An analysis of iris pattern as a risk factor for skin cancer development in immunosuppressed renal transplant recipients.

INTRODUCTION: Renal transplant recipients are at increased risk of keratinocyte skin cancers with a tendency to have multiple, aggressive and difficult to treat tumours. The eye and the skin share the same embryological ectoderm. Iris pattern has recently been reported as a predictive risk factor for skin cancer in non-immunosuppressed Southern European (Grigore et al., J Eur Acad Dermatol Venereol, 2018, 1662) and Irish populations (Ridge et al., J Eur Acad Dermatol Venereol, 2022, e542). AIMS: To analyse if an individual's iris pattern is an independent risk factor for the development of keratinocyte skin cancers in renal transplant recipients. METHODS: Iris patterns of 110 renal transplant recipients were evaluated using the Simionescu visual three-step technique (iris periphery, colarette and iris freckling [Simionescu et al., Ann Res Rev Biol, 2014, 2525]). Established risk factors for skin cancer in transplant patients were recorded as confounding factors. RESULTS: Observational cross-sectional study including 110 renal transplant population. Thirty-one participants had skin cancer. In the skin cancer group, iris periphery was blue/grey in 74.3% (p = 0.053, OR 2.5), the colarette was light brown in 57.1% (p < 0.0043) and iris freckles were present in 55%(p = 0.044). Dark brown and blue colarettes were observed in controls. Binary Logistic Regression analysis showed light brown colarette is a significant independent risk factor for skin cancer (OR 4.54, p < 0.02, CI 1.56-10.57). CONCLUSION: Within this renal transplant population a blue iris periphery, light brown colarette and presence of freckling confers an independent risk for keratinocyte skin cancer. Iris pattern is a useful tool for identification of transplant patients at risk of keratinocyte skin cancer and an easy-to-use technique for risk evaluation in this cohort. This is the first study looking at iris pattern and keratinocyte skin cancer risk in renal transplant population.

Tris(bicyclo[1.1.1]pentyl)phosphine: An Exceptionally Small Tri-tert-alkylphosphine and Its Bis-Ligated Pd(0) Complex.

Tris(bicyclo[1.1.1]pentyl)phosphine can be prepared by radical addition of PH3 to [1.1.1]propellane, giving the smallest tri-tert-alkylphosphine known. PBcp3 is substantially smaller than PCy3 and is comparable in electron-donating power to PEt3. It gives a bis-ligated Pd(0) complex Pd(PBcp3)2 that is exceptionally reactive toward alkyl halide oxidative addition and functions as a general ligand for palladium-catalyzed cross-coupling of sp3 electrophiles. Radical addition of [1.1.1]propellane to phenylphosphine gives the bis(bicyclo[1.1.1]pentyl)phosphine derivative PBcp2Ph, illustrating the generality of this approach to bicyclopentylphosphine synthesis.

A Synthesis of Alstonlarsine A via Alstolucines†B and F Demonstrates the Chemical Feasibility of a Proposed Biogenesis.

We offer a new biogenetic proposal for the origin of the complex alkaloid alstonlarsine A, through rearrangement of the Strychnos alkaloids alstolucines B and F. Further, we provide evidence of the chemical feasibility of this proposal in the facile conversion of synthetic alstolucines into alstonlarsine A through a short, efficient sequence of N-methylation, ß-elimination, and a cascade 1,7-hydride shift/Mannich cyclization. We believe that this is the first biogenetic proposal involving the "tert-amino effect", a hydride-shift-based internal redox trigger of a Mannich cyclization. A further interesting feature of the cascade is that its stereochemical outcome most likely originates in conformational preferences during the hydride shift.

Hydrogen-Atom-Transfer-Initiated Radical/Polar Crossover Annulation Cascade for Expedient Access to Complex Tetralins.

A radical/polar crossover annulation between allyl-substituted arenes and electron-deficient alkenes is described. Cobalt-catalyzed hydrogen atom transfer (HAT) facilitates tandem radical C-C bond formation that generates functionalized tetralin products in the face of potentially problematic hydrofluorination, hydroalkoxylation, hydrogenation, alkene isomerization, and radical polymerization reactions. The reactions proceed under mild conditions that tolerate many functional groups, leading to a broad substrate scope. This powerful ring-forming reaction very quickly assembles complex tetralins that are the formal products of the largely infeasible Diels-Alder cycloadditions of styrenes.

