Deep palmar phenotyping in atopic eczema: patterns associated with filaggrin variants, disease severity and barrier function in a South Asian population.

BACKGROUND: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG). OBJECTIVES: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants. METHODS: A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants. RESULTS: There were 506 complete cases available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74-3.67], SH (ME 0.85, 95% CI 0.78-0.96) and TEWL (ME 1.32, 95% CI 1.11-1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91-80.73], improving to 77.99% (73.70-82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02-94.19). CONCLUSIONS: This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively.

Suicide and Suicidality in Children and Adolescents with Chronic Skin Disorders: A Systematic Review.

Suicide in young children is rare; the incidence increases towards the end of adolescence. Skin disorders confer a high prevalence of psychiatric and psycho-logical comorbidities. However, published research on suicidal behaviour in adolescents and children with skin disorders is sparse. The aim of this study was to identify the prevalence of suicidal behaviour in children and adolescents under 18 years of age with chronic skin disorders and associated contributing risk factors. MEDLINE, PsycINFO, EMBASE, CINAHL and Cochrane databases were searched from inception to October 2020 for suicide or suicide attempts in patients under 18 years old with chronic skin disorders. The study protocol was logged on PROSPERO (CRD42020083528). Returned texts were reviewed independently by 2 authors. Bias was assessed according to Joanna Briggs Institute criteria. Five studies met the inclusion criteria; 4 cross-sectional surveys and 1 retrospective matched-cohort study. A total of 31,641 patients with acne, atopic dermatitis, body dysmorphic disorder or psoriasis were identified. Prevalence of suicidal ideation was 0.45% (psoriasis) to 67% (body dysmorphic disorder). The prevalence of suicidal attempts ranged from 0.08% (psoriasis) to 21.9% (acne). Patients with acne or atopic dermatitis had significantly increased odds ratio for suicidal attempts. Meta-analysis could not be performed owing to the heterogeneity and sparsity of data. Suicidal risk in skin disorders amongst adolescents and children under the age of 18 years old is broad and complex. The suicidal risk remained after adjusting for depression, suggestive of an alternative mechanism.

Topical treatment of actinic keratoses in organ transplant recipients: a feasibility study for SPOT (Squamous cell carcinoma Prevention in Organ transplant recipients using Topical treatments).

BACKGROUND: The risk of cutaneous squamous cell carcinoma (cSCC) is significantly increased in organ transplant recipients (OTRs). Clearance of actinic keratoses (AKs) is generally regarded as a surrogate biomarker for cSCC prevention. OTR-cSCC chemoprevention with topical AK treatments has not been investigated in randomized controlled trials (RCTs), although there is evidence that 5% 5-fluorouracil (5-FU) may be chemoprotective in immunocompetent patients. OBJECTIVES: To assess the feasibility, activity and evaluation outcomes relevant to the design of a future phase III RCT of topical cSCC chemoprevention in OTRs. METHODS: OTRs with 10 or more AKs in predefined areas were randomized 1 : 1 : 1 to topical 5-FU, 5% imiquimod (IMIQ) or sunscreen (sun-protective factor 30+) in a phase II, open-label RCT over 15 months. Feasibility outcomes included proportions of eligible OTRs randomized, completing treatment and willing to be re-treated. AK activity [AK clearance, new AK development, patient-centred outcomes (toxicity, health-related quality of life, HRQoL)] and evaluation methodology (clinical vs. photographic) were assessed. RESULTS: Forty OTRs with 903 AKs were randomized. All feasibility outcomes were met (56% of eligible OTRs were randomized; 89% completed treatment; 81% were willing to be re-treated). AK activity analyses found 5-FU and IMIQ were superior to sunscreen for AK clearance and prevention of new AKs. 5-FU was more effective than IMIQ in AK clearance and prevention in exploratory analyses. Although toxicity was greater with 5-FU, HRQoL outcomes were similar. CONCLUSIONS: Trials of topical AK treatments in OTRs for cSCC chemoprevention are feasible and AK activity results support further investigation of 5-FU-based treatments in future phase III trials. What is already known about this topic? Cutaneous squamous cell carcinoma (cSCC) is significantly more common in immunocompromised individuals including organ transplant recipients (OTRs) compared with immunocompetent populations. cSCC chemoprevention activity of sunscreen and 5-fluorouracil-based (5-FU) actinic keratosis (AK) treatments has been demonstrated in randomized controlled trials (RCTs) in immunocompetent populations but not in OTRs. AKs are cSCC precursors and their clearance and prevention are generally regarded as surrogate endpoint biomarkers for potential cSCC chemoprevention activity. What does this study add? SPOT (SCC Prevention in OTRs using Topical treatments) has confirmed that RCTs of OTR-cSCC chemoprevention with topical AK treatments are feasible. It also suggests that topical 5-FU may be superior to 5% imiquimod and sunscreen in AK clearance and prevention. Together with recent evidence from several RCTs in the general population, these data provide a compelling rationale for further studies of intervention with 5-FU-based topical chemoprevention approaches in OTR-cSCC prevention.

