Terahertz in vivo imaging of human skin: Toward detection of abnormal skin pathologies.

Terahertz (THz) imaging has long held promise for skin cancer detection but has been hampered by the lack of practical technological implementation. In this article, we introduce a technique for discriminating several skin pathologies using a coherent THz confocal system based on a THz quantum cascade laser. High resolution in vivo THz images (with diffraction limited to the order of 100 µm) of several different lesion types were acquired and compared against one another using the amplitude and phase values. Our system successfully separated pathologies using a combination of phase and amplitude information and their respective surface textures. The large scan field (50 × 40 mm) of the system allows macroscopic visualization of several skin lesions in a single frame. Utilizing THz imaging for dermatological assessment of skin lesions offers substantial additional diagnostic value for clinicians. THz images contain information complementary to the information contained in the conventional digital images.

Do improvements in clinical practice guidelines alter pregnancy outcomes in asthmatic women? A single-center retrospective cohort study.

OBJECTIVE: Asthma occurs in ∼17% of Australian pregnancies and is associated with adverse perinatal outcomes, which worsen with poor asthma control. Consequently, the South Australian 'Asthma in Pregnancy' perinatal guidelines were revised in 2012 to address management according to severity. This study investigated if these revised guidelines reduced the impact of maternal asthma on risks of adverse perinatal outcomes before (Epoch 1, 2006-2011) and after the revision (Epoch 2, 2013-2018). METHODS: Routinely collected perinatal and neonatal datasets from the Women's and Children's Hospital (Adelaide, Australia) were linked. Maternal asthma (prevalence:7.5%) was defined as asthma medication use or symptoms described to midwives. In imputation (n = 59131) and complete case datasets (n = 49594), analyses were conducted by inverse proportional weighting and multivariate logistic regression, accounting for confounders. RESULTS: Overall, maternal asthma was associated with increased risks of any antenatal corticosteroid treatment for threatened preterm birth (aOR 1.319, 95% CI 1.078-1.614), any Cesarean section (aOR 1.196, 95% CI 1.059-1.351), Cesarean section without labor (aOR 1.241, 95% CI 1.067-1.444), intrauterine growth restriction (IUGR, aOR 1.285, 95% CI 1.026-1.61), and small for gestational age (aOR 1.324, 95% CI 1.136-1.542). After guideline revision, asthma-associated risks of any Cesarean section (p < 0.001), any antenatal corticosteroids (p = 0.041), and small for gestational age (p = 0.050), but not IUGR and Cesarean section without labor, were reduced. CONCLUSIONS: Clinical practice guidelines based on the latest evidence do not guarantee clinical efficacy. Since adverse perinatal outcomes did not all improve, this work highlights the need to evaluate the ongoing impact of guidelines on clinical outcomes.

A model to predict difficult airway alerts after videolaryngoscopy in adults with anticipated difficult airways - the VIDIAC score.

A model to classify the difficulty of videolaryngoscopic tracheal intubation has yet to be established. The videolaryngoscopic intubation and difficult airway classification (VIDIAC) study aimed to develop one based on variables associated with difficult videolaryngoscopic tracheal intubation. We studied 374 videolaryngoscopic tracheal intubations in 320 adults scheduled for ear, nose and throat or oral and maxillofacial surgery, for whom airway management was expected to be difficult. The primary outcome was whether an anaesthetist issued a 'difficult airway alert' after videolaryngoscopy. An alert was issued after 183 (49%) intubations. Random forest and lasso regression analysis selected six intubation-related variables associated with issuing an alert: impaired epiglottic movement; increased lifting force; direct epiglottic lifting; vocal cords clearly visible; vocal cords not visible; and enlarged arytenoids. Internal validation was performed by a 10-fold cross-validation, repeated 20 times. The mean (SD or 95%CI) area under the receiver operating characteristic curve was 0.92 (0.05) for the cross validated coefficient model and 0.92 (0.89-0.95) for a simplified unitary score (VIDIAC score with component values of -1 or 1 only). The calibration belt for the coefficient model was consistent with observed alert probabilities, from 0% to 100%, while the unitary VIDIAC score overestimated probabilities < 20% and underestimated probabilities > 70%. Discrimination of the VIDIAC score for patients more or less likely to be issued an alert was better than discrimination by the Cormack-Lehane classification, with mean (95%CI) areas under the receiver operating characteristic curve of 0.92 (0.89-0.95) vs. 0.75 (0.70-0.80), respectively, p < 0.001. Our model and score can be used to calculate the probabilities of difficult airway alerts after videolaryngoscopy.

