability and schizophrenia.

Schizophrenia (SCZ), bipolar disorder (BD) and recurrent major depressive disorder (rMDD) are common psychiatric illnesses. All have been associated with lower cognitive ability, and show evidence of genetic overlap and substantial evidence of pleiotropy with cognitive function and neuroticism. Disrupted in schizophrenia 1 (DISC1) protein directly interacts with a large set of proteins (DISC1 Interactome) that are involved in brain development and signaling. Modulation of DISC1 expression alters the expression of a circumscribed set of genes (DISC1 Regulome) that are also implicated in brain biology and disorder. Here we report targeted sequencing of 59 DISC1 Interactome genes and 154 Regulome genes in 654 psychiatric patients and 889 cognitively-phenotyped control subjects, on whom we previously reported evidence for trait association from complete sequencing of the DISC1 locus. Burden analyses of rare and singleton variants predicted to be damaging were performed for psychiatric disorders, cognitive variables and personality traits. The DISC1 Interactome and Regulome showed differential association across the phenotypes tested. After family-wise error correction across all traits (FWERacross), an increased burden of singleton disruptive variants in the Regulome was associated with SCZ (FWERacross P=0.0339). The burden of singleton disruptive variants in the DISC1 Interactome was associated with low cognitive ability at age 11 (FWERacross P=0.0043). These results identify altered regulation of schizophrenia candidate genes by DISC1 and its core Interactome as an alternate pathway for schizophrenia risk, consistent with the emerging effects of rare copy number variants associated with intellectual disability.

Suitability of somatic cell count, electrical conductivity, and lactate dehydrogenase activity in foremilk before versus after alveolar milk ejection for mastitis detection.

Mastitis is responsible for substantial economic loss and significant animal welfare concerns for the dairy industry. Sensors that measure electrical conductivity (EC) and enzyme concentrations of lactate dehydrogenase (LDH) are presently used for automatic detection of mastitis. However, EC is not sensitive enough to detect mastitis, and the ability of LDH activity to identify mastitis caused by different pathogens is a potential option that needs to be investigated. This study was conducted to test the following hypotheses: (a) strict foremilk before milk ejection is more informative in detecting mastitis, in general, than foremilk removed after cows were stimulated for milk ejection; and (b) the value of LDH activity as a mastitis indicator depends on the type of pathogen associated with the infection. Milk samples (before afternoon milking) from 48 Holstein-Friesian cows at the University of Sydney's dairy farm (Camden, New South Wales, Australia) with EC > 7.5 mS/cm in any of the 4 quarters were collected over a period of 2 mo. Quarter milk samples (n = 343) from 48 cows were collected manually in the automatic milking rotary in 3 steps: foremilk before (strict foremilk) and after milk ejection, followed by an aseptic sample for bacteriological culture. The EC (mS), LDH (U/L), SCC (cells/mL), and milk protein and fat content (%) of foremilk in both sampling times were compared and used as predictors for gram-positive and gram-negative mastitis. Quarter (n = 515) observations from 44 cows were analyzed using a logistic mixed or linear mixed model, with cow and quarter nested within cow as random effects. Milk from both sampling times was also assessed by producing a receiver operating characteristic (ROC) curve and calculating the area under the curve (AUC) to determine ability to detect mastitis. Overall, EC and LDH were greater and milk protein (%) was lower in strict foremilk than in milk fractions obtained after milk ejection. Data from strict foremilk samples had slightly higher AUC values (0.98 to 0.99 vs. 0.97 to 0.98, respectively) than did the after-ejection milk samples. Although gram-negative coliform mastitis had significantly higher LDH activity than did gram-positive mastitis (6.19 vs. 5.34 log10 U/L), the robustness of this result is questionable due to limited sample size. We concluded that milk samples taken before ejection can influence major mastitis indicators, suggesting that automatic milking system sensors could be modified to monitor milk before ejection for more efficient mastitis detection.

Perspectives on oral squamous cell carcinoma prevention-proliferation, position, progression and prediction.