Update on intrathecal management of cerebral vasospasm: a systematic review and meta-analysis.

OBJECTIVE: Aneurysmal subarachnoid hemorrhage (aSAH) accounts for a relatively small portion of strokes but has the potential to cause permanent neurological deficits. Vasospasm with delayed ischemic neurological deficit is thought to be responsible for much of the morbidity associated with aSAH. This has illuminated some treatment options that have the potential to target specific components of the vasospasm cascade. Intrathecal management via lumbar drain (LD) or external ventricular drain (EVD) offers unique advantages in this patient population. The aim of this review was to provide an update on intrathecal vasospasm treatments, emphasizing the need for larger-scale trials and updated protocols using data-driven evidence. METHODS: A search of PubMed, Ovid MEDLINE, and Cochrane databases included the search terms (subarachnoid hemorrhage) AND (vasospasm OR delayed cerebral ischemia) AND (intrathecal OR intraventricular OR lumbar drain OR lumbar catheter) for 2010 to the present. Next, a meta-analysis was performed of select therapeutic regimens. The primary endpoints of analysis were vasospasm, delayed cerebral ischemia (DCI), cerebral infarction, and functional outcome. RESULTS: Twenty-nine studies were included in the analysis. There were 10 studies in which CSF drainage was the primary experimental group. Calcium channel antagonists were the focus of 7 studies. Fibrinolytics and other vasodilators were each examined in 6 studies. The meta-analysis included studies examining CSF drainage via LD (n = 4), tissue plasminogen activator in addition to EVD (n = 3), intraventricular nimodipine (n = 2), and cisternal magnesium (n = 2). Results showed that intraventricular nimodipine decreased vasospasm (OR 0.59, 95% CI 0.37-0.94; p = 0.03). Therapies that significantly reduced DCI were CSF drainage via LD (OR 0.47, 95% CI 0.25-0.88; p = 0.02) and cisternal magnesium (OR 0.27, 95% CI 0.07-1.02; p = 0.05). CSF drainage via LD was also found to significantly reduce the incidence of cerebral infarction (OR 0.35, 95% 0.24-0.51; p < 0.001). Lastly, functional outcome was significantly better in patients who received CSF drainage via LD (OR 2.42, 95% CI 1.39-4.21; p = 0.002). CONCLUSIONS: The authors' results showed that intrathecal therapy is a safe and feasible option following aSAH. It has been shown to attenuate cerebral vasospasm, reduce the incidence of DCI, and improve clinical outcome. The authors support the use of intrathecal management in the prevention and rescue management of cerebral vasospasm. More randomized controlled trials are warranted to determine the best combination of pharmaceutical agents and administration route in order to formulate a standardized treatment approach.

A retrospective review of pregnancies on biologics for the treatment of dermatological conditions.

Psoriasis often first presents in young adulthood, with the average age of diagnosis in women being 28 years, thus in the prime reproductive years. In addition, approximately 50% of pregnancies worldwide are unplanned. Although biologic therapies have revolutionized the treatment of moderate-to-severe psoriasis, there are no controlled studies of biologics in pregnant women. The increasing use of these agents in women of childbearing age highlights the need to further assess their safety during pregnancy. Postmarketing experience regarding the safety of these drugs is accumulating and being published, with largely reassuring results. We present our real-world experience of 17 pregnancies occurring in women on treatment with biologic agents for dermatological conditions to further add to the body of knowledge.

Automated detection of fluorescent cells in in-resin fluorescence sections for integrated light and electron microscopy.

Integrated array tomography combines fluorescence and electron imaging of ultrathin sections in one microscope, and enables accurate high-resolution correlation of fluorescent proteins to cell organelles and membranes. Large numbers of serial sections can be imaged sequentially to produce aligned volumes from both imaging modalities, thus producing enormous amounts of data that must be handled and processed using novel techniques. Here, we present a scheme for automated detection of fluorescent cells within thin resin sections, which could then be used to drive automated electron image acquisition from target regions via 'smart tracking'. The aim of this work is to aid in optimization of the data acquisition process through automation, freeing the operator to work on other tasks and speeding up the process, while reducing data rates by only acquiring images from regions of interest. This new method is shown to be robust against noise and able to deal with regions of low fluorescence.

