Fragment Screening to Identify Inhibitors Targeting Ribosome Binding of Shiga Toxin 2.

Shiga toxins are the main virulence factors of Shiga toxin producing E. coli (STEC) and S. dysenteriae. There is no effective therapy to counter the disease caused by these toxins. The A1 subunits of Shiga toxins bind the C-termini of ribosomal P-stalk proteins to depurinate the sarcin/ricin loop. The ribosome binding site of Shiga toxin 2 has not been targeted by small molecules. We screened a fragment library against the A1 subunit of Shiga toxin 2 (Stx2A1) and identified a fragment, BTB13086, which bound at the ribosome binding site and mimicked the binding mode of the P-stalk proteins. We synthesized analogs of BTB13086 and identified a series of molecules with similar affinity and inhibitory activity. These are the first compounds that bind at the ribosome binding site of Stx2A1 and inhibit activity. These compounds hold great promise for further inhibitor development against STEC infection.

The Proposed 9th Edition TNM Classification of Lung Cancer.

A universal nomenclature of the anatomic extent of lung cancer has been critical for individual patient care as well as research advances. As progress occurs, new details emerge that need to be included in a refined system that aligns with contemporary clinical management issues. The 9th edition TNM classification of lung cancer, which is scheduled to take effect in January of 2025, addresses this need. It is based on a large international database, multidisciplinary input and extensive statistical analyses. Key features of the 9th edition include validation of the significant changes in the T component introduced in the 8th edition, subdivision of N2 after exploration of fundamentally different ways of categorizing the N component, and further subdivision of the M component. This has led to reordering of the TNM combinations included in stage groups, primarily involving stage groups IIA, IIB, IIIA and IIIB. This paper summarizes the analyses and revisions for the TNM classification of lung cancer to familiarize the broader medical community and facilitate implementation of the 9th edition system.

Gate-opening Induced by C8 Aromatics in a Double Diamondoid Coordination Network.

Coordination networks (CNs) that undergo guest-induced structural transformations are of topical interest thanks to their potential utility in separations and storage applications. Herein, we report a double diamondoid (ddi) topology CN, [Ni2(bimpz)2(bdc)2(H2O)] n or X-ddi-2-Ni (H2bdc = 1,4-benzenedicarboxylic acid, bimpz = 3,6-bis(imidazol-1-yl)pyridazine), that undergoes structural transformations induced by C8 isomers, i.e., xylenes (o-xylene, OX; m-xylene, MX; p-xylene, PX) and ethylbenzene (EB). X-ddi-2-Ni was characterized by single-crystal to single-crystal transformations from a nonporous phase, X-ddi-2-Ni-ß, to isostructural C8-loaded phases, namely X-ddi-2-Ni-OX, X-ddi-2-Ni-MX, X-ddi-2-Ni-PX and X-ddi-2-Ni-EB. X-ddi-2-Ni accommodates two C8 isomers per Ni unit, resulting in relatively high uptake (ca. 50 wt %), but with low selectivity toward C8 isomers as found using nuclear magnetic resonance (NMR) and gas chromatography (GC). In addition, a narrow range of gate-opening pressures for each isomer was determined from dynamic vapor sorption, consistent with the nonadaptable nature of the C8-loaded phase determined crystallographically, also supported by modeling.

Competitive oxidation of key pentose phosphate pathway enzymes modulates the fate of intermediates and NAPDH production.

