Skin cancer multiplicity in lung transplant recipients: a prospective population-based study.

BACKGROUND: Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown. OBJECTIVES: To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients. METHODS: A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records. RESULTS: During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up); however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer. CONCLUSIONS: Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020; 183:416-417.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

Distinguishing Petroleum (Crude Oil and Fuel) From Smoke Exposure within Populations Based on the Relative Blood Levels of Benzene, Toluene, Ethylbenzene, and Xylenes (BTEX), Styrene and 2,5-Dimethylfuran by Pattern Recognition Using Artificial Neural Networks.

Studies of exposure to petroleum (crude oil/fuel) often involve monitoring benzene, toluene, ethylbenzene, xylenes (BTEX), and styrene (BTEXS) because of their toxicity and gas-phase prevalence, where exposure is typically by inhalation. However, BTEXS levels in the general U.S. population are primarily from exposure to tobacco smoke, where smokers have blood levels on average up to eight times higher than nonsmokers. This work describes a method using partition theory and artificial neural network (ANN) pattern recognition to classify exposure source based on relative BTEXS and 2,5-dimethylfuran blood levels. A method using surrogate signatures to train the ANN was validated by comparing blood levels among cigarette smokers from the National Health and Nutrition Examination Survey (NHANES) with BTEXS and 2,5-dimethylfuran signatures derived from the smoke of machine-smoked cigarettes. Classification agreement for an ANN model trained with relative VOC levels was up to 99.8% for nonsmokers and 100.0% for smokers. As such, because there is limited blood level data on individuals exposed to crude oil/fuel, only surrogate signatures derived from crude oil and fuel were used for training the ANN. For the 2007-2008 NHANES data, the ANN model assigned 7 out of 1998 specimens (0.35%) and for the 2013-2014 NHANES data 12 out of 2906 specimens (0.41%) to the crude oil/fuel signature category.

Mesenchymal Stromal Cells are Readily Recoverable from Lung Tissue, but not the Alveolar Space, in Healthy Humans.

Stromal support is critical for lung homeostasis and the maintenance of an effective epithelial barrier. Despite this, previous studies have found a positive association between the number of mesenchymal stromal cells (MSCs) isolated from the alveolar compartment and human lung diseases associated with epithelial dysfunction. We hypothesised that bronchoalveolar lavage derived MSCs (BAL-MSCs) are dysfunctional and distinct from resident lung tissue MSCs (LT-MSCs). In this study, we comprehensively interrogated the phenotype and transcriptome of human BAL-MSCs and LT-MSCs. We found that MSCs were rarely recoverable from the alveolar space in healthy humans, but could be readily isolated from lung transplant recipients by bronchoalveolar lavage. BAL-MSCs exhibited a CD90Hi , CD73Hi , CD45Neg , CD105Lo immunophenotype and were bipotent, lacking adipogenic potential. In contrast, MSCs were readily recoverable from healthy human lung tissue and were CD90Hi or Lo , CD73Hi , CD45Neg , CD105Int and had full tri-lineage potential. Transcriptional profiling of the two populations confirmed their status as bona fide MSCs and revealed a high degree of similarity between each other and the archetypal bone-marrow MSC. 105 genes were differentially expressed; 76 of which were increased in BAL-MSCs including genes involved in fibroblast activation, extracellular matrix deposition and tissue remodelling. Finally, we found the fibroblast markers collagen 1A1 and α-smooth muscle actin were increased in BAL-MSCs. Our data suggests that in healthy humans, lung MSCs reside within the tissue, but in disease can differentiate to acquire a profibrotic phenotype and migrate from their in-tissue niche into the alveolar space. Stem Cells 2016;34:2548-2558.

Validity of the American Board of Orthodontics Discrepancy Index and the Peer Assessment Rating Index for comprehensive evaluation of malocclusion severity.