Interventions for basal cell carcinoma of the skin.

BACKGROUND: Basal cell carcinoma (BCC) is the commonest cancer affecting white-skinned individuals, and worldwide incidence is increasing. Although rarely fatal, BCC is associated with significant morbidity and costs. First-line treatment is usually surgical excision, but alternatives are available. New published studies and the development of non-surgical treatments meant an update of our Cochrane Review (first published in 2003, and previously updated in 2007) was timely. OBJECTIVES: To assess the effects of interventions for BCC in immunocompetent adults. SEARCH METHODS: We updated our searches of the following databases to November 2019: Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL, and LILACS. SELECTION CRITERIA: Randomised controlled trials (RCTs) of interventions for BCC in immunocompetent adults with histologically-proven, primary BCC. Eligible comparators were placebo, active treatment, other treatments, or no treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Primary outcome measures were recurrence at three years and five years (measured clinically) (we included recurrence data outside of these time points if there was no measurement at three or five years) and participant- and observer-rated good/excellent cosmetic outcome. Secondary outcomes included pain during and after treatment, early treatment failure within six months, and adverse effects (AEs). We used GRADE to assess evidence certainty for each outcome. MAIN RESULTS: We included 52 RCTs (26 new) involving 6690 participants (median 89) in this update. All studies recruited from secondary care outpatient clinics. More males than females were included. Study duration ranged from six weeks to 10 years (average 13 months). Most studies (48/52) included only low-risk BCC (superficial (sBCC) and nodular (nBCC) histological subtypes). The majority of studies were at low or unclear risk of bias for most domains. Twenty-two studies were industry-funded: commercial sponsors conducted most of the studies assessing imiquimod, and just under half of the photodynamic therapy (PDT) studies. Overall, surgical interventions have the lowest recurrence rates. For high-risk facial BCC (high-risk histological subtype or located in the facial 'H-zone' or both), there may be slightly fewer recurrences with Mohs micrographic surgery (MMS) compared to surgical excision (SE) at three years (1.9% versus 2.9%, respectively) (risk ratio (RR) 0.64, 95% confidence interval (CI) 0.16 to 2.64; 1 study, 331 participants; low-certainty evidence) and at five years (3.2% versus 5.2%, respectively) (RR 0.61, 95% CI 0.18 to 2.04; 1 study, 259 participants; low-certainty evidence). However, the 95% CI also includes the possibility of increased risk of recurrence and no difference between treatments. There may be little to no difference regarding improvement of cosmetic outcomes between MMS and SE, judged by participants and observers 18 months post-operatively (one study; low-certainty evidence); however, no raw data were available for this outcome. When comparing imiquimod and SE for nBCC or sBCC at low-risk sites, imiquimod probably results in more recurrences than SE at three years (16.4% versus 1.6%, respectively) (RR 10.30, 95% CI 3.22 to 32.94; 1 study, 401 participants; moderate-certainty evidence) and five years (17.5% versus 2.3%, respectively) (RR 7.73, 95% CI 2.81 to 21.3; 1 study, 383 participants; moderate-certainty evidence). There