Squamous cell carcinoma arising from oral mucosal epithelium remains a lethal and deforming disease due to tumour invasion, oro-facial destruction, cervical lymph node metastasis and ultimate blood-borne dissemination. Worldwide, 300 000 new cases are seen each year, with a recent and significant rise in incidence affecting particularly the young. To rationalize perspectives on preventive strategies in oral cancer management, this study addresses a number of fundamental questions regarding carcinogenesis: proliferation-what epithelial cell changes precede tumour development? Position-why are certain oral sites so predisposed to cancer? Progression-why do some precursor lesions progress to invasive carcinoma and others do not? Prediction-how can we predict individual patient and/or lesion behaviour to prevent disease progression? By improving our understanding of oral carcinogenesis, can we thereby facilitate more effective primary, secondary and tertiary preventive strategies and ultimately reduce the global burden of oral squamous cell carcinoma (OSCC)?

Development of a new clinical mastitis detection method for automatic milking systems.

This study investigated the potential for accurate detection of clinical mastitis (CM) in an automatic milking system (AMS) using electronic data from the support software. Data from cows were used to develop the model, which was then tested on 2 independent data sets, 1 with 311 cows (same farm but from a different year) and 1 with 568 cows (from a different farm). In addition, the model was used to test how well it could predict CM 1 to 3 d before actual clinical diagnosis. Logistic mixed models were used for the analysis. Twelve measurements were included in the initial model before a backward elimination, which resulted in the following 6 measurements being included in the final model: quarter-level milk yield (MY; kg), electrical conductivity (EC; mS/cm), average milk flow rate (MF; kg/min), occurrence of incompletely milked quarters in each milking session (IM; yes or no), MY per hour (MYH; kg/h), and EC per hour (ECH; mS/cm/h) between successive milking sessions. The other 6 measurements tested but not included in the final model were peak milk flow rate (kg/min), kick-offs (yes or no) in each milking session, lactation number, days in milk (d), blood in milk (yes or no), and a calculated mastitis detection index used by DeLaval (DelPro software; DeLaval International AB, Tumba, Sweden). All measurements were assessed to determine their ability to detect CM as both individual variables and combinations of the 12 above-mentioned variables. These were assessed by producing a receiver operating characteristic curve and calculating the area under the curve (AUC) for each model. Overall, 9 measurements (i.e., EC, ECH, MY, MYH, MF, IM, peak flow rate, lactation number, and mastitis detection index) had significant mastitis detection ability as separate predictors. The best mastitis prediction was possible by incorporating 6 measurements (i.e., EC, ECH, MY, MYH, MF, and IM) as well as the random cow and quarter effects in the model, resulting in 90% sensitivity and 91% specificity with excellent AUC (0.96). Assessment of the model was found to produce robust results (AUC >0.9) in different data sets and could detect CM with reductions in sensitivity and specificity with increasing days before actual diagnosis. This study demonstrated that improved mastitis status prediction can be achieved by using multiple measurements, and new indexes based on that are expected to result in improved accuracy of mastitis alerts, thereby improving the detection ability and utility on farm.

The effect of temperate or tropical pasture grazing state and grain-based concentrate allocation on dairy cattle production and behavior.