MicroRNA expression is associated with human papillomavirus status and prognosis in mucosal head and neck squamous cell carcinomas.

OBJECTIVES: The major cause of mucosal squamous cell carcinomas of the head and neck (HNSCCs) has been attributed to human papillomavirus (HPV) infection. Here we investigate if microRNA expression in HNSCC can be used as a prognostic tool with or without HPV status. MATERIALS AND METHODS: We performed a discovery miRNA microarray (miRBase v.21) profiling of 52 tonsillar SCCs with TaqMan real-time PCR validation of 228 HNSCCs. Patients had a histologically confirmed primary SCC of the oropharynx, oral cavity, hypopharynx or larynx. Logistic regression models were used to estimate the magnitude of the effect of association with clinical factors and miRNAs associated with HPV status. For recurrence and survival analysis, we used unadjusted and multivariable adjusted Cox proportional hazard regression models. RESULTS: Seventeen miRNAs were significantly associated with better prognosis in the discovery phase and were validated in the extended dataset. The best fitting model (AUC = 0.92) for HPV status included age, smoking, and miRNAs: miR-15b, miR-20b, miR-29a, miR-29c, miR-142, miR-146a and miR-205. Using Cox regression model for recurrence, miR-29a was associated with 49% increased risk of recurrence while miR-30e and miR-342 were associated with decreased risk of recurrence with HRs 0.92 (95% CI 0.85-0.99) and 0.84 (95% CI 0.73-0.98), respectively. Our best fitting model for survival included age, gender, alcohol consumption, N stage, recurrence, HPV status, together with miRNAs-20b, 29a, and 342. CONCLUSION: miRNAs show potential to serve as usual biomarkers to predict the clinical course of patients with mucosal HNSCC.

A core outcome set for pre-eclampsia research: an international consensus development study.

OBJECTIVE: To develop a core outcome set for pre-eclampsia. DESIGN: Consensus development study. SETTING: International. POPULATION: Two hundred and eight-one healthcare professionals, 41 researchers and 110 patients, representing 56 countries, participated. METHODS: Modified Delphi method and Modified Nominal Group Technique. RESULTS: A long-list of 116 potential core outcomes was developed by combining the outcomes reported in 79 pre-eclampsia trials with those derived from thematic analysis of 30 in-depth interviews of women with lived experience of pre-eclampsia. Forty-seven consensus outcomes were identified from the Delphi process following which 14 maternal and eight offspring core outcomes were agreed at the consensus development meeting. Maternal core outcomes: death, eclampsia, stroke, cortical blindness, retinal detachment, pulmonary oedema, acute kidney injury, liver haematoma or rupture, abruption, postpartum haemorrhage, raised liver enzymes, low platelets, admission to intensive care required, and intubation and ventilation. Offspring core outcomes: stillbirth, gestational age at delivery, birthweight, small-for-gestational-age, neonatal mortality, seizures, admission to neonatal unit required and respiratory support. CONCLUSIONS: The core outcome set for pre-eclampsia should underpin future randomised trials and systematic reviews. Such implementation should ensure that future research holds the necessary reach and relevance to inform clinical practice, enhance women's care and improve the outcomes of pregnant women and their babies. TWEETABLE ABSTRACT: 281 healthcare professionals, 41 researchers and 110 women have developed #preeclampsia core outcomes @HOPEoutcomes @jamesmnduffy. [Correction added on 29 June 2020, after first online publication: the order has been corrected.].

