Statistical analysis plan for the TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation of potentially clinically significant prostate cancer) multicentre randomised controlled trial

Background: The TRANSLATE (TRANSrectal biopsy versus Local Anaesthetic Transperineal biopsy Evaluation) trial assesses the clinical and cost-effectiveness of two biopsy procedures in terms of detection of clinically significant prostate cancer (PCa). This article describes the statistical analysis plan (SAP) for the TRANSLATE randomised controlled trial (RCT). Methods/design: TRANSLATE is a parallel, superiority, multicentre RCT. Biopsy-naïve men aged ≥ 18 years requiring a prostate biopsy for suspicion of possible PCa are randomised (computer-generated 1:1 allocation ratio) to one of two biopsy procedures: transrectal (TRUS) or local anaesthetic transperineal (LATP) biopsy. The primary outcome is the difference in detection rates of clinically significant PCa (defined as Gleason Grade Group ≥ 2, i.e. any Gleason pattern ≥ 4 disease) between the two biopsy procedures. Secondary outcome measures are th eProBE questionnaire (Perception Part and General Symptoms) and International Index of Erectile Function (IIEF, Domain A) scores, International Prostate Symptom Score (IPSS) values, EQ-5D-5L scores, resource use, infection rates, complications, and serious adverse events. We describe in detail the sample size calculation, statistical models used for the analysis, handling of missing data, and planned sensitivity and subgroup analyses. This SAP was pre-specified, written and submitted without prior knowledge of the trial results. Discussion: Publication of the TRANSLATE trial SAP aims to increase the transparency of the data analysis and reduce the risk of outcome reporting bias. Any deviations from the current SAP will be described and justified in the final study report and results publication. Trial registration: International Standard Randomised Controlled Trial Number ISRCTN98159689, registered on 28 January 2021 and registered on the ClinicalTrials.gov (NCT05179694) trials registry

The kinetics and product state distributions from gas-phase reactions of small atomic and molecular cations with C₂H₄, C₂H₃F, 1,1-C₂H₂F₂, C₂HF₃ and C₂F₄

Reactions between atomic and small molecular ions with a series of fluorinated ethenes are studied in a selected ion flow tube. Kinetics and product state distributions are measured. The latter are compared with those from photoionisation.</p

Do Clinical Correlates of Knee Osteoarthritis Predict Outcome to Intra-Articular Steroid Injections?

OBJECTIVE:To determine if clinical correlates of knee osteoarthritis(OA) affect likelihood of outcome to intra-articular steroid injections(IASI) in symptomatic knee OA. METHODS:Men and women aged≥40 years with painful knee OA who participated in an open label trial of IASI completed questionnaires and clinical examination. OMERACT-OARSI criteria were used to assess response to therapy in the short-term(within 2-weeks). Among those who initially responded, those whose pain had not returned to within 20% of the baseline KOOS-pain score at 6-months were characterised as longer-term responders. Log binomial regression was used to examine factors associated with outcome. RESULTS:199 participants were included, of whom 146(73.4%) were short-term and 40(20.1%) longer-term responders. Compared to short-term non-responders, participants with medial joint-line tenderness(RR=1.42;1.10-1.82), medial & lateral joint-line tenderness(RR=1.38;1.03-1.84), patellofemoral tenderness(RR=1.27;1.04-1.55), anserine tenderness(RR=1.27;1.06-1.52) and a belief that treatment would be effective(RR/unit increase, [range 0-10]=1.05;1.01-1.09), were more likely to be short-term responders. Aspiration of joint fluid(RR=0.79;0.66-0.95) and previous ligament/meniscus injury(RR=0.63;0.44-0.91) were associated with a reduced risk of being a short-term responder. Compared to initial non-responders and those whose pain recurred within 6-months, participants with higher number of pain sites(RR/unit increase, [range 0-10]=0.83;0.72-0.97), chronic widespread pain(RR=0.32;0.10-0.98), perceived chronicity of disease(RR/unit increase, [range 0-10]=0.86;0.78-0.94) and a higher depression score(RR/unit increase, [range 0-21]=0.89;0.81-0.99) were less likely to be longer-term responders. CONCLUSION:Among patients with symptomatic knee OA, tenderness around the knee was associated with better short-term outcome to IASI. However, clinical-related factors did not predict longer-term response while those with chronic widespread pain and depressive symptoms were less likely to obtain longer-term benefit

The relationship between reductions in knee loading and immediate pain response whilst wearing lateral wedged insoles in knee osteoarthritis.

