Normal, dust-obscured galaxies in the epoch of reionization.

Over the past decades, rest-frame ultraviolet (UV) observations have provided large samples of UV luminous galaxies at redshift (z) greater than 6 (refs. 1-3), during the so-called epoch of reionization. While a few of these UV-identified galaxies revealed substantial dust reservoirs4-7, very heavily dust-obscured sources at these early times have remained elusive. They are limited to a rare population of extreme starburst galaxies8-12 and companions of rare quasars13,14. These studies conclude that the contribution of dust-obscured galaxies to the cosmic star formation rate density at z > 6 is sub-dominant. Recent ALMA and Spitzer observations have identified a more abundant, less extreme population of obscured galaxies at z = 3-6 (refs. 15,16). However, this population has not been confirmed in the reionization epoch so far. Here, we report the discovery of two dust-obscured star-forming galaxies at z = 6.6813 ± 0.0005 and z = 7.3521 ± 0.0005. These objects are not detected in existing rest-frame UV data and were discovered only through their far-infrared [C II] lines and dust continuum emission as companions to typical UV-luminous galaxies at the same redshift. The two galaxies exhibit lower infrared luminosities and star-formation rates than extreme starbursts, in line with typical star-forming galaxies at z ≈ 7. This population of heavily dust-obscured galaxies appears to contribute 10-25% to the z > 6 cosmic star formation rate density.

Colour dimorphism in labrid fishes as an adaptation to life on coral reefs.

Conspicuous coloration displayed by animals that express sexual colour dimorphism is generally explained as an adaptation to sexual selection, yet the interactions and relative effects of selective forces influencing colour dimorphism are largely unknown. Qualitatively, colour dimorphism appears more pronounced in marine fishes that live on coral reefs where traits associated with strong sexual selection are purportedly more common. Using phylogenetic comparative analysis, we show that wrasses and parrotfishes exclusive to coral reefs are the most colour dimorphic, but surprisingly, the effect of habitat is not influenced by traits associated with strong sexual selection. Rather, habitat-specific selective forces, including clear water and structural refuge, promote the evolution of pronounced colour dimorphism that manifests colours less likely to be displayed in other habitats. Our results demonstrate that environmental context ultimately determines the evolution of conspicuous coloration in colour-dimorphic labrid fishes, despite other influential selective forces.

Cross validated serum small extracellular vesicle microRNAs for the detection of oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is often diagnosed at an advanced stage because the disease often causes minimal symptoms other than metastasis to neck lymph nodes. Better tools are required to assist with the early detection of OPSCC. MicroRNAs (miRNAs, miRs) are potential biomarkers for early head and neck squamous cell cancer diagnosis, prognosis, recurrence, and presence of metastatic disease. However, there is no widespread agreement on a panel of miRNAs with clinically meaningful utility for head and neck squamous cell cancers. This could be due to variations in the collection, storage, pre-processing, and isolation of RNA, but several reports have indicated that the selection and reproducibility of biomarkers has been widely affected by the methods used for data analysis. The primary analysis issues appear to be model overfitting and the incorrect application of statistical techniques. The purpose of this study was to develop a robust statistical approach to identify a miRNA signature that can distinguish controls and patients with inflammatory disease from patients with human papilloma virus positive (HPV +) OPSCC. METHODS: Small extracellular vesicles were harvested from the serum of 20 control patients, 20 patients with gastroesophageal reflux disease (GORD), and 40 patients with locally advanced HPV + OPSCC. MicroRNAs were purified, and expression profiled on OpenArray™. A novel cross validation method, using lasso regression, was developed to stabilise selection of miRNAs for inclusion in a prediction model. The method, named StaVarSel (for Stable Variable Selection), was used to derive a diagnostic biomarker signature. RESULTS: A standard cross validation approach was unable to produce a biomarker signature with good cross validated predictive capacity. In contrast, StaVarSel produced a regression model containing 11 miRNA ratios with potential clinical utility. Sample permutations indicated that the estimated cross validated prediction accuracy of the 11-miR-ratio model was not due to chance alone. CONCLUSIONS: We developed a novel method, StaVarSel, that was able to identify a panel of miRNAs, present in small extracellular vesicles derived from blood serum, that robustly cross validated as a biomarker for the detection of HPV + OPSCC. This approach could be used to derive diagnostic biomarkers of other head and neck cancers.