Who is the Teacher and Who is the Student? The Dual Service- and Engaged-Learning Pedagogical Model of Anatomy Academy.

Anatomy Academy is a simultaneous service-learning experience for preprofessional school undergraduate students and preclinical professional students acting as classroom paraprofessional teachers (Mentors), and engaged-learning experience for fourth to sixth grade elementary school children (Students). Using didactic and kinesthetic active learning teaching strategies in small-group classroom environments, Mentors taught anatomy, physiology, and nutrition concepts to Students. In this study of the program's early years (2012-2014), overall objectives of improving Mentors' pedagogical confidence; and Students' science interest, science knowledge, and exercise self-efficacy were assessed. Mentors showed (89% response of 595 surveyed) improvement in content delivery (P < .001), student engagement (P < .001), classroom management (P < .001), and professionalism (P = .0001). Postprogram Mentor reflections were categorized into 7 major themes that demonstrated personal growth through the service-learning opportunity: (1) realization of an ability to make a difference in the world now; (2) acknowledgment of the importance of listening in teaching; (3) recognition that lives can and will change with "a little love"; (4) insight into the effectiveness of guiding Students through material rather than lecturing; (5) awareness of the value of respect in the learning environment; (6) cognizance of the power of individualized attention to motivate Students; and (7) reflection of one's own personal growth through the open influence of Students. Students showed (88% response of 1259 surveyed) improvement in science knowledge (P = .014) and exercise self-efficacy (P = .038), but not science interest (P = .371). Thus, while Students are learning more science and becoming more aware of their health, we need to be more overt in our presence as scientists in the educational arena.

Prp8 in a Reduced Spliceosome Lacks a Conserved Toggle that Correlates with Splicing Complexity across Diverse Taxa.

Conformational rearrangements are critical to regulating the assembly and activity of the spliceosome. The spliceosomal protein Prp8 undergoes multiple conformational changes during the course of spliceosome assembly, activation, and catalytic activity. Most of these rearrangements of Prp8 involve the disposition of the C-terminal Jab-MPN and RH domains with respect to the core of Prp8. Here we use x-ray structural analysis to show that a previously characterized and highly conserved ß-hairpin structure in the RH domain that acts as a toggle in the spliceosome is absent in Prp8 from the reduced spliceosome of the red alga Cyanidioschyzon merolae. Using comparative sequence analysis, we show that the presence or absence of this hairpin corresponds to the presence or absence of protein partners that interact with this hairpin as observed by x-ray and cryo-EM studies. The presence of the toggle correlates with increasing intron number suggesting a role in the regulation of splicing.

Does episiotomy always equate violence in obstetrics? Routine and selective episiotomy in obstetric practice and legal questions.

OBJECTIVE: The study's main goal is to figure out whether episiotomy, a widely applied invasive procedure, may constitute a determining factor of liability for practitioners according to the standards of obstetric violence. MATERIALS AND METHODS: The authors have aimed to analyze laws and documentation issued on the matter by sovereign states, statements and remarks from International health organizations, in addition to scientific article available on the main search engines (PubMed, Scopus, Google Scholar) and legal databases (Lexis, Justia). RESULTS: The body of research has highlighted the existence of a wide-ranging agreement as to routine episiotomy, deemed to be a scientifically unfounded procedure, and which should, therefore, be avoided. By virtue of that, routine episiotomy might easily give rise to charges and liability for doctors and midwives alike; likewise to claims may stem from a failure to perform an episiotomy when it was actually needed. CONCLUSIONS: Unlike routine episiotomy, selective episiotomy is far more unlikely to cause charges of obstetric violence against operators. Unfortunately, the criteria in order to establish when a selective episiotomy is indicated are far from consistent and would require an additional effort on the part of scientific societies towards a more clearly defined and shared description.