may be little to no difference in the number of participant-rated good/excellent cosmetic outcomes (RR 1.00, 95% CI 0.94 to 1.06; 1 study, 326 participants; low-certainty evidence). However, imiquimod may result in greater numbers of good/excellent cosmetic outcomes compared to SE when observer-rated (60.6% versus 35.6%, respectively) (RR 1.70, 95% CI 1.35 to 2.15; 1 study, 344 participants; low-certainty evidence). Both cosmetic outcomes were measured at three years. Based on one study of 347 participants with high- and low-risk primary BCC of the face, radiotherapy may result in more recurrences compared to SE under frozen section margin control at three years (5.2% versus 0%, respectively) (RR 19.11, 95% CI 1.12 to 325.78; low-certainty evidence) and at four years (6.4% versus 0.6%, respectively) (RR 11.06, 95% CI 1.44 to 84.77; low-certainty evidence). Radiotherapy probably results in a smaller number of good participant- (RR 0.76, 95% CI 0.63 to 0.91; 50.3% versus 66.1%, respectively) or observer-rated (RR 0.48, 95% CI 0.37 to 0.62; 28.9% versus 60.3%, respectively) good/excellent cosmetic outcomes compared to SE, when measured at four years, where dyspigmentation and telangiectasia can occur (both moderate-certainty evidence). Methyl-aminolevulinate (MAL)-PDT may result in more recurrences compared to SE at three years (36.4% versus 0%, respectively) (RR 26.47, 95% CI 1.63 to 429.92; 1 study; 68 participants with low-risk nBCC in the head and neck area; low-certainty evidence). There were no useable data for measurement at five years. MAL-PDT probably results in greater numbers of participant- (RR 1.18, 95% CI 1.09 to 1.27; 97.3% versus 82.5%) or observer-rated (RR 1.87, 95% CI 1.54 to 2.26; 87.1% versus 46.6%) good/excellent cosmetic outcomes at one year compared to SE (2 studies, 309 participants with low-risk nBCC and sBCC; moderate-certainty evidence). Based on moderate-certainty evidence (single low-risk sBCC), imiquimod probably results in fewer recurrences at three years compared to MAL-PDT (22.8% versus 51.6%, respectively) (RR 0.44, 95% CI 0.32 to 0.62; 277 participants) and five years (28.6% versus 68.6%, respectively) (RR 0.42, 95% CI 0.31 to 0.57; 228 participants). There is probably little to no difference in numbers of observer-rated good/excellent cosmetic outcomes at one year (RR 0.98, 95% CI 0.84 to 1.16; 370 participants). Participant-rated cosmetic outcomes were not measured for this comparison. AEs with surgical interventions include wound infections, graft necrosis and post-operative bleeding. Local AEs such as itching, weeping, pain and redness occur frequently with non-surgical interventions. Treatment-related AEs resulting in study modification or withdrawal occurred with imiquimod and MAL-PDT. AUTHORS' CONCLUSIONS: Surgical interventions have the lowest recurrence rates, and there may be slightly fewer recurrences with MMS over SE for high-risk facial primary BCC (low-certainty evidence). Non-surgical treatments, when used for low-risk BCC, are less effective than surgical treatments, but recurrence rates are acceptable and cosmetic outcomes are probably superior. Of the non-surgical treatments, imiquimod has the best evidence to support its efficacy. Overall, evidence certainty was low to moderate. Priorities for future research include core outcome measures and studies with longer-term follow-up.

Mesenchymal stromal cell-derived exosomes improve mitochondrial health in pulmonary arterial hypertension.

