Accuracy of diagnosis and classification of COPD in primary and specialist nurse-led respiratory care in Rotherham, UK : a cross-sectional study

Background: Studies have suggested that chronic obstructive pulmonary disease (COPD) is commonly misdiagnosed and misclassified in primary care, but less is known about the quality of diagnosis in specialist respiratory care. Aims: To measure the accuracy of COPD diagnosis and classification of airway obstruction in primary care and at a specialist respiratory centre, and to explore associations between misdiagnosis and misclassification and a range of explanatory factors. Methods: Data were obtained for 1,205 referrals to a specialist respiratory centre between 2007 and 2010. Standard analysis methods were used. Results: The majority of patients were referred for pulmonary rehabilitation (676/1,205, 56%). Of 1,044 patients with a primary care diagnosis of COPD, 211 (20%) had spirometry inconsistent with COPD. In comparison, of 993 specialist centre diagnoses, 65 (6.5%) had inconsistent spirometry. There was poor agreement between the airflow obstruction grade recorded on the referral and that based on spirometry (kappa=0.26, n=448), whereas agreement between the respiratory centre assessment of airflow obstruction and spirometry was good (kappa=0.88, n=1,016). Referral by practice nurse was associated with accuracy of airflow obstruction classification in primary care (OR 1.85, 95% CI 1.33 to 2.57). Males were more likely than females to have an accurate specialist care classification of airway obstruction (OR 1.40, 95% CI 1.01 to 1.93). Grade of airway obstruction changed between referral and assessment in 56% of cases. Conclusions: In primary care, a proportion of patients diagnosed with COPD do not have COPD, and misclassification of grade of airflow obstruction is common. Misdiagnosis and misclassification is less common in the specialist care setting of BreathingSpace

Exploring the mechanism of tryptophan 2,3-dioxygenase

The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes

Characterizing the protein-protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization

Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein-protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a 'multivalent' fashion. Instead, the two phosphorylated MDM2 motifs 'rock' between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ-MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers.</p

A Matched-Pair Analysis after Robotic and Retropubic Radical Prostatectomy: A New Definition of Continence and the Impact of Different Surgical Techniques

Radical prostatectomy is considered the gold-standard treatment for patients with localized prostate cancer. The literature suggests there is no difference in oncological and functional outcomes between robotic-assisted radical prostatectomy (RARP) and open (RRP). (2) Methods: The aim of this study was to compare continence recovery rates after RARP and RRP measured with 24 h pad weights and the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF). After matching the population (1:1), 482 met the inclusion criteria, 241 patients per group. Continent patients with a 24 h pad test showing &lt;20 g of urinary leakage were considered, despite severe incontinence, and categorized as having &gt;200 g of urinary leakage. (3) Results: There was no difference between preoperative data. As for urinary continence (UC) and incontinence (UI) rates, RARP performed significantly better than RRP based on objective and subjective results at all evaluations. Univariable and multivariable Cox Regression Analysis pointed out that the only significant predictors of continence rates were the bilateral nerve sparing technique (1.25 (CI 1.02,1.54), p = 0.03) and the robotic surgical approach (1.42 (CI 1.18,1.69) p ≤ 0.001). (4) Conclusions: The literature reports different incidences of UC depending on assessment and definition of continence "without pads" or "social continence" based on number of used pads per day. In this, our first evaluation, the advantage of objective measurement through the weight of the 24 h and subjective measurement with the ICIQ-SF questionnaire best demonstrates the difference between the two surgical techniques by enhancing the use of robotic surgery over traditional surgery

The Mechanism of Substrate Inhibition in Human Indoleamine 2,3-Dioxygenase

Indoleamine 2,3-dioxygenase catalyzes the O(2)-dependent oxidation of L-tryptophan (L-Trp) to N-formylkynurenine (NFK) as part of the kynurenine pathway. Inhibition of enzyme activity at high L-Trp concentrations was first noted more than 30 years ago, but the mechanism of inhibition has not been established. Using a combination of kinetic and reduction potential measurements, we present evidence showing that inhibition of enzyme activity in human indoleamine 2,3-dioxygenase (hIDO) and a number of site-directed variants during turnover with L-tryptophan (L-Trp) can be accounted for by the sequential, ordered binding of O(2) and L-Trp. Analysis of the data shows that at low concentrations of L-Trp, O(2) binds first followed by the binding of L-Trp; at higher concentrations of L-Trp, the order of binding is reversed. In addition, we show that the heme reduction potential (E(m)(0)) has a regulatory role in controlling the overall rate of catalysis (and hence the extent of inhibition) because there is a quantifiable correlation between E(m)(0) (that increases in the presence of L-Trp) and the rate constant for O(2) binding. This means that the initial formation of ferric superoxide (Fe(3+)-O(2)(•-)) from Fe(2+)-O(2) becomes thermodynamically less favorable as substrate binds, and we propose that it is the slowing down of this oxidation step at higher concentrations of substrate that is the origin of the inhibition. In contrast, we show that regeneration of the ferrous enzyme (and formation of NFK) in the final step of the mechanism, which formally requires reduction of the heme, is facilitated by the higher reduction potential in the substrate-bound enzyme and the two constants (k(cat) and E(m)(0)) are shown also to be correlated. Thus, the overall catalytic activity is balanced between the equal and opposite dependencies of the initial and final steps of the mechanism on the heme reduction potential. This tuning of the reduction potential provides a simple mechanism for regulation of the reactivity, which may be used more widely across this family of enzymes