Studies of lateral wedge insoles (LWIs) in medial knee osteoarthritis (OA) have shown reductions in the average external knee adduction moment (EKAM) but no lessening of knee pain. Some treated patients actually experience increases in the EKAM which could explain the overall absence of pain response. We examined whether, in patients with painful medial OA, reductions in the EKAM were associated with lessening of knee pain. Each patient underwent gait analysis whilst walking in a control shoe and two LWI’s. We evaluated the relationship between change in EKAM and change in knee pain using Spearman Rank Correlation coefficients and tested whether dichotomising patients into biomechanical responders (decreased EKAM) and non-responders (increased EKAM) would identify those with reductions in knee pain. In 70 patients studied, the EKAM was reduced in both LWIs vs. control shoe (-5.21% and -6.29% for typical and supported wedges, respectively). The change in EKAM using LWIs was not significantly associated with the direction of knee pain change. Further, 54% were biomechanical responders, but these persons did not have more knee pain reduction than non-responders. Whilst LWIs reduce EKAM, there is no clearcut relationship between change in medial load when wearing LWIs and corresponding change in knee pain

Exactly Marginal Operators and Duality in Four Dimensional N=1 Supersymmetric Gauge Theory

We show that manifolds of fixed points, which are generated by exactly marginal operators, are common in N=1 supersymmetric gauge theory. We present a unified and simple prescription for identifying these operators, using tools similar to those employed in two-dimensional N=2 supersymmetry. In particular we rely on the work of Shifman and Vainshtein relating the \bt-function of the gauge coupling to the anomalous dimensions of the matter fields. Finite N=1 models, which have marginal operators at zero coupling, are easily identified using our approach. The method can also be employed to find manifolds of fixed points which do not include the free theory; these are seen in certain models with product gauge groups and in many non-renormalizable effective theories. For a number of our models, S-duality may have interesting implications. Using the fact that relevant perturbations often cause one manifold of fixed points to flow to another, we propose a specific mechanism through which the N=1 duality discovered by Seiberg could be associated with the duality of finite N=2 models.Comment: 35 pages, 7 Postscript figures, uses revtex.sty (revised version corrects some important details, tex problems

A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301)

The study was funded and the investigational drug NUC-3373 was supplied by NuCana plc. The centres that conducted this study are National Institute for Health and Care Research (NIHR) Biomedical Research Centres that also receive institutional funding as Cancer Research UK (CRUK) and Experimental Cancer Medicine Centres (ECMC). The Glasgow Experimental Cancer Medicine Centre (ECMC) is funded by Cancer Research UK and The Chief Scientist’s Office, Scotland (grant award A25174).Purpose 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. Patients and methods NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. Results Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0–11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. Conclusion NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. Trial registration Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240.Peer reviewe

Thermally triggerable, anchoring block copolymers for use in aqueous inkjet printing

Towards the goal of shifting from toxic organic solvents to aqueous-based formulations in commercial inkjet printing, a series of well-defined poly[(2-hydroxyethyl acrylate-stat-N-hydroxymethyl acrylamide)-block-propyl methacrylate], P[(HEA-st-HMAA)-b-PMA], amphiphilic block copolymers with varying degrees of polymerization and comonomer compositions were synthesized via reversible addition–fragmentation chain transfer (RAFT) polymerization. Optimized RAFT polymerization conditions were found to allow larger batch synthesis (>20 g scale) without compromise over molecular design control (molecular mass, hydrophobic/hydrophilic balance, dispersity, etc.). The copolymers were subsequently investigated for their crosslinking and adhesive properties, as well as jetting performance, to determine their suitability for use in aqueous ink formulations. Crosslinking was found to occur much faster for copolymers containing more of the crosslinkable HMAA monomer units and at higher molecular masses, allowing control over the required post-deposition processing time. The amphiphilic block copolymers synthesized herein demonstrate enhanced adhesive properties compared to a selection of commercial inks whilst also achieving high print quality and performance for use in aqueous continuous inkjet (CIJ) printing, which is a key step towards greener processes in the packaging industries, where printing onto hydrophobic substrates is needed

Interobserver and intraobserver reliability of clinical assessments in knee osteoarthritis

© 2016 The Journal of Rheumatology. All rights reserved. Objective. Clinical examination of the knee is subject to measurement error. The aim of this analysis was to determine interobserver and intraobserver reliability of commonly used clinical tests in patients with knee osteoarthritis (OA). Methods. We studied subjects with symptomatic knee OA who were participants in an open-label clinical trial of intraarticular steroid therapy. Following standardization of the clinical test procedures, 2 clinicians assessed 25 subjects independently at the same visit, and the same clinician assessed 88 subjects over an interval period of 2-10 weeks; in both cases prior to the steroid intervention. Clinical examination included assessment of bony enlargement, crepitus, quadriceps wasting, knee effusion, joint-line and anserine tenderness, and knee range of movement (ROM). Intraclass correlation coefficients (ICC), estimated kappa (k), weighted kappa (k?), and Bland-Altman plots were used to determine interobserver and intraobserver levels of agreement. Results. Using Landis and Koch criteria, interobserver k scores were moderate for patellofemoral joint (k = 0.53) and anserine tenderness (k = 0.48); good for bony enlargement (k = 0.66), quadriceps wasting (k = 0.78), crepitus (k = 0.78), medial tibiofemoral joint tenderness (k = 0.76), and effusion assessed by ballottement (k = 0.73) and bulge sign (k? = 0.78); and excellent for lateral tibiofemoral joint tenderness (k = 1.00), flexion (ICC = 0.97), and extension (ICC = 0.87) ROM. Intraobserver k scores were moderate for lateral tibiofemoral joint tenderness (k = 0.60); good for crepitus (k = 0.78), effusion assessed by ballottement test (k = 0.77), patellofemoral joint (k = 0.66), medial tibiofemoral joint (k = 0.64), and anserine tenderness (k = 0.73); and excellent for effusion assessed by bulge sign (k? = 0.83), bony enlargement (k = 0.98), quadriceps wasting (k = 0.83), flexion (ICC = 0.99), and extension (ICC = 0.96) ROM. Conclusion. Among individuals with symptomatic knee OA, the reliability of clinical examination of the knee was at least good for the majority of clinical signs of knee OA