Citalopram and sertraline exposure compromises embryonic bone development.

Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.

Phenotype analysis impacts testing strategy in patients with Currarino syndrome.

Currarino syndrome (OMIM 175450) presents with sacral, anorectal, and intraspinal anomalies and presacral meningocele or teratoma. Autosomal dominant loss-of-function mutations in the MNX1 gene cause nearly all familial and 30% of sporadic cases. Less frequently, a complex phenotype of Currarino syndrome can be caused by microdeletions of 7q containing MNX1. Here, we report one familial and three sporadic cases of Currarino syndrome. To determine the most efficient genetic testing approach for these patients, we have compared results from MNX1 sequencing, chromosomal microarray, and performed a literature search with analysis of genotype-phenotype correlation. Based on the relationship between the type of mutation (intragenic MNX1 mutations vs 7q microdeletion) and the presence of intellectual disability, growth retardation, facial dysmorphism, and associated malformations, we propose a testing algorithm. Patients with the classic Currarino triad of malformations but normal growth, intellect, and facial appearance should have MNX1 sequencing first, and only in the event of a normal result should the clinician proceed with chromosomal microarray testing. In contrast, if growth delay and/or facial dysmorphy and/or intellectual disability are present, chromosomal microarray should be the first method of choice for genetic testing.

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.

Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

The association between major depressive disorder, use of antidepressants and bone mineral density (BMD) in men.

OBJECTIVE: Both depression and use of antidepressants have been negatively associated with bone mineral density (BMD) but mainly in studies among postmenopausal women. Therefore, the aim of this study was to investigate these relationships in men. METHODS: Between 2006 and 2011, 928 men (aged 24-98 years) from the Geelong Osteoporosis Study completed a comprehensive questionnaire, clinical measurements and had BMD assessments at the forearm, spine, total hip and total body. Major depressive disorder (MDD) was identified using a structured clinical interview (SCID-I/NP). The cross-sectional associations between BMD and both MDD and antidepressant use were analyzed using multivariable linear regression. RESULTS: Of the study population, 84 (9.1%) men had a single MDD episode, 50 (5.4%) had recurrent episodes and 65 (7.0%) were using antidepressants at the time of assessment. Following adjustments, recurrent MDD was associated with lower BMD at the forearm and total body (-6.5%, P=0.033 and -2.5%, P=0.033, respectively compared to men with no history of MDD), while single MDD episodes were associated with higher BMD at the total hip (+3.4%, P=0.030). Antidepressant use was associated with lower BMD only in lower-weight men (<75-110 kg depending on bone site). CONCLUSIONS: Both depression and use of antidepressants should be taken into account as possible risk factors for osteoporosis in men.

Expanding the use of monoclonal antibody therapy of cancer by using ionising radiation to upregulate antibody targets.

BACKGROUND: Monoclonal antibody (mAb) therapy for the treatment of solid and haematologic malignancies has shown poor response rates as a monotherapy. Furthermore, its use is limited to tumours expressing certain molecular targets. It has been shown that single-dose radiation can induce immunogenic modulation that is characterised by cell-surface phenotypic changes leading to augmented tumour cell/cytotoxic T-cell interaction. METHODS: We examined radiation's ability to upregulate mAb therapy targets. We also used radiation to sensitise tumour cells to antibody-dependent cell-mediated cytotoxicity (ADCC). RESULTS: Radiation significantly increased cell-surface and total protein expression of mAb targets HER2, EGFR, and CD20. Focusing on HER2, targeted by trastuzumab, we observed significant upregulation of HER2 following radiation of 3 out of 3 breast cancer cell lines, one of which was triple negative, as well as in residential stem-cell populations. HER2 upregulation was sustained up to 96 h following radiation exposure and was largely dependent on intracellular reactive oxygen species. Improved ADCC and sensitisation to the antiproliferative effects of trastuzumab demonstrated the functional significance of radiation-induced HER2 upregulation. CONCLUSIONS: We show that single-dose radiation enhances mAb therapy. These findings highlight a mechanism for combining radiation with immunotherapy and expand the patient population that can be treated with targeted therapy.