Grain-based concentrate (GBC) supplement is of high cost to dairy farmers as a feed source as opposed to grazed pasture. Milk production response to GBC is affected by the composition and nutritive value of the remainder of the diet, animal factors, and interactions between forage type and level of GBC. In grazing systems, dairy cattle encounter contrasting pasture states, primarily because the social structure of the herd affects the timing of when each animal accesses a paddock after milking as a result of a relatively consistent cow milking order. However, the effect of feed management, namely pasture state and GBC allocation, on dairy cattle production and behavior is unknown. We examined the effect of varying GBC allocation for dairy cattle grazing differing states of kikuyu grass (Pennisetum clandestinum, a tropical pasture species; experiment 1) and annual ryegrass (Lolium multiflorum L., a temperate pasture species; experiment 2) on dry matter intake, milk production and composition, and grazing behavior. For each experiment, 90 lactating dairy cattle were randomly allocated to 2 consistent (fresh-fresh and depleted-depleted) and 2 inconsistent (fresh-depleted and depleted-fresh pasture state treatments (defined as sequences of pasture state allocation for the morning and afternoon grazing events) and 3 GBC treatments [2.7, 5.4, and 8.1 kg of dry matter (DM)/cow per day], giving 12 treatment combinations for each experiment. The duration of each experiment was 14 d, with the first 7 d used as adaptation to treatment. In each experiment, 3 cattle were selected from each of the 12 pasture type × GBC treatment groups within the experimental herd to determine herbage intake and total DM digestibility using the n-alkanes method (n = 36). There was no interaction between kikuyu grass or ryegrass pasture state and GBC level for intake, digestibility, or milk yield or components. Dairy cattle offered fresh-fresh and depleted-fresh ryegrass produced 9% more milk yield, in line with greater pasture intakes, compared with fresh-depleted and depleted-depleted pasture states. Dairy cattle offered fresh-fresh kikuyu grass had 8% more milk yield and 14% more milk protein yield than other pastures states, but there was no effect of pasture state on milk composition. Milk yield increased with GBC level for both pasture species (∼0.7-0.8 kg of milk/kg of DM GBC) as GBC level increased from 2.5 to 5.4 kg of DM/cow per day. There was a poor response (0.3 kg of milk/kg of DM GBC), and no response, when GBC levels increased from 5.4 to 8.1 kg of DM/cow per day for kikuyu grass and ryegrass, respectively, in line with pasture DMD. Time spent grazing, lying, and ruminating were not associated with kikuyu grass pasture state, GBC, or their interaction. Despite this, there was a linear increase in grazing time in the afternoon coinciding with a linear decrease in lying and rumination time for both kikuyu grass and ryegrass pasture. Together these findings reveal the effect of pasture state and GBC allocation on dairy cattle production and behavior. Tailoring GBC allocation to the state of pasture accessed by cattle appears unwarranted, but there is an opportunity to alter the timing of pasture access to increase herd-level milk production efficiency.

Associations between bone and energy metabolism in cows fed diets differing in level of dietary cation-anion difference and supplemented with cholecalciferol or calcidiol.

Bone-derived hormones play an important role in metabolism. This study examined the hypothesis that interactions between bone and energy metabolism, particularly those involving osteocalcin, are present in dairy cattle and have feedback mechanisms over time. Associations between metabolites in blood were examined in 32 Holstein cows blocked by parity and milk yield and randomly allocated to diets containing either 0.27 mg/kg dry matter (DM) calcidiol or cholecalciferol for an anticipated intake of 3 mg/d (120,000 IU/d) at 11 kg of DM, and positive (+130 mEq/kg DM) or negative (-130 mEq/kg DM) dietary cation-anion difference (DCAD) from 252 d of gestation to calving. Blood was sampled every 3 d, from 9 d prepartum to 30 d postpartum, and plasma concentrations of vitamin D3, 25-hydroxyvitamin D3, adiponectin, C-telopeptide of type 1 collagen (CTX1), glucose, insulin-like growth factor 1 (IGF1), insulin, undercarboxylated osteocalcin (uOC), and carboxylated osteocalcin (cOC) were determined. Feeding calcidiol compared with cholecalciferol increased plasma concentrations of 25-hydroxyvitamin D3 pre- (264.2 ± 8.0 vs. 61.3 ± 8.0 ng/mL) and postpartum (170.8 ± 6.2 vs. 51.3 ± 6.2 ng/mL) but decreased concentrations of vitamin D3 pre- (1.2 ± 0.6 vs. 14.5 ± 0.6 ng/mL) and postpartum (1.9 ± 0.4 vs. 3.2 ± 0.6 ng/mL). Prepartum, cows fed the negative DCAD diet had reduced concentrations of vitamin D3 and glucose compared with cows fed a positive DCAD. The combination of negative DCAD and cholecalciferol reduced IGF1 concentrations prepartum. The DCAD treatment had no effect on postpartum concentrations of metabolites. Nulliparous cows had increased concentrations of OC, CTX1, IGF1, glucose, and insulin compared with parous cows. Time series analysis identified associations between metabolites on the same day and over 3-d lags up to ±9 d that suggest feedback between 25-hydroxyvitamin D3 and vitamin D3 in the negative lags, indicating that 25-hydroxyvitamin D3 may exert feedback on vitamin D3 but not vice versa. We found evidence of a feedback mechanism between vitamin D3 and IGF1, with positive effect size (ES) on the same day and 3 d later, and negative ES 9 d later, that was more evident in cholecalciferol-fed cows. This suggests an important role of IGF1 in integrating bone metabolism with energy and protein metabolic pathways. Evidence of feedback was found between uOC and particularly cOC with IGF1, with positive ES on the same day but negative ES 6 d before and 6 d after. An association between uOC or cOC and IGF1 has not been previously identified in cattle and suggests that both uOC and cOC may have marked biological activity. Associations between OC and insulin identified in mice were not observed herein, although associations between OC and glucose were similar to those between IGF1 and glucose, supporting associations between glucose, OC, and IGF1. We provide further statistical evidence of crosstalk between vitamin D compounds, bone hormones, and energy metabolism in cattle. In particular, associations between uOC or cOC and IGF1 may provide links between prepartum diets and observations of prolonged increases in milk production and allow better control of peripartum metabolism.