An assessment of early colonisation of implant-abutment metal surfaces by single species and co-cultured bacterial periodontal pathogens

Objective Numerous studies have proposed that smooth metal surfaces reduce initial bacterial attachment in the establishment of an early biofilm formation. However, these studies have largely examined single bacterial species, which are not always relevant as pathogens identified as initiators of inflammatory peri-implantitis. This study investigated the adherence of four periodontally-relevant bacterial species to implant and abutment surfaces in current clinical use. Methods Discs of polished cobalt chromium (CoCr-polished) and milled titanium (Ti-milled), representing two clinically relevant surfaces, were prepared and surfaces were characterised. Bacterial species Porphyromonas gingivalis, Fusobacterium nucleatum, Prevotella intermedia and Aggregatibacter actinomycetemcomitans were cultured to mid-log or stationary growth phase. Co-cultures of P. gingivalis, F. nucleatum and P. gingivalis, F. nucleatum, Pr. intermedia were similarly prepared. Bacteria were inoculated onto discs for 2 h, stained with a live/dead fluorescent stain and percentage bacterial coverage was calculated by confocal microscopy and image analysis. Results CoCr-polished discs had smooth surfaces with gentle valley structures, whilst Ti-milled discs had sharp edged peaks. Both discs demonstrated a partial wetting ability capable of initiating bacterial adhesion. P. gingivalis, F. nucleatum and co-cultures, at both mid-log and stationary concentrations, demonstrated equally high coverage of both the smooth CoCr-polished and the rougher Ti-milled metal surfaces. Pr. intermedia and A. actinomycetemcomitans demonstrated lower surface coverage which was slightly higher for Ti-milled. Conclusion Variability was noted in the adherence potential for the respective periodontal pathogens examined. Particularly high adherence was noted for P. gingivalis and F. nucleatum, despite the manufacture of a smooth surface. Clinical significance Both surfaces studied may be used at implant-abutment junctions and both possess an ability to establish a bacterial biofilm containing a periodontally-relevant species. These surfaces are thus able to facilitate the apical migration of bacteria associated with peri-implantitis

A new approach to prevention of knee osteoarthritis: reducing medial load in the contralateral knee

Background. Few if any prevention strategies are available for knee osteoarthritis (OA). In those with symptomatic medial OA, the contralateral knee may be at high risk of disease and a reduction in medial loading in that knee might prevent disease or its progression there. Lateral wedge insoles reduce loading across an affected medial knee but their effect on the contralateral knee is unknown. Methods: To determine the proportion of persons with medial knee OA who had concurrent medial contralateral OA or developed contralateral medial OA later, we examined knee radiographs from the longitudinal Framingham Osteoarthritis Study. Then, to examine an approach to reducing medial load in the contralateral knee, 51 people from a separate study with painful medial tibiofemoral OA underwent gait analysis wearing bilateral controlled shoes with i) no insoles ii) two types of lateral wedge insoles laterally posted by 5 degrees. Primary outcome was the external knee adduction moment (EKAM) in the contralateral knee. Non-parametric confidence intervals were constructed around the median differences in percentage change in the affected and contralateral sides. Results: Of Framingham subjects with medial radiograph knee OA, 137/152 (90%) either had concurrent contralateral medial OA or developed it within 10 years. 43/67 (64%) of those with medial symptomatic knee OA had or developed the same disease state in the contralateral knee. Compared to a control shoe, medial loading was reduced substantially on both the affected (median percentage EKAM change =-4.84%; 95% CI -11.33% to -0.65%) and contralateral sides (median EKAM percentage change -9.34% (95% CI -10.57% to -6.45%). Conclusions: In persons with medial OA, the contralateral knee is also at high risk of medial OA. Bilateral reduction in medial loading in knees by use of strategies such as lateral wedge insoles might not only reduce medial load in affected knees but prevent knee OA or its progression on the contralateral side