The oxidative phase of the pentose phosphate pathway (PPP) involving the enzymes glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL), and 6-phosphogluconate dehydrogenase (6PGDH), is critical to NADPH generation within cells, with these enzymes catalyzing the conversion of glucose-6-phosphate (G6P) into ribulose-5-phosphate (Ribu5-P). We have previously studied peroxyl radical (ROO•) mediated oxidative inactivation of E. coli G6PDH, 6PGL, and 6PGDH. However, these data were obtained from experiments where each enzyme was independently exposed to ROO•, a condition not reflecting biological reality. In this work we investigated how NADPH production is modulated when these enzymes are jointly exposed to ROO•. Enzyme mixtures (1:1:1 ratio) were exposed to ROO• produced from thermolysis of 100 mM 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH). NADPH was quantified at 340 nm, and protein oxidation analyzed by liquid chromatography with mass spectrometric detection (LC-MS). The data obtained were rationalized using a mathematical model. The mixture of non-oxidized enzymes, G6P and NADP+ generated ∼175 µM NADPH. Computational simulations showed a constant decrease of G6P associated with NADPH formation, consistent with experimental data. When the enzyme mixture was exposed to AAPH (3 h, 37 ºC), lower levels of NADPH were detected (∼100 µM) which also fitted with computational simulations. LC-MS analyses indicated modifications at Tyr, Trp, and Met residues but at lower concentrations than detected for the isolated enzymes. Quantification of NADPH generation showed that the pathway activity was not altered during the initial stages of the oxidations, consistent with a buffering role of G6PDH towards inactivation of the oxidative phase of the pathway.

Open and Endoscopic Gluteus Medius/Minimus Repair Achieves Clinical Success Regardless of Tear Grade: High-Grade Fatty Infiltration Portends Worse Outcomes.

PURPOSE: The primary aim of this study was to evaluate minimum 2-year gluteus medius/minimus repair clinical success rates stratified by the Three-Grade Magnetic Resonance Imaging (MRI)-Based Classification (MRI-Grade). Secondary aims were to evaluate clinical success rates by the surgical approach used at each MRI-Grade and by the Goutallier-Fuchs (GF) classification. METHODS: A retrospective review identified patients who underwent primary endoscopic or open gluteus medius/minimus repair from 2012 to 2021 by a single surgeon. Preoperative MRIs were classified using the MRI-Grade and GF classifications. Patient reported outcomes (PROs) were collected preoperatively and at minimum 2-year follow-up. Cohort-specific minimal clinically important difference (MCID) and patient acceptable symptomatic state (PASS) achievement was recorded. Clinical success rates, defined as achievement of 2-year MCID or PASS with avoidance of revision surgery, were compared by MRI-Grade, by surgical approach at each MRI-Grade, and by GF classification. RESULTS: A total of 112 patients (MRI Grade 1=71, Grade 2=19, Grade 3=22) were included. MRI-Grade 1 patients underwent endoscopic repair (p<0.001) more often compared to the other groups. The overall clinical success rate was 90%. Clinical success rates by MRI-Grade were: Grade 1=93%, Grade 2=95%, Grade 3=77% (P=0.087). Clinical success rates by the endoscopic and open surgical approaches used at each MRI-Grade were: Grade 1: 93% vs. 90% (P=0.543), Grade 2: 91% vs. 100% (P=1.000), Grade 3: 60% vs. 92% (P=0.135). GF Grade 1 tears achieved a higher rate of clinical success compared to GF Grade 4 tears (100% vs. 71%, P=0.030). CONCLUSION: Primary repair of gluteus medius/minimus tears resulted in clinical success in most patients irrespective of MRI-Grade and irrespective of the surgical approach used at each MRI-Grade, yet GF Grade 1 tears showed a significantly higher clinical success rate compared to GF Grade 4 tears. LEVEL OF EVIDENCE: Prognostic Retrospective Case Series.

Shared and unique transcriptomic signatures of antidepressant and probiotics action in the mammalian brain.

Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action. Intersection of DEG sets against neuropsychiatric GWAS loci, sex-specific transcriptomic portraits of major depressive disorder (MDD), and mouse models of stress and depression reveals significant similarities and differences across treatments. Interestingly, molecular responses in the infralimbic cortex, basolateral amygdala and locus coeruleus are region-specific and highly similar across treatments, whilst responses in the Raphe, medial preoptic area, cingulate cortex, prelimbic cortex and ventral dentate gyrus are predominantly treatment-specific. Mechanistically, ADs concordantly downregulate immune pathways in the amygdala and ventral dentate gyrus. In contrast, protein synthesis, metabolism and synaptic signaling pathways are axes of variability among treatments. We use spatial transcriptomics to further delineate layer-specific molecular pathways and DEGs within the prefrontal cortex. Our study reveals complex AD and probiotics action on the mammalian brain and identifies treatment-specific cellular processes and gene targets associated with mood disorders.

