Comparative assessment of radiation therapy-induced vasculitis using [18F]FDG-PET/CT in patients with non-small cell lung cancer treated with proton versus photon radiotherapy.

PURPOSE: To assess radiation therapy (RT)-induced vasculitis in patients with non-small cell lung cancer (NSCLC) by examining changes in the uptake of 18F-fluoro-D-deoxyglucose ([18F]FDG) by positron emission tomography/computed tomography (PET/CT) images of the ascending aorta (AA), descending aorta (DA), and aortic arch (AoA) before and after proton and photon RT. METHOD: Thirty-five consecutive locally advanced NSCLC patients were definitively treated with proton (n = 27) or photon (n = 8) RT and concurrent chemotherapy. The patients were prospectively enrolled to undergo [18F]FDG-PET/CT imaging before and 3 months after RT. An adaptive contrast-oriented thresholding algorithm was applied to generate mean standardized uptake values (SUVmean) for regions of interest (ROIs) 3 mm outside and 3 mm inside the outer perimeter of the AA, DA, and AoA. These ROIs were employed to exclusively select the aortic wall and remove the influence of blood pool activity. SUVmeans before and after RT were compared using two-tailed paired t-tests. RESULTS: RT treatments were associated with increased SUVmeans in the AA, DA, and AoA-1.9%, 0.3%, and 1.3% for proton and 15.8%, 9.5%, and 15.5% for photon, respectively. There was a statistically significant difference in the ∆SUVmean (post-RT SUVmean - pre-RT SUVmean) in patients treated with photon RT when compared to ∆SUVmean in patients treated with proton RT in the AA (p = 0.043) and AoA (p = 0.015). There was an average increase in SUVmean that was related to dose for photon patients (across structures), but that was not seen for proton patients, although the increase was not statistically significant. CONCLUSION: Our results suggest that patients treated with photon RT for NSCLC may exhibit significantly more RT-induced inflammation (measured as ∆SUVmean) in the AA and AoA when compared to patients who received proton RT. Knowledge gained from further analyses in larger cohorts could aid in treatment planning and help prevent the significant morbidity and mortality associated with RT-induced vascular complications. TRIAL REGISTRATION: NCT02135679.

The direct role of nuclear motion in spin-orbit coupling in strongly correlated spin systems.

The interaction between the magnetic moment of an electron and the magnetic field generated by a moving charge is one component of the spin-orbit interaction. The nuclei in a molecule or solid are charged, are generally in vibrational motion, and so contribute to this interaction, but the direct coupling between nuclear momentum and electron spin is normally ignored in discussions of spin-forbidden phenomena such as transitions between states of different spin, even when the nuclei are recognized as playing a fundamental role (spin-vibronic coupling). Here, we investigate the spin-orbit interaction in a Heisenberg model interacting with vibrating point charges representing nearby bridging ligands. To reach the model, we apply second order perturbation theory to the Hubbard model with the spin-orbit interaction. In contrast to the other components of the spin-orbit interaction, the part that directly couples the momentum of the charge and electron spin appears at first order as an effective magnetic field at each site. We find that the inclusion of this nuclear-motion induced spin-orbit coupling can increase the rate of otherwise spin-forbidden transitions between different spin states of the Heisenberg model by many orders of magnitude. This overlooked interaction may, therefore, play a significant role in spin-forbidden phenomena such as spin relaxation in coupled spin-qubits.

Exploring experiences of living with removable dentures-A scoping review of qualitative literature.

OBJECTIVE: Examine the literature on the experiences of living with removable dentures (complete or partial) to identify any gaps and provide a map for future research. BACKGROUND: Increasing proportions of society are living partially dentate with some form of restoration, including removable dentures. Previous studies have reported on the location, materials and usage of these prostheses, along with effects on oral-health-related quality of life (OHRQoL). However, less is known about experiences with removable dentures from a patient-centred perspective. METHODS: A scoping review of the qualitative literature was undertaken using the framework of Arksey and O'Malley, updated by Levac et al. Literature searches were carried out using Medline and Web of Science. Papers were screened by title and abstract using inclusion and exclusion criteria. Remaining papers were read in full and excluded if they did not meet the required criteria. Nine papers were included in the final review. FINDINGS: Key themes from these papers were: impact of tooth loss and living without teeth, and its impacts in relation to social position, appearance, confidence and function (chewing and speaking); social norms and tooth loss, including attitudes to tooth retention and treatment costs, and changes in intergenerational norms towards dentures; expectations of treatment, including patients being more involved in decision making, viewing the denture as a "gift" and dentures helping to achieve "an ideal"; living with a removable denture (complete or partial), including patient preparedness for a denture, adaptation and impacts on activities and participation; and the dentist-patient relationship, including issues with information and communication, and differing priorities between patients and dentists. CONCLUSION: Little qualitative research exists on experiences of living with a removable denture. Existing literature demonstrates the importance of dispersed activities in differing social, spatial and temporal contexts when wearing removable dentures. Focusing on processes of positive adaptation to dentures and OHRQoL, rather than deficits, is also required to fully understand patients' experiences. Additionally, more complex technological advances may not always be in the best interest of every patient.