Identification of single gene deletions at 15q13.3: further evidence that CHRNA7 causes the 15q13.3 microdeletion syndrome phenotype.

The 15q13.3 microdeletion syndrome (OMIM #612001) is characterized by a wide range of phenotypic features, including intellectual disability, seizures, autism, and psychiatric conditions. This deletion is inherited in approximately 75% of cases and has been found in mildly affected and normal parents, consistent with variable expressivity and incomplete penetrance. The common deletion is approximately 2 Mb and contains several genes; however, the gene(s) responsible for the resulting clinical features have not been clearly defined. Recently, four probands were reported with small deletions including only the CHRNA7 gene. These patients showed a wide range of phenotypic features similar to those associated with the larger 15q13.3 microdeletion. To further correlate genotype and phenotype, we queried our database of >15,000 patients tested in the Mayo Clinic Cytogenetics Laboratory from 2008 to 2011 and identified 19 individuals (10 probands and 9 family members) with isolated heterozygous CHRNA7 gene deletions. All but two infants displayed multiple features consistent with 15q13.3 microdeletion syndrome. We also identified the first de novo deletion confined to CHRNA7 as well as the second known case with homozygous deletion of CHRNA7 only. These results provide further evidence implicating CHRNA7 as the gene responsible for the clinical findings associated with 15q13.3 microdeletion.

Validation of the TNM-8 AJCC classification for HPV-positive oropharyngeal cancers in patients undergoing trans-oral robotic surgery.

High-risk human papillomaviruses (HPV) are associated with some oropharyngeal squamous cell carcinomas (OPSCC). HPV-OPSCC have better survival outcomes compared to HPV negative tumours. The new TNM-8 AJCC staging (2018) is based on ICON-S data with 98% of patients treated with primary chemoradiation. To validate the TNM-8 AJCC classification in HPV-OPSCC treated primarily with surgery (trans-oral robotic surgery or open). There were 102 patients with HPV-OPSCC treated between July 2009 and December 2014 at the Royal Adelaide Hospital. The median age was 57 years (range: 38-83) and mostly males (84.5%). 27.2% were active smokers and 50.5% reformed smokers. Early T-stage cancer in 72.8%. Primary treatment was surgery & adjuvant therapy (70%) while primary chemoradiation (30%). Survival analyses were performed for the 7th and 8th AJCC systems. The reclassification to the AJCC 8th edition staging system resulted in a change of 54 patients from stage 4 to stages 1 and 2. This was mainly an effect of changes with N2a and N2b nodal disease being reclassified to N1. Survival outcomes were comparable with the ICON-S data. The new TNM-8 classification is, therefore, validated in a cohort treated, predominantly, with primary surgery and adjuvant therapy.

The pulmonary pharmacology of [4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide] (2NTX-99), an anti-atherotrombotic compound with therapeutic potential in pathological conditions that target lung vasculature.

The pharmacological activity of 2NTX-99 ([4-methoxy-N1-(4-trans-nitrooxycyclohexyl)-N3-(3-pyridinylmethyl)-1,3-benzenedicarboxamide]) was investigated in vitro in the intact, rat pulmonary vasculature and in guinea pig airways. Rat lungs were perfused at constant flow and changes in vascular tone recorded. Challenge with the TXA2 analogue 9,11-dideoxy-9α11α-methanoepoxy ProstaglandinF2 (U46619, 0.5 µM) increased vessel tone (32.48±1.5 vs 13.13±0.56 mmHg; n=12). 2NTX-99 (0.1-100 µM; n=5), caused a concentration-dependent relaxation, prevented by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 10 µM, n=4), an inhibitor of soluble guanylate cyclase. Acetylcholine (0.1-10 µM; n=3) and a reference NO-donor, isosorbide-5-mononitrate (5-100 µM; n=4), were ineffective. Intraluminal perfusion of washed human platelets (2 × 108 cells/ml) increased intravascular pressure after challenge with arachidonic acid (AA, 2 µM; n=5), an increase abolished by acetylsalicylic acid and significantly reduced by 2NTX-99 (40 µM; n=5). TXB2 in the lung perfusate was detected after platelet activation, 2NTX-99 inhibited TXA2 synthesis (6.45±0.6 and 1.10±0.2 ng/ml, respectively). 2NTX-99 did not alter central or peripheral airway responsiveness to Histamine (0.001-300 µM; n=6), U46619 (0.001-3 µM, n=3) or LTD4 (1 pM-1 µM; n=6). 2NTX-99 vasodilates the pulmonary vasculature via the release of nitric oxide (NO) and reduces intraluminal, AA-induced, TXA2 formation. The combined activity of 2NTX-99 as an NO-donor and a TXA2-synthesis inhibitor provides strong support for its potential therapeutic use in pathologies of the pulmonary vascular bed (e.g. pulmonary hypertension).