Secreted exosomes are bioactive particles that elicit profound responses in target cells. Using targeted metabolomics and global microarray analysis, we identified a role of exosomes in promoting mitochondrial function in the context of pulmonary arterial hypertension (PAH). Whereas chronic hypoxia results in a glycolytic shift in pulmonary artery smooth muscle cells (PASMCs), exosomes restore energy balance and improve O2 consumption. These results were confirmed in a hypoxia-induced mouse model and a semaxanib/hypoxia rat model of PAH wherein exosomes improved the mitochondrial dysfunction associated with disease. Importantly, exosome exposure increased PASMC expression of pyruvate dehydrogenase (PDH) and glutamate dehydrogenase 1 (GLUD1), linking exosome treatment to the TCA cycle. Furthermore, we show that although prolonged hypoxia induced sirtuin 4 expression, an upstream inhibitor of both GLUD1 and PDH, exosomes reduced its expression. These data provide direct evidence of an exosome-mediated improvement in mitochondrial function and contribute new insights into the therapeutic potential of exosomes in PAH.

Bcl-xL dependency coincides with the onset of neurogenesis in the developing mammalian spinal cord.

The bcl-2 family of survival and death promoting proteins play a key role in regulating cell numbers during nervous system development. Bcl-xL, an anti-apoptotic bcl-2 family member is highly expressed in the developing nervous system. However; the early embryonic lethality of the bcl-x germline null mouse precluded an investigation into its role in nervous system development. To identify the role of bcl-x in spinal cord neurogenesis, we generated a central nervous system-specific bcl-x conditional knockout (BKO) mouse. Apoptotic cell death in the BKO embryo was initially detected at embryonic day 11 (E11) in the ventrolateral aspect of the spinal cord corresponding to the location of motor neurons. Apoptosis reached its peak at E13 having spread across the ventral and into the dorsal spinal cord. By E18, the wave of apoptosis had passed and only a few apoptotic cells were observed. The duration and direction of spread of apoptosis across the spinal cord is consistent with the spatial and temporal sequence of neuronal differentiation. Motor neurons, the first neurons to become post mitotic in the spinal cord, were also the first apoptotic cells. As neurogenesis spread across the spinal cord, later born neuronal populations such as Lim2+ interneurons were also affected. The onset of apoptosis occurred in cells that had exited the cell cycle within the previous 24h and initiated neural differentiation as demonstrated by BrdU birthdating and ßIII tubulin immunohistochemistry. This data demonstrates that spinal cord neurons become Bcl-xL dependent at an early post mitotic stage in developmental neurogenesis.

The utility of the abdominal series in the emergency setting: a retrospective review.

PURPOSE: The abdominal series (AXR) remains a frequently ordered test in the emergency department (ED), despite existing literature questioning its utility. The aim of this study was to characterize the use of the AXR in the ED by quantifying how often it is ordered and the frequency of subsequent imaging. Additionally, a time estimate in ED associated with the AXR was quantified. We hypothesized that there would be a low clinical utility of the AXR, and long associated time period spent in the ED. METHODS: A retrospective audit of AXRs performed in the ED from January to December 2019 was performed. The local picture archiving and communication system (PACS) and electronic medical record were used to collect the variables. RESULTS: Of 701 AXRs, 438 (62.4%) were reported normal, and 263 (37.6%) were abnormal. A Chi Squared test showed that the two variables (abdominal series result and follow up imaging completion) were significantly related, with p < 0.001. However, the effect size was small (Nagelkerke R square = 0.022). The average time spent in the ED for these patients was 7.27 h, and the average time between the AXR being ordered and interpreted was 1.31 h. CONCLUSION: The majority of AXRs were reported as normal. Our results showed that AXR had a statistically significant, but low clinically significant predictive ability on subsequent imaging ordering. This supports our hypothesis that the AXR is of low clinical utility with respect to the rate of ordering follow up imaging. The AXR also translated to a quantifiable time interval during the patient's stay in ED. Minimizing overuse of the AXR may result in a decrease in patient duration in the ED.

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states.

Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials.

Headache Over Heels: CT Negative Subarachnoid Hemorrhage.