Hidradenitis Suppurativa Area and Severity Index Revised (HASI-R): psychometric property assessment.

BACKGROUND: Validated, reliable, globally accepted outcome measurement instruments for hidradenitis suppurativa (HS) are needed. Current tools to measure the physical signs domain for HS rely on lesion counts, which are time-consuming and unreliable. OBJECTIVES: To assess the reliability and validity of the Hidradenitis suppurativa Area and Severity Index Revised (HASI-R) tool, a novel method for assessing HS severity, incorporating signs of inflammation and body surface area involved. METHODS: The measurement properties of the HASI-R tool were evaluated. The tool was created by combining the previously published HASI and Severity and Area Score for Hidradenitis instruments. Twenty raters evaluated 15 patients with HS in a hospital-based ambulatory dermatology clinic. The objectives of the study were to assess inter- and intra-rater reliability of the HASI-R and its components, as well as its construct and known-groups validity. Existing lesion count-based clinician-reported measures of HS and their components were also assessed. Raters were also asked their preferences regarding the various HS severity assessment tools. RESULTS: The HASI-R had moderate inter-rater reliability [intra-class correlation coefficients (ICC) 0·60]. This was better than all other HS physical sign outcome measures evaluated, which had poor inter-rater reliability (ICC < 0·5). HASI-R had the highest intra-rater reliability (ICC 0·91). The HASI-R had good construct validity and demonstrated known-groups validity. The HASI-R was also the most preferred tool by all raters. CONCLUSIONS: Results from the clinometric assessment of the HASI-R are encouraging, and support continued evaluation of this clinician-reported outcome measure.

Identifying key components and therapeutic targets of the immune system in hidradenitis suppurativa with an emphasis on neutrophils.

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent and debilitating skin disease of the hair follicle unit that typically develops after puberty. The disorder is characterized by comedones, painful inflammatory nodules, abscesses, dermal tunnels and scarring, with a predilection for intertriginous areas of the body (axillae, inguinal and anogenital regions). Recruitment of neutrophils to HS lesion sites may play an essential role in the development of the painful inflammatory nodules and abscesses that characterize the disease. This is a review of the major mediators involved in the recruitment of neutrophils to sites of active inflammation, including bacterial components (endotoxins, exotoxins, capsule fragments, etc.), the complement pathway anaphylatoxins C3a and C5a, tumour necrosis factor-alpha, interleukin (IL)-17, IL-8 (CXCL8), IL-36, IL-1, lipocalin-2, leukotriene B4, platelet-activating factor, kallikreins, matrix metalloproteinases, and myeloperoxidase inhibitors. Pharmacological manipulation of the various pathways involved in the process of neutrophil recruitment and activation could allow for successful control and stabilization of HS lesions and the remission of active, severe flares.

Real-world effectiveness of adalimumab in patients with moderate-to-severe hidradenitis suppurativa: the 1-year SOLACE study.

BACKGROUND: Long-term, real-word data are needed to help manage patients with hidradenitis suppurativa (HS) through this recurrent, painful and debilitating disease. OBJECTIVES: To primarily measure real-world effectiveness of adalimumab in HS and to secondarily observe clinical course of HS in the light of patients' response. METHODS: In SOLACE, adults with moderate-to-severe HS in need for change in ongoing therapy were treated with adalimumab for up to 52 weeks as per physician's medical practice. Treatment effectiveness was measured by Hidradenitis Suppurativa Clinical Response (HiSCR). Inflammatory nodules, abscesses and draining fistulas were counted, Hurley stage was assessed, and disease severity was rated using the International HS Severity Scoring System (IHS4). A post hoc analysis further explored the HiSCR response by abscess and inflammatory nodule (AN) count at baseline (low, medium and high) and gender. Spontaneously reported safety events were collected. RESULTS: From 23 Canadian centres, 69% of the 138 patients achieved HiSCR at week 24, which increased to 82% and 75% at week 52 in patients with medium and high AN counts, respectively. Gender (4 times the odds for female) and age at HS onset (5% decrease with each additional year) had an effect on achieving HiSCR. Treatment with adalimumab led to an important decrease in number of lesions in responders, with most gains observed in inflammatory nodules, more frequently in the lower body area of patients in the high AN count group. The IHS4 scores of responders were substantially lowered, with a larger decrease in patients of the high AN count group. No new safety signal was detected. CONCLUSIONS: The effectiveness of adalimumab was maintained during this 1-year period, and an optimal gain was documented for patients with medium and high AN counts. These real-world data support a prompt treatment of HS patients and the use of IHS4 to monitor treatment.