OBJECTIVES: To assess the validity of the American Board of Orthodontics Discrepancy Index (ABO-DI) and Peer Assessment Rating (PAR) Index in evaluating malocclusion severity in Chinese orthodontic patients. SETTING AND SAMPLE POPULATION: A stratified random sample of 120 orthodontic patients based on Angle classification was collected from six university orthodontic centres. MATERIAL AND METHODS: Sixty-nine orthodontists rated malocclusion severity on a five-point scale by assessing a full set of pre-treatment records for each case and listed reasons for their decision. Their judgement was then compared with ABO-DI and PAR scores determined by three calibrated examiners. RESULTS: Excellent interexaminer reliability of clinician judgement, ABO-DI and PAR index was demonstrated by the Intraclass Correlation Coefficient (rho= 0.995, 0.990 and 0.964, respectively). Both the ABO-DI and US-PAR index showed good correlation with clinician judgement (r=.700 and r=.707, respectively). There was variability among the different Angle classifications: the ABO-DI showed the highest correlation with clinician judgement in Class II patients (r=.780), whereas the US-PAR index showed the highest correlation with clinician judgement in Class III patients (r=.710). Both indices demonstrated the lowest correlations with clinician judgement in Class I patients. CONCLUSION: With strong interexaminer agreement, the panel consensus was used for validating the ABO-DI and US-PAR index for malocclusion severity. Overall, the ABO-DI and US-PAR index were reliable for measuring malocclusion severity with significantly variable weightings for different Angle classifications. Further modification of the indices for different Angle classification may be indicated.

Posaconazole in lung transplant recipients: use, tolerability, and efficacy.

BACKGROUND: Fungal infection is a common cause of mortality and morbidity in lung transplant recipients (LuTR). Treatment failure to first-line antifungals because of resistance or intolerance is an increasing problem. Posaconazole (PCZ), a triazole antifungal, is an attractive treatment option. METHODS: We performed a single-center retrospective study to describe the use, tolerability, efficacy, and drug interaction effect (with tacrolimus) of PCZ oral suspension in LuTR. RESULTS: Seventy-eight patients were treated with PCZ oral suspension for prophylaxis (n = 15), pre-emptive treatment (n = 31), and treatment of possible (n = 7) and probable (n = 25) invasive fungal infection. A range of fungal isolates was encountered. Resolution was observed in 52.4% (probable, possible, and pre-emptive treatment groups). Aggregate all-cause 1-year mortality was 12.8%. PCZ was well tolerated with 11.5% of patients experiencing adverse effects. Despite dose adjustment strategies, 11.7% of patients experienced supratherapeutic tacrolimus levels, which in 5 cases was associated with a rise (mean 21.6 µmol/L) in serum creatinine. CONCLUSIONS: PCZ is well tolerated and appears effective in the management of fungal infection after lung transplantation. Patients receiving concurrent tacrolimus require careful therapeutic drug monitoring.

Can performance on summative evaluation of wax-added dental anatomy projects be better predicted from the combination of supervised and unsupervised practice than from supervised practice alone?

PURPOSE: The study explored the effects of adding student-directed projects in pre-clinical dental anatomy laboratory on improving the predictability of students' eventual performance on summative evaluation exercises, given the presence of intervening faculty-controlled, in-class practice. METHOD: All students from four consecutive classes (n = 555) completed wax-added home projects (HP), spending as much or as little time as desired and receiving no faculty feedback; followed by similar laboratory projects (LP) with time limits and feedback; and then summative practical projects (PP) in a timed format but without faculty feedback. Path analysis was used to assess if the student-directed HP had any effect over and above the laboratory projects. RESULTS: Average scores were HP = 0.785 (SD = 0.089); LP = 0.736 (SD = 0.092); and PP = 0.743 (SD = 0.108). Path analysis was applied to show the effects of including a student-controlled home practice exercise on summative exercise performance. HP contributed 57% direct effect and 37% mediated effect through the LP condition. CONCLUSION: Student-directed home practice provided a measureable improvement in ability to predict eventual performance in summative test cases over and above the predictive contribution of intervening faculty-controlled practice conditions.

Cross-cultural perception of six commercial olive oils: A study with Spanish and US consumers.

A cross-cultural study was conducted with Spanish and US consumers to gain an insight into the preferred characteristics of olive oils in both countries. Six commercial olive oils (four samples from Spain and two samples from the US) were analyzed by a highly trained panel (descriptive analysis) and also by two consumers' groups (100 consumers from Spain and 100 from the US). Demographic, acceptability, and Just-About-Right data were collected to study the preferences of both groups, and the relationships with descriptive data were explored to determine the drivers of like/dislike. The Spanish extra virgin olive oils and the imported US extra virgin olive oil were characterized by having bitter, pungent, and more green notes, and were preferred by the Spanish consumers. The US consumers liked the bland Spanish refined olive oil, and the Californian olive oil that was characterized by fruity, floral, and sweet notes. The results showed that the Spanish consumers were more aware about olive oil quality in general than their US counterparts, maybe because of a higher usage of the product in Spain. The present study provides essential data which might help producers in designing and promoting olive oils matching US consumers' requirements, an emerging market for this Mediterranean product.