Predictors for the use of systemic therapy in stage IB Mycosis fungoides.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is aprospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) inpatients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB)staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centresin 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smallerpercentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariateanalysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA,20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs.T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%,while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improvedsignificantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices,and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, futuretreatment guidelines for early-stage MF need to address these issues.

Multi-centre digital radiography reject analysis for different clinical room use types: The establishment of local reject reference levels for public hospital departments.

INTRODUCTION: Reject analysis in digital radiography helps guide the training of staff to reduce patient radiation dose and improve department efficiency. The purpose of this study was to perform a multi-centre, vendor agnostic reject analysis across different room usage types, and to provide benchmarks for comparison. METHODS: Retrospective reject and exposure log data were collected via USB from fixed general X-ray systems across multiple Australian sites, for collation and analysis. The overall reject rate, local reject reference level, absolute and relative reject rates for body part categories, reject rates by room usage types and the reject rate for each reason of rejection were calculated. RESULTS: Data were collected from 44 X-ray systems, across 11 hospitals. A total of 2,031,713 acquired images and 172,495 rejected images were included. The median reject rate was 9.1%. The local reject reference level (LRRL), set as the 75th percentile of all reject rates, was 10.6%. Median reject rates by room type were emergency (7.4%), inpatients + outpatients (9.6%), outpatients (9.2%), and hybrid (10.1%). The highest absolute reject rates by body part were chest (2.1%) and knee (1.4%). The highest relative rates by body part were knee (18.1%) and pelvis (17.2%). The most frequent reasons for image rejection were patient positioning (76%) and patient motion (7.5%). CONCLUSIONS: The results compare well with previously published data. The range of reject rates highlights the need to analyse typical reject rates in different ways. With analysis feedback to participating sites and the implementation of standardised reject reasons, future analysis should monitor whether reject rates reduce.

Single-cell transcriptome atlases of soybean root and mature nodule reveal new regulatory programs controlling the nodulation process.

The soybean root system is complex. In addition to being composed of various cell types, the soybean root system includes the primary root, the lateral roots, and the nodule, an organ in which mutualistic symbiosis with the N-fixing rhizobia occurs. A mature soybean root nodule is characterized by a central infection zone where the atmospheric nitrogen is fixed and assimilated by the symbiont, resulting from the close cooperation between the plant cell and the bacteria. To date, the transcriptome of individual cells isolated from developing soybean nodules has been established, but the transcriptomic signatures of the cells of the mature soybean nodule have not yet been characterized. Applying single nucleus RNA-seq and Molecular CartographyTM technologies, we precisely characterized the transcriptomic signature of the soybean root and mature nodule cell types and revealed the co-existence of different sub-populations of B. diazoefficiens-infected cells in the mature soybean nodule including those actively involved in nitrogen fixation, and those engaged in senescence. The mining of the single cell-resolution nodule transcriptome atlas and associated gene co-expression network confirmed the role of known nodulation-related genes and identified new genes controlling the nodulation process. For instance, we functionally characterized the role of GmFWL3, a plasma membrane microdomain-associated protein controlling rhizobia infection. Our study reveals the unique cellular complexity of the mature soybean nodule and helps redefine the concept of cell types when considering the infection zone of the soybean nodule.

Determinants of successful ictal SPECT injection in phase 1 epilepsy presurgical evaluation: Findings from the pediatric epilepsy research consortium surgery database project.