Constraints on the Ecomorphological Convergence of Zooplanktivorous Butterflyfishes.

Whether distantly related organisms evolve similar strategies to meet the demands of a shared ecological niche depends on their evolutionary history and the nature of form-function relationships. In fishes, the visual identification and consumption of microscopic zooplankters, selective zooplanktivory, is a distinct type of foraging often associated with a suite of morphological specializations. Previous work has identified inconsistencies in the trajectory and magnitude of morphological change following transitions to selective zooplanktivory, alluding to the diversity and importance of ancestral effects. Here we investigate whether transitions to selective zooplanktivory have influenced the morphological evolution of marine butterflyfishes (family Chaetodontidae), a group of small-prey specialists well known for several types of high-precision benthivory. Using Bayesian ancestral state estimation, we inferred the recent evolution of zooplanktivory among benthivorous ancestors that hunted small invertebrates and browsed by picking or scraping coral polyps. Traits related to the capture of prey appear to be functionally versatile, with little morphological distinction between species with benthivorous and planktivorous foraging modes. In contrast, multiple traits related to prey detection or swimming performance are evolving toward novel, zooplanktivore-specific optima. Despite a relatively short evolutionary history, general morphological indistinctiveness, and evidence of constraint on the evolution of body size, convergent evolution has closed a near significant amount of the morphological distance between zooplanktivorous species. Overall, our findings describe the extent to which the functional demands associated with selective zooplanktivory have led to generalizable morphological features among butterflyfishes and highlight the importance of ancestral effects in shaping patterns of morphological convergence.

A evolução de estratégias similares para suprir as demandas de nichos ecológicos compartilhados em organismos pouco relacionados, depende da sua história evolutiva e da natureza das relações entre forma e função. Em peixes, a identificação visual e o consumo de zooplanctôn microscópico, a zooplanctivoria seletiva, é um tipo distinto de forrageamento frequentemente associado a um conjunto de especializações morfológicas. Estudos anteriores identificaram inconsistências na trajetória e magnitude das mudanças morfológicas que surgem a partir das transições para a zooplanctivoria seletiva, fazendo alusão à diversidade e importância dos efeitos ancestrais. Aqui investigamos se transições para a zooplanctivoria seletiva influenciaram a evolução morfológica dos peixes-borboleta marinhos (família Chaetodontidae), um grupo especialista em presas pequenas conhecido pelos muitos tipos de bentivoria de alta precisão. Utilizando uma estimativa ancestral bayesiana, inferimos a evolução recente da zooplanctivoria dentre os ancestrais bentívoros que caçavam pequenos invertebrados e alimentavam-se de pólipos de coral. Características relacionadas a captura de presa parecem ser funcionalmente versáteis com pouca distinção entre as espécies com modo de forrageamento bentívoro e planctívoro. Em contraste, várias características relacionadas a detecção da presa ou capacidade natatória estão evoluindo em direção a um novo ótimo, específico para a zooplanctivoria. Apesar da história evolutiva relativamente recente, uma morfologia geral comum, e evidência de uma restrição na evolução do tamanho corporal, a evolução convergente reduziu significativamente a distância morfológica entre as espécies zooplanctívoras. No geral, nossos resultados descrevem até que ponto as demandas funcionais associadas à zooplanctivoria seletiva levaram a características morfológicas generalizadas nos peixes-borboleta e destacam a importância dos efeitos ancestrais em moldar os padrões de convergência morfológica.