High naevus count and MC1R red hair alleles contribute synergistically to increased melanoma risk.

BACKGROUND: A high total body naevus count is the highest risk factor for melanoma; the phenotype of red hair colour, freckling and pale skin that burns easily, produced by MC1R R alleles, also predisposes to melanoma. OBJECTIVES: To determine whether the known melanoma risk factors of high naevus count and red hair or MC1R R alleles act synergistically to increase melanoma risk. METHODS: The Brisbane Naevus Morphology Study involved 1267 participants from volunteers presenting at a melanoma unit, dermatology outpatient clinic, private dermatology clinics, the Brisbane Longitudinal Twin Study and the QSkin Study. We examined pigmentation characteristics, total body naevus ≥ 5 mm count, and MC1R, ASIP and CDKN2A genotype in participants with and without a personal history of melanoma, living in Queensland, Australia, which is an area of high ultraviolet radiation. RESULTS: Cases were older than controls (median 57 vs. 33 years). Compared with individuals with dark brown hair and zero to four naevi, individuals with red hair and ≥ 20 naevi had a melanoma odds ratio of 10·0 (95% confidence interval 4·2-24·3). Individuals with MC1R R/R genotype and ≥ 20 naevi (≥ 5 mm diameter) had a melanoma odds ratio of 25·1 (95% confidence interval 8·4-82·7) compared with wild-type (WT)/WT individuals with zero to four naevi. The highest risk group is Australian men with the MC1R R/R genotype and ≥ 20 moles, who have an absolute risk of melanoma to age 75 years of 23·3%, compared with 0·8% for men with the WT/WT genotype and zero to four naevi. CONCLUSIONS: Patients who live in areas of high ultraviolet radiation, and have many large naevi and the red hair colour phenotype, particularly those with the MC1R R/R genotype, have a high risk of melanoma above the threshold recommended for screening in other cancers. Therefore, they should undergo intensive physician-led surveillance. What's already known about this topic? A high number of acquired melanocytic naevi, the red hair phenotype and MC1R R alleles all independently increase melanoma risk. Women with atypical naevi have an increasing melanoma risk gradient from darker hair to lighter hair. Women with many naevi have an increasing melanoma risk gradient from those with no elements of the red hair phenotype, to those with freckles but not red hair, to those with red hair. What does this study add? In Queensland, Australia, people with ≥ 20 naevi (≥ 5 mm diameter) and MC1R R/R genotype have a 25-fold increased melanoma risk, relative to people with zero to four naevi and the MC1R WT/WT genotype. In Queensland, individuals with ≥ 20 naevi and the MC1R R/R genotype have an absolute melanoma risk to age 75 years of 23·3% for men and 19·3% for women. This effect is independent of CDKN2A genotype. Further research is required to determine the effect of areas of lower ultraviolet radiation, as this study took place in the Queensland, Australia, which is an area of high ultraviolet radiation. MC1R R/r genotype is associated with increased total body naevus count but this is not the case for R/R. What is the translational message? Patients with many large naevi and the red hair colour phenotype, particularly those with an MC1R R/R genotype, have an unusually high risk of melanoma. In a high ultraviolet environment, this risk exceeds the threshold recommended for screening in other cancers, and such individuals should undergo intensive, regular, physician-led surveillance. Patients with many large naevi but with non-red colour hair may benefit further from clinical MC1R genotyping.

Estimation of the Composition of the Resting State fMRI Networks in Subjects with Mild Depression and Healthy Volunteers.