OBJECTIVES: The main goal of presurgical evaluation in drug-resistant focal epilepsy is to identify a seizure onset zone (SOZ). Of the noninvasive, yet resource-intensive tests available, ictal single-photon emission computed tomography (SPECT) aids SOZ localization by measuring focal increases in blood flow within the SOZ via intravenous peri-ictal radionuclide administration. Recent studies indicate that geographic and center-specific factors impact utilization of these diagnostic procedures. Our study analyzed successful ictal SPECT acquisition (defined as peri-ictal injection during inpatient admission) using surgery-related data from the Pediatric Epilepsy Research Consortium (PERC) surgery database. We hypothesized that a high seizure burden, longer duration of video EEG monitoring (VEEG), and more center-specific hours of SPECT availability would increase the likelihood of successful ictal SPECT. METHODS: We identified study participants (≤18 years of age) who underwent SPECT as part of their phase 1 VEEG from January 2018 to June 2022. We assessed association between ictal SPECT outcomes (success vs. failure) and variables including patient demographics, epilepsy history, and center-specific SPECT practices. RESULTS: Phase 1 VEEG monitoring with ictal SPECT injection was planned in 297 participants and successful in 255 participants (85.86%). On multivariable analysis, the likelihood of a successful SPECT injection was higher in patients of non-Hispanic ethnicity (p = 0.040), shorter duration VEEG (p = 0.004), and higher hours of available SPECT services (p < 0.001). Higher seizure frequency (p = 0.033) was significant only in bivariate analysis. Patients treated at centers with more operational hours were more likely to experience pre-admission protocols prior to VEEG (p = 0.002). SIGNIFICANCE: There is inter-center variability in protocols and SPECT acquisition capabilities. Shorter duration of EEG monitoring, non-Hispanic ethnicity (when on private insurance), extended operational hours of nuclear medicine as noted on multivariate analysis and higher seizure frequency in bivariate analysis are strongly associated with successful ictal SPECT injection. PLAIN LANGUAGE SUMMARY: In pediatric patients with drug-resistant epilepsy, single-photon emission computed tomography (SPECT) scans can be helpful in localizing seizure onset zone. However, due to many logistical challenges described below, which include not only the half-life of the technetium isotope used to inject intravenously during a seizure (called the ictal SPECT scan) but also available nuclear scanner time in addition to the unpredictability of seizures, obtaining an ictal SPECT during a planned elective inpatient hospital stay is not guaranteed. Thus, as healthcare costs increase, planning a prolonged hospital stay during which an ictal SPECT scan is not feasible is not optimal. We leveraged our prospective surgery database to look at center-specific factors and patient-specific factors associated with an ictal SPECT injection in the first, pediatric-focussed, large-scale, multicenter, prospective, SPECT feasibility study. We found that longer availability of the scanner is the most important center-specific factor in assuring ictal SPECT injection. Although seizure frequency is an important patient-specific factor on bivariate analysis, this factor lost statistical significance when other factors like patient insurance status and video EEG duration were also considered in our multivariable logistical model.

Developing a core outcome set for acetabular fractures: a systematic review protocol.

BACKGROUND: Clinical trials investigating acetabular fractures are heterogeneous in their investigated outcomes and their corresponding measurements. Standardization may facilitate comparability and pooling of research results, which would lead to an increase in knowledge about the optimal treatment of acetabular fractures, resulting in long-term evidence-based treatment decisions and improvements in patient care. The aim of this systematic review is to identify the reported outcomes and their measurements from studies on treatments for acetabular fractures to develop a core outcome set which contains the most relevant outcome measures to be included in future studies. METHODS: Studies published in English and German including patients aged 16 years and older, with a surgically treated acetabular fracture, will be included. Studies with nonsurgical treatment, pathologic fractures, polytraumatized patients, and patients younger than 16 years of age will be excluded because other outcomes may be of interest in these cases. Any prospective and retrospective study will be included. Systematic reviews will be excluded, but their included studies will be screened for eligibility. The literature will be searched on MEDLINE, CENTRAL, Web of Science, ClinicalTrials.gov, and WHO ICTRP. Risk of selective reporting of outcomes will be assessed using the Outcome Reporting Bias in Trials classification system. Heterogeneously defined outcomes that measure the same outcome will be grouped and subsequently categorized into outcome domains using the taxonomy of the Core Outcome Measures in Effectiveness Trials Initiative. DISCUSSION: It is expected that a high number of studies will be included, and many outcomes will be identified using different definitions and measurement instruments. A limitation of this systematic review is that only previously investigated outcomes will be detected, thus disregarding potentially relevant outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022357644.

GLP-1 RA for cardiometabolic risk reduction in obesity - How do we best describe benefit and value?