Implementation of a workplace intervention using financial rewards to promote adherence to physical activity guidelines: a feasibility study.

BACKGROUND: We designed and implemented the Brigham and Women's Wellness Initiative (B-Well), a single-arm study to examine the feasibility of a workplace program that used individual and team-based financial incentives to increase physical activity among sedentary hospital employees. METHODS: We enrolled sedentary, non-clinician employees of a tertiary medical center who self-reported low physical activity. Eligible participants formed or joined teams of three members and wore Fitbit Flex activity monitors for two pre-intervention weeks followed by 24 weeks during which they could earn monetary rewards. Participants were rewarded for increasing their moderate-to-vigorous physical activity (MVPA) by 10% from the previous week or for meeting the Centers for Disease Control and Prevention (CDC) physical activity guidelines (150 min of MVPA per week). Our primary outcome was the proportion of participants meeting weekly MVPA goals and CDC physical activity guidelines. Secondary outcomes included Fitbit-wear adherence and factors associated with meeting CDC guidelines more consistently. RESULTS: B-Well included 292 hospital employees. Participants had a mean age of 38 years (SD 11), 83% were female, 38% were obese, and 62% were non-Hispanic White. Sixty-three percent of participants wore the Fitbit ≥4 days per week for ≥20 weeks. Two-thirds were satisfied with the B-Well program, with 79% indicating that they would participate again. Eighty-six percent met either their personal weekly goal or CDC physical activity guidelines for at least 6 out of 24 weeks, and 52% met their goals or CDC physical activity guidelines for at least 12 weeks. African Americans, non-obese subjects, and those with lower impulsivity scores reached CDC guidelines more consistently. CONCLUSIONS: Our data suggest that a financial incentives-based workplace wellness program can increase MVPA among sedentary employees. These results should be reproduced in a randomized controlled trial. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02850094 . Registered July 27, 2016 [retrospectively registered].

A geometric model of defensive peripersonal space.

Potentially harmful stimuli occurring within the defensive peripersonal space (DPPS), a protective area surrounding the body, elicit stronger defensive reactions. The spatial features of the DPPS are poorly defined and limited to descriptive estimates of its extent along a single dimension. Here we postulated a family of geometric models of the DPPS, to address two important questions with respect to its spatial features: What is its fine-grained topography? How does the nervous system represent the body area to be defended? As a measure of the DPPS, we used the strength of the defensive blink reflex elicited by electrical stimulation of the hand (hand-blink reflex, HBR), which is reliably modulated by the position of the stimulated hand in egocentric coordinates. We tested the goodness of fit of the postulated models to HBR data from six experiments in which we systematically explored the HBR modulation by hand position in both head-centered and body-centered coordinates. The best-fitting model indicated that 1) the nervous system's representation of the body area defended by the HBR can be approximated by a half-ellipsoid centered on the face and 2) the DPPS extending from this area has the shape of a bubble elongated along the vertical axis. Finally, the empirical observation that the HBR is modulated by hand position in head-centered coordinates indicates that the DPPS is anchored to the face. The modeling approach described in this article can be generalized to describe the spatial modulation of any defensive response.

Multilayering of Calcium Aerosol-OT at the Mica/Water Interface Studied with Neutron Reflection: Formation of a Condensed Lamellar Phase at the CMC.

Using specular neutron reflection, the adsorption of sodium and calcium salts of the surfactant bis(2-ethylhexyl) sulfosuccinate (Aerosol-OT or AOT) has been studied at the mica/water interface at concentrations between 0.1 and 2 CMC. The pH dependence of the adsorption was also probed. No evidence of the adsorption of Na(AOT) was found even at the critical micelle concentration (CMC) while the calcium salt was found to adsorb significantly at concentrations of 0.5 CMC and above. This interesting and somewhat unexpected finding demonstrates that counterion identity may be used to tune the adsorption of anionic surfactants on anionic surfaces. At the CMC, three condensed bilayers of Ca(AOT)2 were adsorbed at pH 7 and 9 and four bilayers adsorbed at pH 4. Multilayering at the CMC of Ca(AOT)2 on the mica surface is an unusual feature of this surfactant/surface combination. Only single bilayer adsorption has been observed at other surfaces at the CMC. We suggest this arises from the high charge density of mica which must provide an excellent template for the surfactant.