Audience: This simulation is intended for MS4 or PGY-1 learners. Introduction: Both headache and syncope are common chief complaints in the emergency department (ED); however, subarachnoid hemorrhage (SAH) is uncommon (accounting for 1-3% of all patients presenting to the ED with headache), with near 50% mortality.1-3 It is important to recognize the signs and symptoms that point to this specific diagnosis. Once subarachnoid hemorrhage is suspected, it is critical to understand the appropriate workup to diagnose SAH, depending on the timing of presentation. Once SAH is diagnosed, appropriately managing the patient's glucose, blood pressure, and pain is important. Educational Objectives: By the end of this case, the participant will be able to: 1) construct a broad differential diagnosis for a patient presenting with syncope, 2) name the history and physical exam findings consistent with SAH, 3) identify SAH on computer tomography (CT) imaging, 4) identify the need for lumbar puncture (LP) to diagnose SAH when CT head is non-diagnostic > 6 hours after symptom onset, 5) correctly interpret cerebral fluid studies (CSF) to aid in the diagnosis of SAH, and 6) specify blood pressure goals in SAH and suggest appropriate medication management. Educational Methods: High-fidelity simulation was utilized since this modality forces learners to actively construct a differential for syncope, recognize the possibility of subarachnoid hemorrhage, recall the need for lumbar puncture, and talk through management considerations in real time as opposed to a more passive lecture format. Research Methods: Twenty emergency medicine residents and medical student learners completed the simulation activity. Each learner was asked to complete an eight question post-simulation survey. The survey addressed the utility and appropriate training level of the simulation activity while also including an open-ended prompt for suggestions for improvement. Results: Five PGY3, four PGY2, four PGY1, and seven medical students completed the survey. Ninety-five percent felt that the case was more helpful in a simulation format than in a lecture format. All learners felt that the simulation was an appropriate level of difficulty. Of the comments received, a few learners noted they preferred more complexity. Discussion: Overall, the educational content was effective in teaching about the SAH diagnostic algorithm, CSF interpretation, and blood pressure management in SAH. Overall, learners very much enjoyed the activity and felt it was appropriate for their level of training. The most common constructive feedback was to include more specific neurologic findings on physical examination to help guide the student to the diagnosis of SAH. Topics: Syncope, subarachnoid hemorrhage, cerebrospinal fluid interpretation, lumbar puncture, intracranial bleed, blood pressure goals and management.

Mitochondrial transplant after ischemia reperfusion promotes cellular salvage and improves lung function during ex-vivo lung perfusion.

BACKGROUND: In lung transplantation, ischemia-reperfusion injury associated with mitochondrial damage can lead to graft rejection. Intact, exogenous mitochondria provide a unique treatment option to salvage damaged cells within lung tissue. METHODS: We developed a novel method to freeze and store allogeneic mitochondria isolated from porcine heart tissue. Stored mitochondria were injected into a model of induced ischemia-reperfusion injury using porcine ex-vivo lung perfusion. Treatment benefits to immune modulation, antioxidant defense, and cellular salvage were evaluated. These findings were corroborated in human lungs undergoing ex-vivo lung perfusion. Lung tissue homogenate and primary lung endothelial cells were then used to address underlying mechanisms. RESULTS: Following cold ischemia, mitochondrial transplant reduced lung pulmonary vascular resistance and tissue pro-inflammatory signaling and cytokine secretion. Further, exogenous mitochondria reduced reactive oxygen species by-products and promoted glutathione synthesis, thereby salvaging cell viability. These results were confirmed in a human model of ex-vivo lung perfusion wherein transplanted mitochondria decreased tissue oxidative and inflammatory signaling, improving lung function. We demonstrate that transplanted mitochondria induce autophagy and suggest that bolstered autophagy may act upstream of the anti-inflammatory and antioxidant benefits. Importantly, chemical inhibitors of the MEK autophagy pathway blunted the favorable effects of mitochondrial transplant. CONCLUSIONS: These data provide direct evidence that mitochondrial transplant improves cellular health and lung function when administered during ex-vivo lung perfusion and suggest the mechanism of action may be through promotion of cellular autophagy. Data herein contribute new insights into the therapeutic potential of mitochondrial transplant to abate ischemia-reperfusion injury during lung transplant, and thus reduce graft rejection.