Nemolizumab is associated with a rapid improvement in atopic dermatitis signs and symptoms: subpopulation (EASI ≥ 16) analysis of randomized phase 2B study.

BACKGROUND: Nemolizumab is a humanized anti-IL-31 receptor blocker in phase 3 for atopic dermatitis (AD). OBJECTIVE: Analyse onset of action of nemolizumab 30 mg and compare efficacy and safety vs placebo (SC q4wk plus loading dose) in moderate-to-severe AD. METHODS: Post hoc analysis of patients with Eczema Area and Severity Index (EASI) scores ≥ 16 from a phase 2b trial of moderate-to-severe AD. Endpoints were change in EASI score at week 16, peak pruritus numeric rating scale (PP-NRS), Investigator's Global Assessment (IGA), changes in sleep and responders with ≥ 4-point improvement on PP-NRS. RESULTS: There was a significantly greater itch relief apparent by Day 2 (-22.8% vs -12.3% PP-NRS; P = 0.005) which continued to improve through week 16 (-68.5% vs -30.9% PP-NRS; P < 0.001). At week 16, PP-NRS ≥ 4-point response of itch was observed in 68.0% nemolizumab vs 15.9% placebo patients (P ≤ 0.001). There was also a rapid improvement of sleep disturbance with nemolizumab 30 mg, with a significant separation from placebo by Day 3 (-26.6% vs -9.0%; P < 0.001) which further improved till week 16 (-76.0% vs -36.5%; P < 0.001). Also for the EASI score a separation between groups in favour of nemolizumab was observed by week 1 (P ≤ 0.001), which increased through week 16 (-68.6% vs. -42.6%; P = 0.002). Finally, the degree of response was greater in nemolizumab-treated patients; clinically relevant reductions of 75% EASI were observed in 50.0% of nemolizumab patients versus 15.9% of placebo patients, while 90% reductions were reported for 36.0% and 6.8% of patients, respectively (P < 0.001 for both). IGA success (score of 0/1) was 32.0% for nemolizumab vs 6.8% for placebo (P = 0.002). Nemolizumab was safe and well-tolerated in this population; nasopharyngitis and upper respiratory tract infection were the most common adverse events. CONCLUSIONS: Nemolizumab resulted in very rapid, sustained improvements of inflammation, pruritus and sleep in patients with EASI ≥ 16 at baseline.

Identification and evaluation of outcome measurement instruments in pyoderma gangrenosum: a systematic review.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare autoinflammatory skin condition that causes tissue destruction and subsequent painful ulcers. To date, there are no core domains or instruments for assessing PG severity in clinical trials, and current treatment paradigms rely on outcome measurements that have not been well characterized in the literature. OBJECTIVES: To perform two systematic reviews that (i) identify the outcome measurement instruments used in PG clinical trials and their corresponding domains and (ii) identify any associated validation studies and evaluate their measurement properties and methodological quality. METHODS: We systematically searched the MEDLINE and Embase databases for PG outcome measurement instruments. We also systematically searched for PG instrument validation studies. We evaluated the measurement properties and methodological quality of validation studies using the 2018 COSMIN Risk of Bias checklist. RESULTS: In total, seven clinical trials were included. These studies utilized a total of 20 different instruments, including 11 physician-reported instruments, eight patient-reported instruments and one composite instrument. Among these, 85% of the instruments lacked any validation data. Of the remaining three validated instruments (speed of healing, physician global assessment and resolution of inflammation), methodological quality was not available for half of the COSMIN categories. CONCLUSIONS: We identified 17 non-validated outcome measurement instruments used in PG clinical trials. We conclude that PG validation studies are required for existing instruments, and new instruments need to be developed to inform the consensus process for the development of a core outcome set for PG. What is already known about this topic? Pyoderma gangrenosum (PG) is a rare autoinflammatory skin condition that has been characterized by multiple outcome measurement instruments in clinical trials. However, there is no consensus on the most validated and appropriate outcome measurement instruments. What does this study add? This study identifies and evaluates 20 unique outcome measurement instruments for PG in the literature. Of these 20, 17 lack any instrument validation data, highlighting the need for future studies. What are the clinical implications of this work? Despite the current use of several outcome measurement instruments, future studies should explore the validation surrounding these instruments, as no instruments can currently be recommended.

Pilonidal sinus disease: an intergluteal localization of hidradenitis suppurativa/acne inversa: a cross-sectional study among 2465 patients.