El hecho de que organismos con parentesco lejano evolucionen estrategias similares para satisfacer las demandas de un nicho ecológico compartido depende de su historia evolutiva y de la naturaleza de la relación forma-función. En peces, la identificación visual y el consumo de plancton microscópico, la zooplanctivoría selectiva, es un tipo específico de alimentación usualmente asociado a un conjunto de especializaciones morfológicas. Estudios previos han identificado inconsistencias en la trayectoria y magnitud de cambios morfológicos tras transiciones hacia zooplanctivoría selectiva, aludiendo a la diversidad e importancia de efectos ancestrales. Aquí investigamos si las transiciones a zooplanctivoría selectiva han influido en la evolución morfológica de los peces mariposa marinos (familia Chaetodontidae), un grupo especializado en presas pequeñas conocido por varios tipos de alimentación de alta precisión en el bentos. Usando una estimación de estado ancestral Bayesiana, inferimos la evolución reciente de la zooplanctivoría entre ancestros bentívoros que cazaron pequeños invertebrados y se alimentaron de pólipos de coral. Los rasgos relacionados con la captura de presas parecen ser versátiles funcionalmente con escasa distinción morfológica entre especies con modos de alimentación bentívoros y planctívoros. En cambio, múltiples rasgos relacionados con la detección de presas o con la capacidad natatoria están evolucionando hacia un nuevo óptimo específico para zooplanctivoría. A pesar de una historia evolutiva relativamente corta, una morfología general común, y evidencia de restricción en la evolución del tamaño de los peces, una evolución convergente ha reducido la distancia morfológica entre especies zooplanctívoras de forma casi significativa. En conclusión, nuestros hallazgos describen hasta qué punto las demandas funcionales asociadas con la zooplanctivoría selectiva han desembocado en rasgos morfológicos generalizados en peces mariposa y destacan la importancia de los efectos ancestrales en la creación de patrones de morfología convergente.

Predictors of growth and body composition in HIV-infected children beginning or changing antiretroviral therapy.

OBJECTIVES: The aim of the study was to describe growth and body composition changes in HIV-positive children after they had initiated or changed antiretroviral therapy (ART) and to correlate these with viral, immune and treatment parameters. METHODS: Ninety-seven prepubertal HIV-positive children were observed over 48 weeks upon beginning or changing ART. Anthropometry and bioelectrical impedance analysis results were compared with results from the National Health and Nutrition Examination Survey 1999-2002 (NHANES) to generate z-scores and with results for HIV-exposed, uninfected children from the Women and Infants Transmission Study (WITS). Multivariate analysis was used to evaluate associations between growth and body composition and disease parameters. RESULTS: All baseline lean and fat mass measures were below those of controls from NHANES. Weight, height and fat free mass (FFM) index (FFM/height(2)) z-scores increased over time (P = 0.004, 0.037 and 0.027, respectively) and the waist:height ratio z-score decreased (P = 0.045), but body mass index and per cent body fat z-scores did not change. Measures did not increase more than in uninfected WITS controls. In multivariate analysis, baseline height, mid-thigh circumference and FFM z-scores related to CD4 percentage (P = 0.029, P = 0.008 and 0.020, respectively) and change in FFM and FFM index z-scores to CD4 percentage increase (P = 0.010 and 0.011, respectively). Compared with WITS controls, baseline differences in height and mid-thigh muscle circumference were also associated with CD4 percentage. Case-control differences in change in both subscapular skinfold (SSF) thickness and the SSF:triceps skinfold ratio were inversely associated with viral suppression. No measures related to ART class(es) at baseline or over time. CONCLUSIONS: In these HIV-positive children, beginning or changing ART was associated with improved growth and lean body mass (LBM), as indicated by FFM index. Height and LBM related to CD4 percentage at baseline and over time. Altered fat distribution and greater central adiposity were associated with detectable virus but not ART class(es) received.

High-redshift star formation in the Atacama large millimetre/submillimetre array era.