GRACE, time-varying gravity, Earth system dynamics and climate change.

Continuous observations of temporal variations in the Earth's gravity field have recently become available at an unprecedented resolution of a few hundreds of kilometers. The gravity field is a product of the Earth's mass distribution, and these data-provided by the satellites of the Gravity Recovery And Climate Experiment (GRACE)-can be used to study the exchange of mass both within the Earth and at its surface. Since the launch of the mission in 2002, GRACE data has evolved from being an experimental measurement needing validation from ground truth, to a respected tool for Earth scientists representing a fixed bound on the total change and is now an important tool to help unravel the complex dynamics of the Earth system and climate change. In this review, we present the mission concept and its theoretical background, discuss the data and give an overview of the major advances GRACE has provided in Earth science, with a focus on hydrology, solid Earth sciences, glaciology and oceanography.

Model-based failure detection for cylindrical shells from noisy vibration measurements.

Model-based processing is a theoretically sound methodology to address difficult objectives in complex physical problems involving multi-channel sensor measurement systems. It involves the incorporation of analytical models of both physical phenomenology (complex vibrating structures, noisy operating environment, etc.) and the measurement processes (sensor networks and including noise) into the processor to extract the desired information. In this paper, a model-based methodology is developed to accomplish the task of online failure monitoring of a vibrating cylindrical shell externally excited by controlled excitations. A model-based processor is formulated to monitor system performance and detect potential failure conditions. The objective of this paper is to develop a real-time, model-based monitoring scheme for online diagnostics in a representative structural vibrational system based on controlled experimental data.

Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice.

Analysis of classical mouse mutations has been useful in the identification and study of many genes. We previously mapped Sox18, encoding an SRY-related transcription factor, to distal mouse chromosome 2. This region contains a known mouse mutation, ragged (Ra), that affects the coat and vasculature. Here we have directly evaluated Sox18 as a candidate for Ra. We found that Sox18 is expressed in the developing vascular endothelium and hair follicles in mouse embryos. Furthermore, we found no recombination between Sox18 and Ra in an interspecific backcross segregating for the Ra phenotype. We found point mutations in Sox18 in two different Ra alleles that result in missense translation and premature truncation of the encoded protein. Fusion proteins containing these mutations lack the ability to activate transcription relative to wild-type controls in an in vitro assay. Our observations implicate mutations in Sox18 as the underlying cause of the Ra phenotype, and identify Sox18 as a critical gene for cardiovascular and hair follicle formation.

Using a television programme as a tool to increase perceived awareness of mental health and well-being - findings from 'Our Mental Health' survey.

BACKGROUND: International research shows that media can increase knowledge, raise public awareness and reduce stigma relating to mental health. METHODS: Following the broadcast of a documentary on national television featuring interviews with young people who had experienced mental health difficulties and suicidal behaviour, an anonymous online survey, aimed at examining public perceptions of the impact of a television documentary, was conducted, using a mixed methods approach. RESULTS: 2311 people completed the survey. Of those who watched the documentary and answered the closed questions (n = 854), 94% stated that the documentary will positively impact young people's mental health and well-being. The majority (91%) stated that the documentary will encourage young people to talk to someone if experiencing difficulties and 87% indicated it will help to reduce stigma associated with mental health. Viewers had a 5% higher level of intention to seek help than non-viewers. Participants indicated that the identifiable personal stories and discourse around stigma and shame, and the increased understanding and awareness gained, had the most profound impact on them. CONCLUSIONS: These findings indicate that a documentary addressing mental health and suicidal behaviour, which incorporates real life identifiable stories of resilience and recovery, has the potential to impact positively on emotional well-being and general mood, to reduce stigma related to mental health and to encourage help-seeking behaviour. Documentaries including these concepts, with a public mental health focus and a consistent message, incorporating pre- and post-evaluations, and customisation for target audiences in compliance with current media recommendations, should be considered.

Excellent clinical outcomes from a national donation-after-determination-of-cardiac-death lung transplant collaborative.