BACKGROUND: Hidradenitis suppurativa (HS), also referred to as acne inversa, is a debilitating skin disease characterized by inflammatory nodules, chronic abscesses and tunnels (fistulae and sinuses). The association with pilonidal sinus disease (PSD) is frequently reported but not well documented. OBJECTIVES: To determine the prevalence and characteristics of inflammatory skin lesions located in the intergluteal fold (IGF) of patients with HS. METHODS: This was an international multicentre retrospective cross-sectional study based on data collection from a large cohort of patients with HS with and without histopathology. Results From a total of 2465 patients with HS included in the study, 661 (27%) reported lesions in the IGF. These patients were significantly more often smokers and had more severe HS. Of the 238 patients with an available clinical diagnosis, intergluteal-HS (IG-HS) was diagnosed in 52 patients (22%) and PSD was diagnosed in 186 patients (78%). IG-HS was associated with the localization of HS in the proximity of the IGF, including the buttocks, genitals and the anus. There was a possibility of misclassification bias in this study as a clinical/image-based diagnosis or histopathology of the IGF lesions was not always available. CONCLUSIONS: The high prevalence of PSD suggests a strong link between both entities. Therefore, it may be useful to identify common pathophysiological mechanisms and develop common therapeutic strategies. What's already known about this topic? The occurrence of pilonidal sinus disease has not been clearly reported among patients with hidradenitis suppurativa/acne inversa. What does this study add? This is the first study that investigated the prevalence of pilonidal sinus disease among a large cohort of patients and identified the patient characteristics. Risk factors that might help to improve the management of patients were identified.

Projector Quantum Monte Carlo Method for Nonlinear Wave Functions.

We reformulate the projected imaginary-time evolution of the full configuration interaction quantum Monte Carlo method in terms of a Lagrangian minimization. This naturally leads to the admission of polynomial complex wave function parametrizations, circumventing the exponential scaling of the approach. While previously these functions have traditionally inhabited the domain of variational Monte Carlo approaches, we consider recent developments for the identification of deep-learning neural networks to optimize this Lagrangian, which can be written as a modification of the propagator for the wave function dynamics. We demonstrate this approach with a form of tensor network state, and use it to find solutions to the strongly correlated Hubbard model, as well as its application to a fully periodic ab initio graphene sheet. The number of variables which can be simultaneously optimized greatly exceeds alternative formulations of variational Monte Carlo methods, allowing for systematic improvability of the wave function flexibility towards exactness for a number of different forms, while blurring the line between traditional variational and projector quantum Monte Carlo approaches.

Diagnostic yield of FDG-PET/CT in fever of unknown origin: a systematic review, meta-analysis, and Delphi exercise.

AIM: To perform a systematic review, meta-analysis and Delphi exercise to evaluate diagnostic yield of combined 2-[18F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography and computed tomography (FDG-PET/CT) in fever of unknown origin (FUO). MATERIALS AND METHODS: Four databases were searched for studies of FDG-PET/CT in FUO 1/1/2000-1/12/2015. Exclusions were non-English language, case reports, non-standard FDG radiotracer, and significant missing data. Quality was assessed by two authors independently using a standardised tool. Pooled diagnostic yield was calculated using a random-effects model. An iterative electronic and face-to-face Delphi exercise generated interspeciality consensus. RESULTS: Pooled diagnostic yield was 56% (95% confidence interval [CI]: 50-61%, I2=61%) from 18 studies and 905 patients. Only five studies reported results of previous imaging, and subgroup analysis estimated diagnostic yield beyond conventional CT at 32% (95% CI: 22-44%; I2=66%). Consensus was established that FDG-PET/CT is increasingly available with an emerging role, but there is prevailing variability in practice. CONCLUSION: There is insufficient evidence to support the value of FDG-PET/CT in investigative algorithms of FUO. A paradigm shift in research is needed, involving prospective studies recruiting at diagnosis of FUO, with updated case definitions and hard outcome measures. Although these studies will be a significant undertaking with multicentre collaboration, their completion is vital for balancing both radiation exposure and costs against the possible benefits of utilising FDG-PET/CT.

Sexual dimorphism in relation to adipose tissue and intrahepatocellular lipid deposition in early infancy.

Sexual dimorphism in adiposity is well described in adults, but the age at which differences first manifest is uncertain. Using a prospective cohort, we describe longitudinal changes in directly measured adiposity and intrahepatocellular lipid (IHCL) in relation to sex in healthy term infants. At median ages of 13 and 63 days, infants underwent quantification of adipose tissue depots by whole-body magnetic resonance imaging and measurement of IHCL by in vivo proton magnetic resonance spectroscopy. Longitudinal data were obtained from 70 infants (40 boys and 30 girls). In the neonatal period girls are more adipose in relation to body size than boys. At follow-up (median age 63 days), girls remained significantly more adipose. The greater relative adiposity that characterises girls is explained by more subcutaneous adipose tissue and this becomes increasingly apparent by follow-up. No significant sex differences were seen in IHCL. Sex-specific differences in infant adipose tissue distribution are in keeping with those described in later life, and suggest that sexual dimorphism in adiposity is established in early infancy.