Depressive disorders can be associated with changes in not only interaction between neural networks, but also in their composition. Resting state fMRI scanning was performed for 4 min twice for each subject and the results of patients with mild depression (N=15) and healthy subjects (N=19) were analyzed. The fMRI signal was reduced into the independent components and the contrasts between the groups and between the first and second records were constructed for each component. During the first scanning, the auditory network of individuals with depression involved greater volume in the left insular region and lower volume in the right hemisphere. In record 2, depression patients were characterized by expansion of the executive network in the left hemisphere in the region of the middle and inferior frontal cortex. In healthy people, from record 1 to record 2, representation of the dorsal default mode network (DMN) increased in the left medial prefrontal area, the precuneus network expanded in the left hemisphere, and presentation of the ventral DMN in the right precuneus decreased. In the depression group, the auditory network lost some part of the left temporo-insular cortex; the sensorimotor network expanded in the left hemisphere to the cerebellum or to the central parietal region depending on the evaluation method, and the visuospatial network included or excluded a cluster in the left parietal lobe (in different points). Our findings indicate that connection of the auditory network with the left insular cortex could be a possible depression marker and also demonstrate a possibility of evaluating the composition of cerebral networks in intergroup comparisons and in dynamics without interventions.

The BRAF and NRAS mutation prevalence in dermoscopic subtypes of acquired naevi reveals constitutive mitogen-activated protein kinase pathway activation.

BACKGROUND: Acquired naevi can have unique dermoscopic patterns that correspond to distinct microanatomical growth patterns. Previous studies on acquired naevi stratified according to dermoscopic pattern focused on the frequency of somatic BRAF mutations, whereas NRAS mutations remained to be elucidated. OBJECTIVES: To investigate the BRAF and NRAS mutation prevalence and activation of the mitogen-activated protein kinase (MAPK) pathway in distinct dermoscopic subtypes of acquired naevi. METHODS: Common mutations present in BRAF and NRAS were assessed in 40 globular, reticular and peripheral rim of globules (PG) subtypes of acquired naevi from 27 participants (19 male, 8 female; mean age 46·7 years) selected from 1261 eligible volunteers. Mutations were determined using the highly sensitive and quantitative QX200 droplet digital™ polymerase chain reaction (ddPCR) system. RESULTS: The BRAF V600E (c.1799T>A or c.1799_1800delTGinsA) and BRAF V600K mutations were detected in 85% (n = 34/40) of naevi. All BRAF wild-type naevi (15%; n = 6/40) harboured an NRAS codon 12/13 or 61 mutation. BRAF mutations were present in 92% (n = 12/13) of globular and 100% (n = 12/12) of PG naevi, whereas reticular naevi were 67% (n = 10/15) BRAF- and 33% (n = 5/15) NRAS-mutant (P = 0·037). CONCLUSIONS: We discovered that 100% of the assessed acquired naevi had either a BRAF or NRAS mutation. Using sensitive techniques capable of single-cell mutation detection, it is likely that all acquired naevi will be mutated for BRAF or NRAS. Because both of these mutations are prevalent in distinct dermoscopic naevus subsets, our study supports the role of the MAPK pathway in the development of benign melanocytic proliferations, indicating that additional genomic events besides somatic mutations in BRAF or NRAS are required for melanoma development.

Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools.

BACKGROUND: Thymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma. PATIENTS AND METHODS: PCFT, RFC and TS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed by t-test, Fisher's/log-rank test and Cox proportional models. The contribution of PCFT expression and PCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2'-deoxycytidine-mediated demethylation and siRNA-knockdown. RESULTS: Pemetrexed-treated patients with low PCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months, P = 0.01) and validation (N = 51, 12.6 versus 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients. PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2'-deoxycytidine overcame resistance. CONCLUSIONS: These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.

