Clinical outcomes and response to treatment of patients receiving topical treatments for pyoderma gangrenosum: a prospective cohort study

Background: pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment. Objective: to estimate the effectiveness of topical therapies in the treatment of PG. Methods: prospective cohort study of UK secondary care patients with a clinical diagnosis of PG suitable for topical treatment (recruited July 2009 to June 2012). Participants received topical therapy following normal clinical practice (mainly Class I-III topical corticosteroids, tacrolimus 0.03% or 0.1%). Primary outcome: speed of healing at 6 weeks. Secondary outcomes: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality-of-life; treatment failure and recurrence. Results: Sixty-six patients (22 to 85 years) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28/66 (43.8%) of ulcers healed by 6 months. Median time-to-healing was 145 days (95% CI: 96 days, ∞). Initial ulcer size was a significant predictor of time-to-healing (hazard ratio 0.94 (0.88;80 1.00); p = 0.043). Four patients (15%) had a recurrence. Limitations: No randomised comparator Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Biphasic recruitment of TRF2 to DNA damage sites promotes non-sister chromatid homologous recombination repair.

TRF2 (TERF2) binds to telomeric repeats and is critical for telomere integrity. Evidence suggests that it also localizes to non-telomeric DNA damage sites. However, this recruitment appears to be precarious and functionally controversial. We find that TRF2 recruitment to damage sites occurs by a two-step mechanism: the initial rapid recruitment (phase I), and stable and prolonged association with damage sites (phase II). Phase I is poly(ADP-ribose) polymerase (PARP)-dependent and requires the N-terminal basic domain. The phase II recruitment requires the C-terminal MYB/SANT domain and the iDDR region in the hinge domain, which is mediated by the MRE11 complex and is stimulated by TERT. PARP-dependent recruitment of intrinsically disordered proteins contributes to transient displacement of TRF2 that separates two phases. TRF2 binds to I-PpoI-induced DNA double-strand break sites, which is enhanced by the presence of complex damage and is dependent on PARP and the MRE11 complex. TRF2 depletion affects non-sister chromatid homologous recombination repair, but not homologous recombination between sister chromatids or non-homologous end-joining pathways. Our results demonstrate a unique recruitment mechanism and function of TRF2 at non-telomeric DNA damage sites

Colonic Ganglioneuroma: A Combined Single-Institution Experience and Review of the Literature of Forty-Three Patients

Ganglioneuromas (GNs) are rare, benign tumors composed of ganglion cells, nerve fibers, and glial cells. Three types of colonic GN lesions exist: polypoid GNs, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. Less than 100 cases of GN are documented in the literature. A 10-year retrospective search of the pathology database at our institution identified eight cases of colonic GNs. All cases were incidental. Seven of the eight cases presented with colonoscopy findings of small sessile polyps (ranging between 0.1 and 0.7 cm) treated with polypectomy, whereas one case showed a 4 cm partially circumferential and partially obstructing mass in the ascending colon, treated with right hemicolectomy. Almost two-thirds of the cases (5/8) demonstrated associated diverticulosis. All cases were positive for S100 protein and Synaptophysin via immunohistochemistry (IHC). No syndromic association was identified in any of the cases. We also conducted a comprehensive review using PubMed to identify cases of colonic GN reported in the literature. In total, 173 studies were retrieved, among which 36 articles met our inclusion criteria (35 patients and 3 cases on animals). We conclude that while most GNs are incidental and solitary small sessile lesions, many can be diffuse and associated with syndromes. In these cases, the tumor can result in bowel obstruction simulating adenocarcinoma

Managing chronic rhinosinusitis and respiratory disease: a qualitative study of triggers and interactions

Objective: The aim of this analysis is to explore views of patients with CRS (chronic rhinosinusitis) about of the aetiology of their respiratory symptoms and the relationship between upper and lower respiratory symptoms. Methods: This study is part of a larger mixed methods study investigating the epidemiology of CRS which comprises a questionnaire study of patients with CRS and controls and a qualitative study of 21 patients with CRS. Semi structured qualitative interviews were undertaken these patients; 11 male, 10 female. 12 patients had asthma. Patients were recruited from a tertiary outpatient rhinology clinic. Interviews were transcribed verbatim and analysed using thematic analysis using Nvivo software. Several important and recurring themes were highlighted. Results: Patients described many perceived triggering factors and an interaction between upper and lower respiratory tract symptoms. They felt that their symptoms could be managed more holistically. Conclusions: Concerns about triggers of respiratory symptoms and interactions between upper and lower respiratory symptoms are of significant concern to patients. These should be appropriately managed and acknowledged in formal treatment pathways, for example through the use of combined ENT/respiratory clinics

The Low-Redshift Lyman Continuum Survey. Unveiling the ISM properties of low-z Lyman-continuum emitters

Aims: Combining 66 ultraviolet (UV) spectra and ancillary data from the recent Low-Redshift Lyman Continuum Survey (LzLCS) and 23 LyC observations by earlier studies, we form a statistical sample of star-forming galaxies at z ∼ 0.2 − 0.4 with which we study the role of cold interstellar medium (ISM) gas in the leakage of ionizing radiation. We also aim to establish empirical relations between the H I neutral and low-ionization state (LIS) absorption lines with different galaxy properties. Methods: We first constrain the massive star content (stellar ages and metallicities) and UV attenuation by fitting the stellar continuum with a combination of simple stellar population models. The models, together with accurate LyC flux measurements, allow us to determine the absolute LyC photon escape fraction for each galaxy (fescabs). We then measure the equivalent widths and residual fluxes of multiple H I and LIS lines, and the geometrical covering fraction of the UV emission, adopting the picket-fence model. Results: The LyC escape fraction spans a wide range, with a median fescabs (0.16, 0.84 quantiles) of 0.04 (0.02, 0.20), and 50 out of the 89 galaxies detected in the LyC (1σ upper limits of fescabs ≲ 0.01 for non-detections, typically). The H I and LIS line equivalent widths scale with the UV luminosity and attenuation, and inversely with the residual flux of these lines. Additionally, Lyα equivalent widths scale with both the H I and LIS residual fluxes, but anti-correlate with the corresponding H I or LIS equivalent widths. The H I and LIS residual fluxes are correlated, indicating that the neutral gas is spatially traced by the low-ionization transitions. We find that the observed trends of the absorption lines and the UV attenuation are primarily driven by the geometric covering fraction of the gas. The observed nonuniform gas coverage also demonstrates that LyC photons escape through low-column-density channels in the ISM. The equivalent widths and residual fluxes of both the H I and LIS lines strongly correlate with fescabs: strong LyC leakers (highest fescabs) show weak absorption lines, low UV attenuation, and large Lyα equivalent widths. We provide several empirical calibrations to estimate fescabs from UV absorption lines. Finally, we show that simultaneous UV absorption line and dust attenuation measurements can, in general, predict the escape fraction of galaxies. We apply our method to available measurements of UV LIS lines of 15 star-forming galaxies at z ∼ 4 − 6 (plus 3 high-z galaxy composites), finding that these high-redshift, UV-bright galaxies (MUV ≲ −21) may have low escape fractions, fescabs ≲ 0.1. Conclusions: UV absorption lines trace the cold ISM gas of galaxies, which governs the physics of the LyC escape. We show that, with some assumptions, the absolute LyC escape can be statistically predicted using UV absorption lines, and the method can be applied to study galaxies across a wide redshift range, including in the epoch of cosmic reionization