Donation-after-Determination-of-Cardiac-Death (DDCD) donor lungs can potentially increase the pool of lungs available for Lung Transplantation (LTx). This paper presents the 5-year results for Maastricht category III DDCD LTx undertaken by the multicenter Australian National DDCD LTx Collaborative. The Collaborative was developed to facilitate interaction with the Australian Organ Donation Authority, standardization of definitions, guidelines, education and audit processes. Between 2006 and 2011 there were 174 actual DDCD category III donors (with an additional 37 potentially suitable donors who did not arrest in the mandated 90 min postwithdrawal window), of whom 71 donated lungs for 70 bilateral LTx and two single LTx. In 2010 this equated to an "extra" 28% of donors utilized for LTx. Withdrawal to pulmonary arterial flush was a mean of 35.2 ± 4.0 min (range 18-89). At 24 h, the incidence of grade 3 primary graft dysfunction was 8.5%[median PaO(2)/FiO(2) ratio 315 (range 50-507)]. Overall the incidence of grade 3 chronic rejections was 5%. One- and 5-year actuarial survival was 97% and 90%, versus 90% and 61%, respectively, for 503 contemporaneous brain-dead donor lung transplants. Category III DDCD LTx therefore provides a significant, practical, additional quality source of transplantable lungs.

Does our research tool kit equip us to make generalisable claims about dental education?

In this essay on the state of scholarship in dental education, I argue that we are best served by looking at the validity, generalisability and usefulness of claims rather than at the rigour of various research methods. All papers published in 2009 in the European Journal of Dental Education (a quarterly) and the Journal of Dental Education (published monthly), a quarterly journal of the Academy of Management, Learning & Education and the monthly American Journal of Orthodontics and Dentofacial Orthopedics were classified by the type of claim made, method by which evidence was collected and techniques of analysis. The dental education literature, compared with the two other journals, was largely focussed on surveys of opinion or particular practices and lacked scope in generalisability. The dental education literature was thin in use of randomisation, covariable analysis and theory-building.

Dexmedetomidine as a rescue agent during intracranial neurosurgery in the setting of opioid tolerance.

Dexmedetomidine is a versatile sedative agent widely used both in anaesthesia and intensive care. We present the case of a 32-year-old woman with a long-term history of non-prescribed intravenous opioid use who underwent elective resection of a skull base tumour. There was difficulty in achieving an adequate depth of anaesthesia despite the high levels of intravenous and volatile anaesthetic agent. Intra-operatively, a bolus and subsequent infusion of dexmedetomidine helped achieve an adequate depth of anaesthesia. This report highlights some of the benefits of dexmedetomidine for patients who are opioid tolerant, both intra- and postoperatively. It also demonstrates the wide range of beneficial effects dexmedetomidine could have when used as a rescue adjunct in neuroanaesthesia.

Postpartum cerebral venous sinus thrombosis following obstetric neuraxial blockade: a literature review with analysis of 58 case reports.

BACKGROUND: Cerebral venous sinus thrombosis (CVST) is a rare complication of pregnancy. It usually presents with a headache and may mimic a post-dural puncture headache (PDPH) in women who receive a neuraxial block. METHODS: Medline, CINAHL and EMBASE databases were searched to identify postpartum cases of CVST following neuraxial block. The aim was to delineate the characteristics, presentation, investigations, and outcomes of postpartum women who presented with CVST. RESULTS: Forty-nine articles with 58 case reports were identified. Forty-two women (72.4%) had an epidural attempted whilst 16 women (27.6%) received a spinal anaesthetic. Accidental dural puncture (ADP) was reported in 17 women (40.5%). Headache was the presenting symptom in 57 women (98.3%); 26 women (44.8%) also experienced seizures. Post-dural puncture headache was reported in 46 (79.3%) and an epidural blood patch was performed in 26 women (44.8%). Superior sagittal sinus, transverse sinus, and cortical veins were the most common sites of thrombosis. The median time to diagnosis was 6.5 days from delivery. Magnetic resonance imaging was the most common diagnostic neuro-imaging modality. Full neurological recovery was reported in 48 (82.8%), whilst neurological deficits were reported in six (10.3%) women. DISCUSSION: The diagnosis of CVST may be overlooked in women who present with headache following neuraxial block. A change in character of headache with loss of postural element, and focal neurological signs are the key clinical features that could help anaesthetists differentiate headache of CVST from PDPH. The high reported rates of ADP and PDPH lend support to their possible association with CVST.

The impact of pandemic influenza A H1N1 2009 on Australian lung transplant recipients.