Mesenchymal stromal cell-derived extracellular vesicles reduce lung inflammation and damage in nonclinical acute lung injury: Implications for COVID-19.

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are bioactive particles that evoke beneficial responses in recipient cells. We identified a role for MSC-EV in immune modulation and cellular salvage in a model of SARS-CoV-2 induced acute lung injury (ALI) using pulmonary epithelial cells and exposure to cytokines or the SARS-CoV-2 receptor binding domain (RBD). Whereas RBD or cytokine exposure caused a pro-inflammatory cellular environment and injurious signaling, impairing alveolar-capillary barrier function, and inducing cell death, MSC-EVs reduced inflammation and reestablished target cell health. Importantly, MSC-EV treatment increased active ACE2 surface protein compared to RBD injury, identifying a previously unknown role for MSC-EV treatment in COVID-19 signaling and pathogenesis. The beneficial effect of MSC-EV treatment was confirmed in an LPS-induced rat model of ALI wherein MSC-EVs reduced pro-inflammatory cytokine secretion and respiratory dysfunction associated with disease. MSC-EV administration was dose-responsive, demonstrating a large effective dose range for clinical translation. These data provide direct evidence of an MSC-EV-mediated improvement in ALI and contribute new insights into the therapeutic potential of MSC-EVs in COVID-19 or similar pathologies of respiratory distress.

Slow-oscillation activity is reduced and high frequency activity is elevated in older adults with insomnia.

STUDY OBJECTIVES: High-frequency electroencephalographic activity (> 16 Hz activity) is often elevated during nonrapid eye movement sleep among individuals with insomnia, in line with the hyperarousal theory of insomnia. Evidence regarding sleep depth marked by slow-wave activity (< 4 Hz) is more mixed. Distinguishing subcomponents of slow-wave activity (slow-oscillation [< 1 Hz] or delta activity [1-4 Hz)]) may be critical in understanding these discrepancies, given that these oscillations have different neural generators and are functionally distinct. Here we tested the effects of insomnia diagnosis and insomnia treatment on nonrapid eye movement electroencephalography in older adults, distinguishing slow-oscillation and delta power. METHODS: In 93 older adults with insomnia and 71 good sleeper control participants (mean ages 68 years), effects of insomnia and cognitive behavioral therapy for insomnia (insomnia group only) on electroencephalographic spectral power were analyzed. Main effects and interactions with nonrapid eye movement period were assessed for the following frequency bands: slow-oscillation (0.5-1 Hz), delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), sigma (12-16 Hz), and beta (16-32 Hz). RESULTS: Slow-oscillation absolute and relative power were lower in the insomnia group compared with controls. There were no group differences in delta power. Insomnia was also associated with elevated 4-32 Hz absolute and relative power. After cognitive behavioral therapy for insomnia, absolute sigma and beta activity decreased. CONCLUSIONS: Deficits in slow-wave activity in insomnia are specific to the slow-oscillation. Elevated high frequency activity is reduced for sigma and beta power following cognitive behavioral therapy for insomnia . These findings inform the pathophysiology of insomnia, including the mechanisms underlying cognitive behavioral therapy for insomnia in older adults.

Rate of Nondiagnostic Computerized Tomography Pulmonary Angiograms (CTPAs) Performed for the Diagnosis of Pulmonary Embolism in Pregnant and Immediately Postpartum Patients.