Common polygenic risk for autism spectrum disorder (ASD) is associated with cognitive ability in the general population.

Cognitive impairment is common among individuals diagnosed with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). It has been suggested that some aspects of intelligence are preserved or even superior in people with ASD compared with controls, but consistent evidence is lacking. Few studies have examined the genetic overlap between cognitive ability and ASD/ADHD. The aim of this study was to examine the polygenic overlap between ASD/ADHD and cognitive ability in individuals from the general population. Polygenic risk for ADHD and ASD was calculated from genome-wide association studies of ASD and ADHD conducted by the Psychiatric Genetics Consortium. Risk scores were created in three independent cohorts: Generation Scotland Scottish Family Health Study (GS:SFHS) (n=9863), the Lothian Birth Cohorts 1936 and 1921 (n=1522), and the Brisbane Adolescent Twin Sample (BATS) (n=921). We report that polygenic risk for ASD is positively correlated with general cognitive ability (beta=0.07, P=6 × 10(-7), r(2)=0.003), logical memory and verbal intelligence in GS:SFHS. This was replicated in BATS as a positive association with full-scale intelligent quotient (IQ) (beta=0.07, P=0.03, r(2)=0.005). We did not find consistent evidence that polygenic risk for ADHD was associated with cognitive function; however, a negative correlation with IQ at age 11 years (beta=-0.08, Z=-3.3, P=0.001) was observed in the Lothian Birth Cohorts. These findings are in individuals from the general population, suggesting that the relationship between genetic risk for ASD and intelligence is partly independent of clinical state. These data suggest that common genetic variation relevant for ASD influences general cognitive ability.

Potentially malignant disorders-The case for intervention.

Potentially malignant disorders (PMD) are recognisable mucosal conditions preceding invasive squamous carcinoma development. Established oral cancer remains a lethal and deforming disease, with a rising incidence. Management techniques for identifiable oral precursor lesions have traditionally been polarised between observational and interventional surgical techniques. By defining salient management goals for treating potentially malignant disease, and examining the evidence supporting the efficacy of treatment intervention, this paper presents the case for interventional laser surgery as a definitive diagnostic and treatment modality.

Efficacy of oral brush biopsy in potentially malignant disorder management.

BACKGROUND: Oral potentially malignant disorders (PMD) harbour unpredictable risk for squamous cell carcinoma development. Current management requires tissue biopsy for histopathology characterisation, dysplasia grading and targeted intervention to "high-risk" lesions, although evidence-based guidelines are limited and diagnoses subjective. This study investigated the use of adjunctive oral brush biopsy techniques during the management of PMD in a UK hospital population. METHODS: Retrospective review of a 310 PMD patient cohort presenting to Maxillofacial Surgery in Newcastle upon Tyne with new, single-site lesions between December 2009 and May 2014. Patients underwent Orcellex® brush biopsy and liquid-based cytology examination in addition to conventional biopsy techniques, with management proceeding along established care pathways. Patient demographics, cytology data, most significant histopathology diagnoses and clinical outcome were all documented at the study census date (31.12.15). RESULTS: A total of 170 male & 140 female patients (age range 18-91 years), exhibiting primarily leukoplakia (86.5%) at floor of mouth and ventrolateral tongue sites (44.9%), were identified. Management comprised: observation (49.7%), laser surgery (44.9%), antifungal treatment (3.5%) and Head & Neck clinic referral following cancer diagnosis (1.9%). Clinical outcomes were as follows: disease free (51.3%), persistent PMD (42.3%) and malignant transformation (6.4%). Histology and cytology diagnoses strongly correlated (r = .305). Treatment modality, lesion site, histology and cytology diagnoses were the best predictors of clinical outcome. CONCLUSIONS: Orcellex® brush cytology provides reliable diagnoses consistent with conventional histopathology and offers less invasive, adjunctive assessment appropriate for long-term monitoring of patients in specialist clinics.