Important factors determining the nanoscale tracking precision of dynamic microtubule ends.

Tracking dynamic microtubule ends in fluorescence microscopy movies provides insight into the statistical properties of microtubule dynamics and is vital for further analysis that requires knowledge of the trajectories of the microtubule ends. Here we analyse the performance of a previously developed automated microtubule end tracking routine; this has been optimized for comparatively low signal-to-noise image sequences that are characteristic of microscopy movies of dynamic microtubules growing in vitro. Sequences of simulated microtubule images were generated assuming a variety of different experimental conditions. The simulated movies were then tracked and the tracking errors were characterized. We found that the growth characteristics of the microtubules within realistic ranges had a negligible effect on the tracking precision. The fluorophore labelling density, the pixel size of the images, and the exposure times were found to be important parameters limiting the tracking precision which could be explained using concepts of single molecule localization microscopy. The signal-to-noise ratio was found to be a good single predictor of the tracking precision: typical experimental signal-to-noise ratios lead to tracking precisions in the range of tens of nanometres, making the tracking program described here a useful tool for dynamic microtubule end tracking with close to molecular precision.

EPIGENETIC VARIATION AT SKA2 PREDICTS SUICIDE PHENOTYPES AND INTERNALIZING PSYCHOPATHOLOGY.

BACKGROUND: DNA methylation of the SKA2 gene has recently been implicated as a biomarker of suicide risk and posttraumatic stress disorder (PTSD). To examine the specificity and reliability of these findings, we examined associations between SKA2 DNA methylation, broad dimensions of psychiatric symptoms, and suicide phenotypes in adults with high levels of trauma exposure. METHODS: A total of 466 White, non-Hispanic veterans and their intimate partners (65% male) underwent clinical assessment and had blood drawn for genotyping and methylation analysis. DNA methylation of the CpG locus cg13989295 and genotype at the methylation-associated single-nucleotide polymorphism (SNP) rs7208505 were examined in relation to current and lifetime PTSD, internalizing and externalizing psychopathology, and suicide phenotypes (ideation, plans, and attempts). RESULTS: DNA methylation at the previously implicated SKA2 CpG locus (cg13989295) was associated with current and lifetime symptoms of internalizing (but not externalizing) disorders. SKA2 methylation levels also predicted higher rates of current suicidal thoughts and behaviors, even after including well-established psychiatric risk factors for suicide in the model. Associations between PTSD and SKA2 were not significant, and genetic variation at the methylation-associated SNP (rs7208505) was not related to any of the phenotypes examined. CONCLUSIONS: SKA2 methylation may index a general propensity to experience stress-related psychopathology, including internalizing disorders and suicidal thoughts and behaviors. This study demonstrates that SKA2 methylation levels explain unique variance in suicide risk not captured by clinical symptom interviews, providing further evidence of its potential utility as a biomarker of suicide risk and stress-related psychopathology.

Association between activity limitations and pain in patients scheduled for total knee arthroplasty.