How do we assess the overall benefit and value of GLP1-RAs? Current clinical trials often focus narrowly on individual atherosclerotic cardiovascular endpoints like MACE, potentially missing broader GLP-1 RA benefits across multiple comorbidities. Herein, we set out a framework for expanding outcome analyses in large trials that we believe will provide a more holistic understanding of GLP-1 RA benefits across the cardio-kidney-metabolic (CKM) spectrum, guiding patient care, guidelines, and insurance coverage decisions.

What did the transcatheter aortic valve replacement-surgical aortic valve replacement (TAVR-SAVR) trials tell us?

Two families of randomized trials comparing transcatheter aortic valve replacement (TAVR) to surgery for both the Balloon Expandable Valve and the Supra Annular Self-Expanding Valve have been completed to include all surgical risk levels. The result of these trials has led to the approval of TAVR for symptomatic severe aortic stenosis without using risk level as the sole criterion. We have seen an explosion of TAVR in the US to over 98,000 commercial cases in 2022. We have also seen a rapid increase in the use of TAVR in patients less than 65 years of age. With these increases, it is important to ask if they are being driven largely by the data or just the desire for TAVR by both patients and their physicians. Heart team input is a class I indication when deciding between TAVR and surgery. For surgical members of the heart team to appropriately counsel patients, a full understanding of what the TAVR surgery trials tell us as well as what they do not is essential. In this article we will explore those questions.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

A multi-institutional machine learning algorithm for prognosticating facial nerve injury following microsurgical resection of vestibular schwannoma.

Vestibular schwannomas (VS) are the most common tumor of the skull base with available treatment options that carry a risk of iatrogenic injury to the facial nerve, which can significantly impact patients' quality of life. As facial nerve outcomes remain challenging to prognosticate, we endeavored to utilize machine learning to decipher predictive factors relevant to facial nerve outcomes following microsurgical resection of VS. A database of patient-, tumor- and surgery-specific features was constructed via retrospective chart review of 242 consecutive patients who underwent microsurgical resection of VS over a 7-year study period. This database was then used to train non-linear supervised machine learning classifiers to predict facial nerve preservation, defined as House-Brackmann (HB) I vs. facial nerve injury, defined as HB II-VI, as determined at 6-month outpatient follow-up. A random forest algorithm demonstrated 90.5% accuracy, 90% sensitivity and 90% specificity in facial nerve injury prognostication. A random variable (rv) was generated by randomly sampling a Gaussian distribution and used as a benchmark to compare the predictiveness of other features. This analysis revealed age, body mass index (BMI), case length and the tumor dimension representing tumor growth towards the brainstem as prognosticators of facial nerve injury. When validated via prospective assessment of facial nerve injury risk, this model demonstrated 84% accuracy. Here, we describe the development of a machine learning algorithm to predict the likelihood of facial nerve injury following microsurgical resection of VS. In addition to serving as a clinically applicable tool, this highlights the potential of machine learning to reveal non-linear relationships between variables which may have clinical value in prognostication of outcomes for high-risk surgical procedures.

Association between PM2.5 from a coal mine fire and FeNO concentration 7.5 years later.

BACKGROUND AND AIM: There are few long-term studies of respiratory health effects of landscape fires, despite increasing frequency and intensity due to climate change. We investigated the association between exposure to coal mine fire PM2.5 and fractional exhaled nitric oxide (FeNO) concentration 7.5 years later. METHODS: Adult residents of Morwell, who were exposed to the 2014 Hazelwood mine fire over 6 weeks, and unexposed residents of Sale, participated in the Hazelwood Health Study Respiratory Stream in 2021, including measurements of FeNO concentration, a marker of eosinophilic airway inflammation. Individual exposure to coal mine fire PM2.5 was modelled and mapped to time-location diaries. The effect of exposure to PM2.5 on log-transformed FeNO in exhaled breath was investigated using multivariate linear regression models in the entire sample and stratified by potentially vulnerable subgroups. RESULTS: A total of 326 adults (mean age: 57 years) had FeNO measured. The median FeNO level (interquartile range [IQR]) was 17.5 [15.0] ppb, and individual daily exposure to coal mine fire PM2.5 was 7.2 [13.8] µg/m3. We did not identify evidence of association between coal mine fire PM2.5 exposure and FeNO in the general adult sample, nor in various potentially vulnerable subgroups. The point estimates were consistently close to zero in the total sample and subgroups. CONCLUSION: Despite previous short-term impacts on FeNO and respiratory health outcomes in the medium term, we found no evidence that PM2.5 from the Hazelwood coal mine fire was associated with any long-term impact on eosinophilic airway inflammation measured by FeNO levels.