Profiling cancer risk in oral potentially malignant disorders-A patient cohort study.

BACKGROUND: Oral potentially malignant disorders harbour variable and unpredictable risk for squamous carcinoma development. Whilst current management strategies utilise histopathological diagnoses, dysplasia grading and targeted intervention for "high-risk" lesions, clinicians are unable to predict malignant potential. METHODS: Detailed, retrospective clinico-pathological analysis of potentially malignant lesions undergoing malignant transformation, from a 590 patient cohort treated by interventional laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was documented at study census date (31 December 2014). RESULTS: A total of 99 patients (16.8%) developed cancer: 71 (12%) seen "unexpectedly" upon excision and 28 (4.8%) progressing to malignancy at a median of 87.3 months post-surgery. Thirty "unexpected" excisions were micro-invasive (42.3%) arising primarily in severely dysplastic precursors (75%) at ventro-lateral tongue and floor of mouth sites (54.5%); 1 patient (1.4%) had a cancer-related death, whilst 58 (81.7%) were disease free. A total of 19 of 28 "progressive" cancers (67.9%) arose at new sites, with erythroleukoplakia a significant predictor of malignancy (P = .0019). Nine (32.1%) developed at the same precursor site, with 6 (77.7%) on the ventro-lateral tongue and floor of mouth. Three (10.7%) were micro-invasive, 9 patients (32.1%) died from metastatic disease and 12 (42.9%) were disease free (P < .001). CONCLUSION: Squamous carcinoma may arise at the site of a precursor lesion as transformation or new-site development via field cancerisation. Whilst interventional surgery facilitates early diagnosis and treatment of occult disease, thus reducing risk from same-site transformation, new-site cancer is a significant long-term risk for patients with potentially malignant disorder.

Treatment resistance in potentially malignant disorders-'Nature' or 'Nurture' ?

BACKGROUND: Contemporary potentially malignant disorder management is based upon provisional histological diagnosis followed by interventional surgery to excise or ablate 'high-risk' mucosal lesions. Although the majority of patients achieve disease-free status post-treatment, others develop further or persistent disease unresponsive to intervention. METHODS: A detailed, retrospective clinico-pathological review of treatment resistant potentially malignant lesions, from a 590 patient cohort treated by CO2 laser surgery and followed for a mean of 7.3 years, was undertaken. Clinical outcome was determined at study census date (31 December 2014). RESULTS: A total of 87 patients (15%) exhibited PMD disease resistant to treatment: 34 (6%) became disease free following further treatment, whilst 53 (9%) had persistent disease despite intervention. Disease-free patients were younger, changed lesion appearance from erythroleukoplakia to leukoplakia (P = .004), developed further lesions at new sites, demonstrated reduction in dysplasia severity with time and required multiple treatments to achieve disease-free status (P = .0005). In contrast, persistent disease patients were older, male, often presented with proliferative verrucous leukoplakia (PVL) on gingival and alveolar sites, displayed less severe dysplasia initially and underwent laser ablation rather than excision (P = .027). CONCLUSION: Despite clinico-pathological profiling of treatment resistant patients, the precise inter-relationship between the inherent nature of potentially malignant disease and the external influence of treatment intervention remains obscure.

Contemporary group estimates adjusted for climatic effects provide a finer definition of the unknown environmental challenges experienced by growing pigs.