BACKGROUND: Historically, persons scheduled for total knee arthroplasty (TKA) have reported severe pain with low demand activities such as walking, but recent data suggests that TKA recipients may have less preoperative pain. Little is known about people who elect TKA with low levels of preoperative pain. To better understand current TKA utilization, we evaluated the association between preoperative pain and difficulty performing high demand activities, such as kneeling and squatting, among TKA recipients. METHODS: We used baseline data from a randomized control trial designed to improve physical activity following TKA. Prior to TKA, participants were categorized according to Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain scores: Low (0-25), Medium (26-40), and High (41-100). Within each group, limitations in both low demand and high demand activities were assessed. RESULTS: The sample consisted of 202 persons with a mean age of 65 (SD 8) years; 21 %, 34 %, and 45 % were categorized in the Low, Medium, and High Pain groups, respectively. Of the Low Pain group, 60 % reported at least one of the following functional limitations: limited flexion, limp, limited walking distance, and limitations in work or housework. While only 12 % of the Low Pain group reported at least moderate pain with walking on a flat surface, nearly all endorsed at least moderate difficulty with squatting and kneeling. CONCLUSIONS: A substantial number of persons scheduled for TKA report Low WOMAC Pain (≤25) prior to surgery. Persons with Low WOMAC Pain scheduled for TKA frequently report substantial difficulty with high demand activities such as kneeling and squatting. Studies of TKA appropriateness and effectiveness for patients with low WOMAC Pain should include measures of these activities. TRIAL REGISTRATION: Identifier NCT01970631 ; Registered 23 October 2013.

Development and feasibility of a personalized, interactive risk calculator for knee osteoarthritis.

BACKGROUND: The incidence of knee osteoarthritis (OA) is rising. While several risk factors have been associated with the development of knee OA, this information is not readily accessible to those at risk for osteoarthritis. Risk calculators have been developed for several prevalent chronic conditions but not for OA. Using published evidence on established risk factors, we developed an interactive, personalized knee OA risk calculator (OA Risk C) and conducted a pilot study to evaluate its acceptability and feasibility. METHODS: We used the Osteoarthritis Policy (OAPol) Model, a validated, state-transition simulation of the natural history and management of OA, to generate data for OA Risk C. Risk estimates for calculator users were based on a set of demographic and clinical factors (age, sex, race/ethnicity, obesity) and select risk factors (family history of knee OA, occupational exposure, and history of knee injury). OA Risk C presents personalized risk of knee OA in several ways to maximize understanding among a wide range of users. We conducted a study of 45 subjects in a primary care setting to establish the feasibility and acceptability of the OA risk calculator. Pilot study participants were asked several questions regarding ease of use, clarity of presentation, and clarity of the graphical representation of their risk. These questions used a five-level agreement scale ranging from strongly disagree to strongly agree. RESULTS: OA Risk C depicts information about users' risk of symptomatic knee OA in 5 year intervals. Study participants estimated their lifetime risk at 38 %, while their actual lifetime risk, as estimated by OA Risk C, was 25 %. Eighty-four percent of pilot study participants reported that OA Risk C was easy to understand, and 89 % agreed that the graphs depicting their risk were clear and comprehensible. CONCLUSIONS: We have developed a personalized, computer-based OA risk calculator that is easy to use. OA Risk C may be utilized to estimate individuals' knee OA risk and to deliver educational and behavioral interventions focused on osteoarthritis risk reduction.

Epidemiology, management and outcome of paracetamol poisoning in an inner city emergency department.

BACKGROUND: Paracetamol poisoning accounts for just under half of all self-poisoning cases that present to hospitals in England. Treatment with acetylcysteine is routine, yet recommendations regarding its use vary internationally and have recently been revised in England and Wales. METHODS: Data on all cases of paracetamol poisoning presenting to an adult inner city emergency department between May 2011 and April 2012 were prospectively collected using the Bristol Self-harm Surveillance Register. RESULTS: Paracetamol overdoses accounted for 44% of adult self-poisoning cases. A quarter (26.9%) of patients required treatment with acetylcysteine and it was estimated that recent changes in treatment guidelines would increase that proportion to 32.6%. Paracetamol concentration was positively associated with the risk of any adverse reaction to acetylcysteine. 22.5% of patients experienced anaphylactoid reactions to acetylcysteine. There was no clear evidence of an association between risk of anaphylactoid reaction and blood paracetamol levels. Patients presenting with blood paracetamol levels greater than 200 mg/L at 4 h post-ingestion were at greater risk of repeat self-harm (HR 2.17, 95% CI 1.11 to 4.21, p=0.033). DISCUSSION: The recent changes in UK treatment guidelines are expected to increase the proportion of our population requiring acetylcysteine by 5.7%. We found no clear evidence that risk of anaphylactoid or more general adverse reaction to acetylcysteine was increased in patients presenting with lower blood paracetamol concentrations. Blood paracetamol level was highlighted as a potentially useful clinical indicator for risk of repeat self-harm.