OBJECTIVE: To evaluate the nondiagnostic rate of computed tomography pulmonary angiography (CTPA) in pregnant and postpartum patients with suspected pulmonary embolism (PE) to determine whether CTPA or ventilation-perfusion (VQ) scan should be considered first line imaging in this patient population considering their equivalent accuracy and the greater radiation exposure to proliferating breast tissue of CTPA. METHODS: All pregnant/postpartum female patients between 18 and 50 years of age who had CTPA within the Eastern Health Authority between November 2012 and November 2016 were included. Each scan was evaluated for nondiagnosis based on two criteria: contrast density in the main pulmonary artery, and respiratory motion artefact. If either of these criteria were not met, the scan was labelled as nondiagnostic. RESULTS: The nondiagnostic rate overall was 43% (n=83). This is similar to current literature values for rates of CTPA nondiagnosis, and comparable to the reported diagnostic quality of the reporting radiologist. This is much greater compared to rates of ventilation/perfusion nondiagnosis in comparable populations. Even in patients with normal chest radiographs, which represents the main patient group where VQ may be considered as an alternative, the nondiagnostic rate of CT is much higher. CONCLUSION: This is the first study to attempt to identify an objective method of determining nondiagnosis in pregnant and postpartum patients undergoing a CTPA. Our results strengthen the argument that alternative imaging should be considered when investigating for PE in this population in order to protect the proliferating breast tissue, and VQ scan should be considered especially in patients with normal chest X-rays.

WhatsApp platforms in tropical public health resource-poor settings.

In order to deliver equal healthcare access to resource-poor settings, sustainable, cost-effective systems of communication should be used. As mobile phone use increases, remote care can be delivered via teledermatology using Apps. This commentary covers how WhatsApp could be used by dermatologists seeking to deliver healthcare in this context.

Outcomes of early intervention for deaf children with additional needs following an Auditory Verbal approach to communication.

OBJECTIVES: To determine and compare the rates of progress made by pre-school aged children with all degrees and types of hearing impairment and deafness, both with and without additional needs as catalogued using SNOMED CT, at the end of a non-statutory programme of individualised Auditory Verbal (AV) intervention. METHODS: An audit was conducted using a retrospective and comparative study design to examine spoken language outcomes in children who had spent more than two years on an AV programme and had completed their programmes between January 2007 and December 2017. The children were stratified according to i) whether they achieved age appropriate language (AAL) (n =102) or not (n =27); ii) whether they had deafness alone (n = 77) or deafness with additional needs (n =52); and iii) whether children with additional needs achieved AAL (n= 27) or not (n =25). Children undertook standardised spoken language assessments on joining the AV programme and then at intervals of at least 6 months for the duration of their programme. Derived measures of rates of language development (RLD) were used to compare the groups at i) the outset (initial RLD), and ii) the conclusion of the AV programme (programme RLD). RESULTS: Overall, 79% of children within this cohort achieved age appropriate spoken language scores. Children with additional needs (40%) embarked on a non-statutory AV programme at a significantly older age (corrected for prematurity), with significantly lower initial RLD and, as a group, attained significantly lower programme RLD compared with children with deafness alone. One in two of the children with additional needs reached AAL by the end of their individualised programme. The children with additional needs also demonstrated a highly significant increase in their mean programme RLD compared with the mean initial RLD indicating an acceleration in acquiring spoken language competencies while on the AV programme. CONCLUSIONS: For deaf children with additional needs who stay on an AV programme for more than two years, listening and spoken communication is significantly enhanced. Specific access to the AV approach in addition to generic, statutory early intervention could facilitate deaf children with additional needs to achieve or approach AAL. Ensuring families have access to effective early intervention increases the chances that i) a suitable communication approach is adopted at the earliest opportunity, and ii) a child with additional needs acquires listening and spoken language at a rate commensurate with their full potential. Applying the SNOMED CT framework as a means of categorising children's additional needs will enable more effective comparisons across studies from different centres around the world.

Assessing the Prevalence of Incidental Findings Identified by CTPA in Women of Reproductive Age.