The Atacama Large Millimetre/submillimetre Array (ALMA) is currently in the process of transforming our view of star-forming galaxies in the distant ( z ≳ 1 ) universe. Before ALMA, most of what we knew about dust-obscured star formation in distant galaxies was limited to the brightest submillimetre sources-the so-called submillimetre galaxies (SMGs)-and even the information on those sources was sparse, with resolved (i.e. sub-galactic) observations of the obscured star formation and gas reservoirs typically restricted to the most extreme and/or strongly lensed sources. Starting with the beginning of early science operations in 2011, the last 9 years of ALMA observations have ushered in a new era for studies of high-redshift star formation. With its long baselines, ALMA has allowed observations of distant dust-obscured star formation with angular resolutions comparable to-or even far surpassing-the best current optical telescopes. With its bandwidth and frequency coverage, it has provided an unprecedented look at the associated molecular and atomic gas in these distant galaxies through targeted follow-up and serendipitous detections/blind line scans. Finally, with its leap in sensitivity compared to previous (sub-)millimetre arrays, it has enabled the detection of these powerful dust/gas tracers much further down the luminosity function through both statistical studies of colour/mass-selected galaxy populations and dedicated deep fields. We review the main advances ALMA has helped bring about in our understanding of the dust and gas properties of high-redshift ( z ≳ 1 ) star-forming galaxies during these first 9 years of its science operations, and we highlight the interesting questions that may be answered by ALMA in the years to come.

Transoral robotic narrow field oropharyngectomy for tumours of the parapharyngeal space.

The advent of transoral robotic surgery (TORS) has allowed transoral approaches for parapharyngeal space (PPS) tumours to be re-evaluated. It provides enhanced visualisation and instrument access for appropriate tumours. We describe a specific technique, TORS narrow-field oropharyngectomy, that is ideal for benign PPS tumours which have been violated by intra-oral biopsy or incision and drainage. This allows the contaminated, overlying oropharyngeal mucosa to be resected en-bloc with the PPS tumour, reducing the risk of local recurrence. This technique provides a window into the PPS, improving visualisation of underlying neurovascular structures as well as the tumour. This reduces the risk of tumour spillage and leads to superior vascular access and haemorrhage control. This technique is only applicable to PPS tumours that are appropriate for transoral approaches and is specifically designed for those selected patients that have been placed at risk of seeding or local scarring by intra-oral procedures prior to definitive resection. We present two such cases: a 38-year-old male with a PPS inflammatory cyst and a 66-year-old female with a PSS pre-styloid Schwannoma.

How I do it: transnasal retraction during transoral robotic oropharyngeal resection.

Collapse of the resection plane presents a frustrating problem during transoral robotic resection, in a situation already typified by limited vision and access for instruments. We present a quick and cost-effective retraction technique to effectively mitigate this issue and increase the ease and reliability of robotic oropharyngeal resection. This technique utilises a simple transnasal apparatus to create greater exposure of the resection plane. A Y-suction catheter is inserted into the oropharynx via the nasal cavity. A silk suture is then used to attach it to the oropharyngeal resection specimen. When pulled from the nasal cavity, this apparatus adds a non-intrusive, tremor-free fixation point that pulls the resected specimen along a unique cephalo-posterior vector. This significantly improves access and vision of the desired dissection plane. The entire process takes approximately 1-2 min per side to properly execute. It can be adapted for various pathologies and subsites of the oropharynx. This transnasal technique is a simple, minimally invasive, and inexpensive method for improving wound tension during transoral oropharyngeal resection.

Transoral robotic surgery using the Medrobotic Flex® system: the Adelaide experience.

Transoral robotic surgery (TORS) has become an accepted treatment option for a variety of benign and malignant pathologies of the head and neck. The Medrobotics Flex® system is a novel single port platform available as an alternative tool to current multiport robotic technology. We present the Adelaide experience with this system thus far. The Medrobotics Flex® system was introduced in Adelaide in January 2017. Patient demographics, pathology, indication for surgery and complications are prospectively recorded for all cases. The first 20 patients are presented in this case series. 11/20 underwent surgery for malignant disease. Of these nine were diagnosed with oropharyngeal squamous cell carcinoma (OPSCC). Histopathology revealed clear margins of primary tumour excision in 8/9 patients. There were no intraoperative complications. In terms of secondary complications, one patient undergoing tonsillectomy for recurrent tonsillitis experienced a secondary haemorrhage at day 13 following operation and one patient undergoing lateral oropharyngectomy for pT3N2b tonsillar SCC sustained an oro-cervical fistula, which settled with conservative management. We have found the Medrobotic Flex® system to be a safe, reliable tool for managing transoral surgery. The range of pathology managed with this platform, as well as the histologic outcomes presented, demonstrates efficacy in the oropharynx and posterior oral cavity for both benign and malignant disease.