Changes in DXA and quantitative CT measures of musculoskeletal outcomes following pediatric renal transplantation.

This prospective study evaluated changes in dual energy X-ray absorptiometry (DXA) whole body bone mineral content (WB-BMC) and spine areal bone mineral density (spine-BMD), and tibia quantitative computed tomography (QCT) trabecular and cortical volumetric BMD and cortical area in 56 children over 12 months following renal transplantation. At transplant, spine-BMD Z-scores were greater in younger recipients (<13 years), versus 898 reference participants (p < 0.001). In multivariate models, greater decreases in spine-BMD Z-scores were associated with greater glucocorticoid dose (p < 0.001) and declines in parathyroid hormone levels (p = 0.008). Changes in DXA spine-BMD and QCT trabecular BMD were correlated (r = 0.47, p < 0.01). At 12 months, spine-BMD Z-scores remained elevated in younger recipients, but did not differ in older recipients (≥ 13) and reference participants. Baseline WB-BMC Z-scores were significantly lower than reference participants (p = 0.02). Greater glucocorticoid doses were associated with declines in WB-BMC Z-scores (p < 0.001) while greater linear growth was associated with gains in WB-BMC Z-scores (p = 0.01). Changes in WB-BMC Z-scores were associated with changes in tibia cortical area Z-scores (r = 0.52, p < 0.001), but not changes in cortical BMD Z-scores. Despite resolution of muscle deficits, WB-BMC Z-scores at 12 months remained significantly reduced. These data suggest that spine and WB DXA provides insight into trabecular and cortical outcomes following pediatric renal transplantation.

Changes in trabecular bone density in incident pediatric Crohn's disease: a comparison of imaging methods.

UNLABELLED: This study of changes in dual energy x-ray absorptiometry (DXA) spine BMD following diagnosis and treatment for childhood Crohn's disease demonstrated that changes in conventional posteroanterior BMD results were confounded by impaired growth, and suggested that lateral spine measurements and strategies to estimate volumetric BMD were more sensitive to disease and treatment effects. INTRODUCTION: We previously reported significant increases in peripheral quantitative CT (pQCT) measures of trabecular volumetric bone mineral density (vBMD) following diagnosis and treatment of pediatric Crohn's disease (CD). The objective of this study was to compare pQCT trabecular vBMD and three DXA measures of spine BMD in this cohort: (1) conventional posteroanterior BMD (PA-BMD), (2) PA-BMD adjusted for height Z (PA-BMDHtZ), and (3) width-adjusted volumetric BMD (WA-BMD) estimated from PA and lateral scans. METHODS: Spine DXA [lumbar (L1-4) for posteroanterior and L3 for lateral] and tibia pQCT scans were obtained in 65 CD subjects (ages 7-18 years) at diagnosis and 12 months later. BMD results were converted to sex, race, and age-specific Z-scores based on reference data in >650 children (ages 5-21 years). Multivariable linear regression models identified factors associated with BMD Z-scores. RESULTS: At CD diagnosis, all BMD Z-scores were lower compared with the reference children (all p values <0.01). The pQCT vBMD Z-scores (-1.46 ± 1.30) were lower compared with DXA PA-BMD (-0.75 ± 0.98), PA-BMDHtZ (-0.53 ± 0.87), and WA-BMD (-0.61 ± 1.10) among CD participants. Only PA-BMD Z-scores were correlated with height Z-scores at baseline (R = 0.47, p < 0.0001). pQCT and WA-BMD Z-scores increased significantly over 12 months to -1.04 ± 1.26 and -0.20 ± 1.14, respectively. Changes in all four BMD Z-scores were positively associated with changes in height Z-scores (p < 0.05). Glucocorticoid doses were inversely associated with changes in WA-BMD (p < 0.01) only. CONCLUSIONS: Conventional and height Z-score-adjusted PA DXA methods did not demonstrate the significant increases in trabecular vBMD noted on pQCT and WA-BMD scans. WA-BMD captured glucocorticoid effects, potentially due to isolation of the vertebral body on the lateral projection. Future studies are needed to identify the BMD measure that provides greatest fracture discrimination in CD.