BACKGROUND AND OBJECTIVE: Though multiple studies have evaluated the prevalence of incidental findings identified by CTPA, none have done so with a focus on reproductive-age females with normal chest X-ray (CXR). Due to a comparatively lower breast radiation dose, the oft-recommended alternative to CTPA in this patient group is a V/Q scan. However, these are limited in their assessment of these alternate findings; therefore, it is of particular importance to evaluate the likelihood of these findings on CT in this patient group, which is the goal of this study. METHODS: Through a review of our PACS system, female patients aged 18-50 years who underwent diagnostic CTPA prior to April 1, 2017, were identified. The 100 most recent cases which had a normal CXR within 48 hours of CTPA were included. Incidental/non-PE findings were then divided into PE-positive (PE+) and PE-negative (PE-), and subcategorized into types I, II, III, and nil non-PE finding groups. Type I findings required immediate follow-up or intervention, type II findings required outpatient follow-up, and type III findings required no follow-up or were previously known. RESULTS: PE was detected in 15% of scans. Type I findings were found in 8% of patients (0% of PE+, 9.4% of PE-), type II findings in 10% of patients (13.3% of PE+, 9.4% of PE-), type III findings in 34% of patients (40% of PE+, 32.9% of PE-), and nil non-PE finding in 48% of patients (46.7% PE+, 48.2% of PE-). CONCLUSION: While CTPA identifies incidental findings in the majority of patients, a small minority of these findings are likely to alter immediate management. In the context in increased radiation risk, this strengthens the argument that alternate imaging modalities such as V/Q should be strongly considered for the investigation of potential PE in women of reproductive age with normal CXR.

The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature.

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets.

Students' perceptions of effective learning experiences in dental school: a qualitative study using a critical incident technique.

Students' views of their educational experience can be an important source of information for curriculum assessment. Although quantitative methods, particularly surveys, are frequently used to gather such data, fewer studies have employed qualitative methods to examine students' dental education experiences. The purpose of this study is to explore characteristics of effective learning experiences in dental school using a qualitative method. All third-year (seventy) and fourth-year (seventy) dental students enrolled in one midwestern dental school were invited to participate. Fifty-three dental students (thirty-five male and eighteen female; thirty-two third-year and twenty-one fourth-year) were interviewed using a critical incident interview technique. Each student was asked to describe a specific, particularly effective learning incident that he or she had experienced in dental school and a specific, particularly ineffective learning incident, for comparison. Each interview was audiotaped. Students were assured that only the interviewer and one additional researcher would have access to the tapes. Data analysis resulted in identification of key themes in the data describing characteristics of effective learning experiences. The following characteristics of effective learning experiences were identified: 1) instructor characteristics (personal qualities, "checking-in" with students, and an interactive style); 2) characteristics of the learning process (focus on the "big picture," modeling and demonstrations, opportunities to apply new knowledge, high-quality feedback, focus, specificity and relevance, and peer interactions); and 3) learning environment (culture of the learning environment, technology). Common themes emerged across a wide variety of learning incidents. Although additional research is needed, the characteristics of effective learning experiences identified in this study may have implications for individual course design and for the dental school curriculum as a whole.

Impaired binaural hearing in children produced by a threshold level of middle ear disease.

Otitis media with effusion (OME), a form of middle ear disease, is the most common reason for young children both to visit their family doctor and to have surgery. Almost all children have at least a single episode of OME before their first birthday and annual incidence rates exceed 50% in each of the first five years. For most children, OME occurs infrequently, but about 10-15% of children have OME during more than half of their first six years. Middle ear effusions attenuate and delay sound, causing conductive sound distortion during the crucial years for language acquisition. The many studies of OME effects on language and other indices of development have produced mixed results. However, a consensus is emerging of mild language impairment in the preschool years, with subsequent performance, emotional, and behavioral difficulties. In addition to the peripheral hearing loss produced directly by the disease, binaural and other central auditory deficits can outlive the OME. It has been unclear which children are at risk of central impairment following OME, since the children studied have generally been recruited from otolaryngology clinics. Consequently, a detailed prospective history of the middle ear status of participants has not been available. By studying six-year-old children with a lifetime known history of OME, we show in this study that only those children with a cumulative OME experience of more than about half the time during the first five years consistently have residual impaired binaural hearing.