The factor structure of the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen distinct populations

There is considerable evidence that self-criticism plays a major role in the vulnerability to and recovery from psychopathology. Methods to measure this process, and its change over time, are therefore important for research in psychopathology and well-being. This study examined the factor structure of a widely used measure, the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen nonclinical samples (N = 7510) from twelve different countries: Australia (N = 319), Canada (N = 383), Switzerland (N = 230), Israel (N = 476), Italy (N = 389), Japan (N = 264), the Netherlands (N = 360), Portugal (N = 764), Slovakia (N = 1326), Taiwan (N = 417), the United Kingdom 1 (N = 1570), the United Kingdom 2 (N = 883), and USA (N = 331). This study used more advanced analyses than prior reports: a bifactor item-response theory model, a two-tier item-response theory model, and a non-parametric item-response theory (Mokken) scale analysis. Although the original three-factor solution for the FSCRS (distinguishing between Inadequate-Self, Hated-Self, and Reassured-Self) had an acceptable fit, two-tier models, with two general factors (Self-criticism and Self-reassurance) demonstrated the best fit across all samples. This study provides preliminary evidence suggesting that this two-factor structure can be used in a range of nonclinical contexts across countries and cultures. Inadequate-Self and Hated-Self might not by distinct factors in nonclinical samples. Future work may benefit from distinguishing between self-correction versus shame-based self-criticism.Peer reviewe

Recent Trends in the Diagnostic and Surgical Management of Benign Prostatic Hyperplasia in the U.S. from 2004 to 2017: Annual Changes in the Selection of Treatment Options and Medical Costs

Background: Transurethral resection of the prostate (TURP) is the gold-standard treatment for benign prostatic hyperplasia (BPH). However, laser surgery techniques (e.g., photoselective vaporization of the prostate (PVP), holmium laser, thulium laser enucleation of the prostate (HoLEP or ThuLEP)), and minimally invasive treatment options (e.g., UroLift) are increasingly replacing TURP. This study seeks to report the annual incidence, management trends, and costs of BPH procedures in the U.S. Methods: Data analyses of U.S. health insurance claims from 2004 to 2017, collected from the de-identified Optum Clinformatics Claims Database, were performed to determine the number of BPH patients and the treatment selected. Results: A total of 51,448 patients underwent BPH procedures from 2004 to 2017. There was a significant increase in the annual rate from 770 in 2004 to 6571 in 2017. The mean patient age (±SD) increased from 67.6 years old (±8.4) in 2004 to 73.4 years old (±8.4) in 2017. More than 60% of patients underwent cystourethroscopy and a post-void residual urine check for workup prior to surgical management. TURP was the most-common, and PVP was the second-most-common BPH procedure. Medical and total treatment costs increased, while the detection rate of prostate cancer after BPH surgery gradually decreased from 19.87% in 2004 to 5.78% in 2017. Conclusions: Our study demonstrates a recent trend in BPH management that replaces the traditional TURP technique with alternative methods. Due to rising costs, future studies should assess whether these newer methods are cost effective over the long ter

A reassessment of the early archaeological record at Leang Burung 2, a Late Pleistocene rock-shelter site on the Indonesian island of Sulawesi

This paper presents a reassessment of the archaeological record at Leang Burung 2, a key early human occupation site in the Late Pleistocene of Southeast Asia. Excavated originally by Ian Glover in 1975, this limestone rock-shelter in the Maros karsts of Sulawesi, Indonesia, has long held significance in our understanding of early human dispersals into \u27Wallacea\u27, the vast zone of oceanic islands between continental Asia and Australia. We present new stratigraphic information and dating evidence from Leang Burung 2 collected during the course of our excavations at this site in 2007 and 2011-13. Our findings suggest that the classic Late Pleistocene modern human occupation sequence identified previously at Leang Burung 2, and proposed to span around 31,000 to 19,000 conventional 14C years BP (~35-24 ka cal BP), may actually represent an amalgam of reworked archaeological materials. Sources for cultural materials of mixed ages comprise breccias from the rear wall of the rock-shelter-remnants of older, eroded deposits dated to 35-23 ka cal BP-and cultural remains of early Holocene antiquity. Below the upper levels affected by the mass loss of Late Pleistocene deposits, our deep-trench excavations uncovered evidence for an earlier hominin presence at the site. These findings include fossils of now-extinct proboscideans and other \u27megafauna\u27 in stratified context, as well as a cobble-based stone artifact technology comparable to that produced by late Middle Pleistocene hominins elsewhere on Sulawesi