Influenza A H1N1 2009 led to 189 deaths during the Australian pandemic. Community-acquired respiratory viruses not only can cause prolonged allograft dysfunction in lung transplant recipients but have also been linked to bronchiolitis obliterans syndrome (BOS). We report the impact of the 2009 H1N1 pandemic on Australian lung transplant recipients. An observational study of confirmed H1N1 cases was conducted across five Australian lung transplant programs during the pandemic. An electronic database collected patient demographics, clinical presentation, management and outcomes up to a year follow-up. Twenty-four H1N1 cases (mean age 43 ± 14 years, eight females) were identified, incidence of 3%. Illness severity varied from upper respiratory tract symptoms only in 29% to lung allograft dysfunction (≥10% decline FEV1) in 75% to death in 5 (21%) cases (pre-existing BOS grade 3, n = 4). Treatment with oseltamivir occurred in all but one case confirmed after death, reduced immunosuppression, n = 1, augmented corticosteroid therapy, n = 16, and mechanical/noninvasive ventilation, n = 4. There was BOS grade decline within a year in six cases (32%). In conclusion, Australian lung transplant recipients were variably affected by the H1N1 pandemic mirroring the broader community with significant morbidity and mortality. After initial recovery, a considerable proportion of survivors have demonstrated BOS progression.

Importance of immunohistochemical evaluation of developmentally regulated myosin heavy chains in human muscle biopsies.

Our retrospective immunohistochemical study of normal quadriceps muscle biopsies shows that embryonic myosin heavy chains are down-regulated by, or soon after, birth. Fetal myosin heavy chains are down-regulated by 4-6 months. Thus the presence of an appreciable number of fibres with embryonic myosin heavy chains at birth or of fetal myosin heavy chains after 6 months of age suggests a delay in maturation or an underlying abnormality. Regenerating fibres in dystrophic muscle often co-express both embryonic and fetal myosin heavy chains but more fibres with fetal than embryonic myosin heavy chains can occur. Embryonic myosin heavy chains are a useful marker of regeneration but effects of denervation, stress, disuse, and fibre maintenance also have to be taken into account. In neurogenic disorders fibres with embryonic myosin heavy chains are rare but fetal myosin heavy chain expression is common, particularly in 5q spinal muscle atrophy. Nuclear clumps in denervated muscle show fetal and sometimes embryonic myosin heavy chains. Developmentally regulated myosins are useful for highlighting the perifascicular atrophy in juvenile dermatomyositis. Our studies highlight the importance of baseline data for embryonic and fetal myosin heavy chains in human muscle biopsies and the importance of assessing them in a spectrum of neuromuscular disorders.

Combined Heart-Lung-Liver Transplantation for Patients With Cystic Fibrosis: The Australian Experience.

BACKGROUND: Combined multivisceral transplantation has emerged as a therapeutic option for a select patient cohort; however, clinical decision-making remains complex and controversial. The aim of this study was to examine patient characteristics, operative complications, and long-term outcomes of all patients who have undergone combined heart-lung-liver transplantation (HLLTx) in Australia. METHODS: In this study, we performed a retrospective analysis of all adult patients who have undergone combined HLLTx in Australia to date. Recipient clinical characteristics, waitlist, and transplant outcomes are described. RESULTS: Eight adult patients have received HLLTx at a single Australian transplant center. Recipients of HLLTx have typically been young (median age, 30.1 years; range, 24-37), underweight (median body mass index, 19.8 kg/m2; range, 16.2-30.4) patients with cystic fibrosis (n = 8, 100%) with severe airflow obstruction (median forced expiratory volume in the first second of expiration, 24% predicted; range, 17%-48%) accompanied by liver cirrhosis confirmed on histopathology (n = 8, 100%). Despite relative preservation of synthetic function and low model for end-stage liver disease scores (median, 8; range, 6-17), all recipients had complications of portal hypertension prior to transplantation, with many patients having suffered life-threatening variceal hemorrhage. In this cohort, HLLTx was associated with overall posttransplant survival of 87.5% at 30 days, 71.4% at 1 year, and 42.9% at 5 years. Listing for combined HLLTx was associated with prolonged waitlist times relative to bilateral sequential single-lung transplantation (median 556 vs 56 days, respectively), however waitlist mortality and/or delisting was comparable between groups. CONCLUSIONS: Taken together, these findings highlight the opportunities and challenges facing combined (heart-) lung and liver transplantation in patients with multiorgan failure.