Unilateral absence of ascending and transverse trapezius fibers accompanied by mild thoracic scoliosis: a case report

During routine anatomical dissection at the David Geffen School of Medicine at UCLA, a variation of partial unilateral trapezius muscle absence was found in a 95-year-old Caucasian female. A broad sheet of aponeurosis originating from all thoracic vertebrae completely replaced the ascending fibers of the left inferior trapezius muscle. Transverse fibers of the left trapezius muscle appeared hypotrophied and were sparsely distributed within the aponeurosis. Descending fibers of the left trapezius muscle were comparable to the right side. The main clinical finding was a grossly visible 5-degree thoracic scoliosis toward the intact trapezius muscle. No other significant abnormalities in musculature or anatomy could be found. While others have reported on unilateral, bilateral, complete, and partial absence of trapezius muscle, to our knowledge this case is unique from those previously reported in the literature

No disponible

Reduction of biological response modifiers in the supernatant of washed paediatric red blood cells.

BACKGROUND: Washing of red blood cells (RBC) can reduce unwanted biological response modifiers (BRMs) that can mediate transfusion complications in infants. The aim of this study was to examine the in vitro quality and the changes in BRMs following washing in paediatric RBC units. MATERIALS AND METHODS: A pool and split design was used to prepare RBC (either 1 or 4 days old; n = 26 pairs). One unit was washed with 0·9% saline by centrifugation and then resuspended in SAG-M, while the other remained unwashed. Each RBC unit was divided to produce four units of paediatric-sized components. Samples were taken after 3 h and subsequently on days 1, 2, 7 and 14 post-wash. RESULTS: Washing of RBC resulted in some red cell loss, with a minor increase in haemolysis. Washing effectively reduced supernatant potassium and IgA, as well as cytokines and complement proteins. RBC microparticles were significantly reduced in RBC washed at 1, but not 4 days post-collection. Incubation with supernatant from unwashed but not washed RBC led to endothelial cell activation, with increased cell surface expression of CD62E (E-selectin) and CD106 (VCAM). CONCLUSION: Although washing affected some aspects of the in vitro quality of RBC, it effectively reduced the concentration and activity of BRMs in the supernatant of RBC. Such a reduction may be clinically beneficial in selected patient groups.

On Methods for the Analysis of Indefinite Stimuli Perception Characteristics: an fMRT Study of Gender-Specific Differences.

Comparative identification of cerebral regions activated in men and women during perception of indefinite images was carried out by fMRT and psychological testing. Nine men and nine women aged 20-26 years took part in the study. The volunteers examined simple geometric figures, slightly structurized images (tables from Rorschach's test), and images of impossible figures. Activation in the cerebellum and visual cortex (bilateral) was more pronounced in women in response to all types of images and less so in the right G. temporalis medius. The right frontal regions (G. precentralis, G. frontalis superior, G. frontalis medius) were also stronger activated in women in response to indefinite stimuli.

Association of early and late maternal smoking during pregnancy with offspring body mass index at 4 to 5 years of age.

The objective was to investigate the association between early and late maternal smoking during pregnancy on offspring body mass index (BMI). We undertook a retrospective cohort study using linked records from the Women's and Children's Health Network in South Australia. Among a cohort of women delivering a singleton, live-born infants between January 2000 and December 2005 (n=7658), 5961 reported not smoking during pregnancy, 297 reported quitting smoking during the first trimester of pregnancy, and 1400 reported continued smoking throughout pregnancy. Trained nurses measured the height and weight of the children at preschool visits in a state-wide surveillance programme. The main outcome measure was age- and sex-specific BMI z-score. At 4 to 5 years, mean (s.d.) BMI z-score was 0.40 (1.05), 0.60 (1.07) and 0.65 (1.18) in children of mothers who reported never smoking, quitting smoking and continued smoking during pregnancy, respectively. Compared with the group of non-smokers, both quitting smoking and continued smoking were associated with an increase in child BMI z-score of 0.15 (95% confidence interval: 0.01-0.29) and 0.21 (0.13-0.29), respectively. A significant dose-response relationship was also observed between the number of cigarettes smoked per day on average during the second half of pregnancy and the increase in offspring BMI z-score (P<0.001). In conclusion, any maternal smoking in pregnancy, even if mothers quit, is associated with an increase in offspring BMI at 4 to 5 years of age.