FAIR reporting of clinical trials for public health practice.

The number of clinical trials is rapidly growing, and automation of literature processing is becoming desirable but unresolved. Our purpose was to assess and increase the readiness of clinical trial reports for supporting automated retrieval and implementation in public health practice. We searched the Medline database for a random sample of clinical trials of HIV/AIDS management with likely relevance to public health in Africa. Five authors assessed trial reports for inclusion, extracted data, and assessed quality based on the FAIR principles of scientific data management (findable, accessible, interoperable, and reusable). Subsequently, we categorized reported results in terms of outcomes and essentials of implementation. A sample of 96 trial reports was selected. Information about the tested intervention that is essential for practical implementation was largely missing, including personnel resources needed 32·3% (.95 CI: 22·9-41·6); material/supplies needed 33·3% (.95 CI: 23·9-42·8); major equipment/building investment 42·8% (CI: 33·8-53·7); methods of educating providers 53·1% (CI: 43·1-63·4); and methods of educating the community 27·1% (CI: 18·2-36·0). Overall, 65% of studies measured health/biologic outcomes, among them, only a fraction showed any positive effects. Several specific design elements were identified that frequently make clinical trials unreal and their results unusable. To sort and interpret clinical trial results easier and faster, a new reporting structure, a practice- and retrieval-oriented trial outline with numeric outcomes (PROTON) table was developed and illustrated. Many clinical trials are either inconsequential by design or report incomprehensible results. According to the latest expectations of FAIR scientific data management, all clinical trial reports should include a consistent and practical impact-oriented table of clinical trial results.

The clinical and cost-effectiveness of elective primary total knee replacement with PAtellar Resurfacing compared to selective patellar resurfacing: a pragmatic multicentre randomized controlled Trial (PART).

Aims: During total knee replacement (TKR), surgeons can choose whether or not to resurface the patella, with advantages and disadvantages of each approach. Recently, the National Institute for Health and Care Excellence (NICE) recommended always resurfacing the patella, rather than never doing so. NICE found insufficient evidence on selective resurfacing (surgeon's decision based on intraoperative findings and symptoms) to make recommendations. If effective, selective resurfacing could result in optimal individualized patient care. This protocol describes a randomized controlled trial to evaluate the clinical and cost-effectiveness of primary TKR with always patellar resurfacing compared to selective patellar resurfacing. Methods: The PAtellar Resurfacing Trial (PART) is a patient- and assessor-blinded multicentre, pragmatic parallel two-arm randomized superiority trial of adults undergoing elective primary TKR for primary osteoarthritis at NHS hospitals in England, with an embedded internal pilot phase (ISRCTN 33276681). Participants will be randomly allocated intraoperatively on a 1:1 basis (stratified by centre and implant type (cruciate-retaining vs cruciate-sacrificing)) to always resurface or selectively resurface the patella, once the surgeon has confirmed sufficient patellar thickness for resurfacing and that constrained implants are not required. The primary analysis will compare the Oxford Knee Score (OKS) one year after surgery. Secondary outcomes include patient-reported outcome measures at three months, six months, and one year (Knee injury and Osteoarthritis Outcome Score, OKS, EuroQol five-dimension five-level questionnaire, patient satisfaction, postoperative complications, need for further surgery, resource use, and costs). Cost-effectiveness will be measured for the lifetime of the patient. Overall, 530 patients will be recruited to obtain 90% power to detect a four-point difference in OKS between the groups one year after surgery, assuming up to 40% resurfacing in the selective group. Conclusion: The trial findings will provide evidence about the clinical and cost-effectiveness of always patellar resurfacing compared to selective patellar resurfacing. This will inform future NICE guidelines on primary TKR and the role of selective patellar resurfacing.