Environmental descriptors derived from mean performances of contemporary groups (CGs) are assumed to capture any known and unknown environmental challenges. The objective of this paper was to obtain a finer definition of the unknown challenges, by adjusting CG estimates for the known climatic effects of monthly maximum air temperature (MaxT), minimum air temperature (MinT) and monthly rainfall (Rain). As the unknown component could include infection challenges, these refined descriptors may help to better model varying responses of sire progeny to environmental infection challenges for the definition of disease resilience. Data were recorded from 1999 to 2013 at a piggery in south-east Queensland, Australia (n = 31,230). Firstly, CG estimates of average daily gain (ADG) and backfat (BF) were adjusted for MaxT, MinT and Rain, which were fitted as splines. In the models used to derive CG estimates for ADG, MaxT and MinT were significant variables. The models that contained these significant climatic variables had CG estimates with a lower variance compared to models without significant climatic variables. Variance component estimates were similar across all models, suggesting that these significant climatic variables accounted for some known environmental variation captured in CG estimates. No climatic variables were significant in the models used to derive the CG estimates for BF. These CG estimates were used to categorize environments. There was no observable sire by environment interaction (Sire×E) for ADG when using the environmental descriptors based on CG estimates on BF. For the environmental descriptors based on CG estimates of ADG, there was significant Sire×E only when MinT was included in the model (p = .01). Therefore, this new definition of the environment, preadjusted by MinT, increased the ability to detect Sire×E. While the unknown challenges captured in refined CG estimates need verification for infection challenges, this may provide a practical approach for the genetic improvement of disease resilience.

Improving smallholder cattle reproductive efficiency in Cambodia to address expanding regional beef demand.

This study aimed to identify factors associated with cattle reproductive output in rural smallholder farms in Cambodia in order to determine the main causes of reproductive failure and design efficient interventions for improvement. The majority of the nation's beef is produced on smallholder farms where productivity is constrained by poor animal reproductivity reflected in the recent livestock population decline of approximately 13 % from 2009 to 2013. Farmers (n = 240) from 16 villages from five provinces were surveyed in mid-2015 to determine their baseline knowledge, attitude and practices (KAP) associated with cattle reproduction. In addition, 16 case studies from three of these provinces were conducted to provide a more detailed assessment of current cattle reproductive husbandry practices. In order to assess the reproductive impact of previously implemented interventions, an endpoint KAP survey and longitudinal health and husbandry study from three Cambodian provinces conducted between 2008 and 2013 were also analysed. Three multivariable prediction models (two KAP and one longitudinal) identified the following significant factors associated with the reproductive outcomes 'number of calves born' or probability that cows 'gave birth': target feeding (P = 0.074), growing vegetables (P = 0.005), attitudes towards cattle vaccination (P = 0.010), improving bull selection (P = 0.032), local breed use (P = 0.005), number of joining attempts (P < 0.001), discontinuation of animal draught practices (P = 0.003) and retention of breeding animals (P < 0.001). The identification of significant factors and interventions in this study has led to intervention recommendations that can potentially improve reproductive efficiency, combat the declining cattle population and improve smallholder capacity to supply to expanding regional meat demand in South-East Asia and China.

A national follow-up survey of UK graduates opinion of undergraduate oral surgery teaching.

INTRODUCTION: A national follow-up survey was undertaken to determine whether dental graduates from 2009 perceived that their undergraduate oral surgery education had equipped them for general dental practice 4 years after graduating. MATERIALS AND METHODS: Graduates from the same 13 United Kingdom dental schools who had taken part in the original survey were invited to take part in this follow-up online survey. Their contact details were identified via the general dental council register, social media and alumni groups. RESULTS: In total, 161 responded (2009b) which represents 16% of the graduates of the original survey in 2009a. A similar percentage of these respondents perceived that the teaching in oral surgery had given them sufficient knowledge to undertake independent practice (83% and 79% in 2009a and 2009b, respectively). Most respondents (99% in both years) reported confidence in undertaking simple forceps exodontia. Confidence in surgical exodontia was poor in both surveys, but one area that appeared improved in the follow-up related to the sectioning of teeth (84% in 2009b compared with 49% in 2009a). Areas of weakness identified in 2009 were reported to be improved in the follow-up. CONCLUSION: This follow-up survey supports the findings of the original survey. Future longitudinal studies would allow institutions to identify possible weaknesses in their curriculum and to track the career development of their graduates and facilitate robust data collection.