'Immunotherapeutic Strategies for Intra-cranial Metastatic Melanoma - a Meta-analysis and Systematic Review'.

Immune-activating anti-CTLA4 and anti-PD1 monoclonal antibodies (alone or in combination) are being used to treat advanced melanoma patients and can lead to durable remissions, and long-term overall survival may be achieved in between 50-60% of patients. Although intracranial metastases are very common in melanoma (about 50-75% of all patients with advanced disease), most of the pivotal prospective clinical trials exclude patients with intra-cranial metastases, certainly if their lesions are symptomatic and steroid-requiring and the degree of sensitivity of intra-cranial melanoma to immunotherapy remains uncertain, and requires further investigation especially in view of the demonstrable activity of RAF-MEK inhibitors in this clinical setting and the emergence of stereotactic radiotherapy. Our study aimed to evaluate the efficacy and toxicity of immunotherapy against advanced melanoma patients with brain metastases. In terms of comparative studies, only retrospective analyses could be identified. Based on 3 retrospective studies, treatment of patients with melanoma brain metastases with immunotherapeutic approaches improves overall survival substantially compared with supportive measures alone (no active anticancer treatment). The efficacy of targeted therapy appeared to be comparable to that of immune therapy in terms of overall survival, based on a small number of patients. The combination of concurrent radiation therapy to the brain and systemic immunotherapy led to improved overall survival compared to radiotherapy alone, suggesting potential synergism between the approaches, and combination treatment could be delivered safely. Our review supports the use of immunotherapeutic strategies for these patients although treatment efficacy appears to be lower for symptomatic lesions. In view of the extremely high efficacy of stereotactic radiotherapy approaches in the brain, understanding the interaction between radiotherapy and immunotherapy is vital and should be an area of active investigation.

Integrated plasma proteomics identifies tuberculosis-specific diagnostic biomarkers.

BACKGROUNDNovel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections.METHODSWe applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. Bioinformatic analysis using linear modeling and network correlation analyses identified 118 differentially expressed proteins, significant through 3 complementary analytical pipelines. Candidate biomarkers were subsequently analyzed in 2 validation cohorts of differing ethnicity using antibody-based proximity extension assays.RESULTSTB-specific host biomarkers were confirmed. A 6-protein diagnostic panel, comprising FETUB, FCGR3B, LRG1, SELL, CD14, and ADA2, differentiated patients with pulmonary TB from healthy controls and patients with other respiratory infections with high sensitivity and specificity in both cohorts.CONCLUSIONThis biomarker panel exceeds the World Health Organization Target Product Profile specificity criteria for a triage test for TB. The new biomarkers have potential for further development as near-patient TB screening assays, thereby helping to close the case-detection gap that fuels the global pandemic.FUNDINGMedical Research Council (MRC) (MR/R001065/1, MR/S024220/1, MR/P023754/1, and MR/W025728/1); the MRC and the UK Foreign Commonwealth and Development Office; the UK National Institute for Health Research (NIHR); the Wellcome Trust (094000, 203135, and CC2112); Starter Grant for Clinical Lecturers (Academy of Medical Sciences UK); the British Infection Association; the Program for Advanced Research Capacities for AIDS in Peru at Universidad Peruana Cayetano Heredia (D43TW00976301) from the Fogarty International Center at the US NIH; the UK Technology Strategy Board/Innovate UK (101556); the Francis Crick Institute, which receives funding from UKRI-MRC (CC2112); Cancer Research UK (CC2112); and the NIHR Biomedical Research Centre of Imperial College NHS.

Evaluating the impact of pre-hospital trauma team activation criteria.

BACKGROUND: Little evidence exists studying the benefits of pre-hospital trauma team activation. Our study measured the impact of pre-hospital trauma team activation on 24-h survival. Our secondary objectives assessed the effects of pre-hospital trauma team activation on time to emergency procedure, computed tomography, blood transfusion, and critical administration threshold, as well as emergency department length of stay. METHODS: We conducted a 40-month health records review on all trauma team activations at The Ottawa Hospital, a Level 1 Trauma Center. Outcomes were compared between pre-hospital and in-hospital trauma team activations. We used logistic and linear regression models to assess outcomes, while controlling for injury severity score, age, systolic blood pressure, and anti-coagulation use. A P value < 0.05 was considered statistically significant. A sensitivity analysis was also used to validate the primary outcome results. RESULTS: Of the 1013 trauma team activations occurring during the study period, 762 patients were included. The mean age (41.3 vs. 43.8) and percentage of males (79.4% vs. 77.5%) for pre-hospital activations were similar to their counterparts. Pre-hospital activations did not have a statistically significant effect on 24-h mortality (14.4% vs. 4.5%; P = 0.30). However, pre-hospital activations did demonstrate a statistically significant reduction in time (minutes) to emergency procedure (18.0 vs. 27.0; P < 0.001), computed tomography (37.0 vs 42.0; P = 0.009), and blood transfusion (14.0 vs. 28.0; P < 0.001), as well as emergency department length of stay (101.0 vs. 171.0; P < 0.001). CONCLUSION: When controlling for key covariates, pre-hospital trauma team activation did not have a significant effect on 24-h mortality, but did result in a significant reduction in time to emergency procedure, computed tomography, and blood transfusion, as well as emergency department length of stay. Our study demonstrates that pre-hospital trauma team activation can expedite patient intervention and disposition.

RéSUMé: CONTEXTE: Il existe peu de données sur les avantages de l'activation de l'équipe de traumatologie préhospitalière. Notre étude a mesuré l'impact de l'activation de l'équipe de traumatologie pré-hospitalière sur la survie à 24 heures. Nos objectifs secondaires ont évalué les effets de l'activation de l'équipe de traumatologie préhospitalière sur le délai de la procédure d'urgence, de la tomodensitométrie, de la transfusion sanguine et du seuil d'administration critique, ainsi que sur la durée du séjour dans les services d'urgence. MéTHODES: Nous avons procédé à un examen des dossiers médicaux sur 40 mois pour toutes les activations de l'équipe de traumatologie à l'Hôpital d'Ottawa, un centre de traumatologie de niveau 1. Les résultats ont été comparés entre les activations des équipes de traumatologie pré-hospitalières et intra-hospitalières. Nous avons utilisé des modèles de régression logistique et linéaire pour évaluer les résultats, tout en contrôlant le score de gravité des blessures, l'âge, la pression artérielle systolique et l'utilisation d'anticoagulants. Une valeur P < 0.05 a été considérée comme statistiquement significative. Une analyse de sensibilité a également été utilisée pour valider les résultats primaires. RéSULTATS: Sur les 1013 activations d'équipes de traumatologie survenues pendant la période de l'étude, 762 patients ont été inclus. L'âge moyen (41.3 contre 43.8) et le pourcentage d'hommes (79.4% contre 77.5%) pour les activations préhospitalières étaient similaires à ceux de leurs homologues. Les activations préhospitalières n'ont pas eu d'effet statistiquement significatif sur la mortalité à 24 heures (14.4% contre 4.5%; P = 0.30). Cependant, les activations préhospitalières ont démontré une réduction statistiquement significative du temps (minutes) nécessaire à la procédure d'urgence (18.0 contre 27.0; P < 0.001), à la tomodensitométrie (37.0 contre 42.0; P = 0.009) et à la transfusion sanguine (14.0 contre 0.009). 28.0; P < 0.001), ainsi que la durée du séjour aux urgences (101.0 contre 171.0; P < 0.001). CONCLUSION: En tenant compte des principales covariables, l'activation de l'équipe de traumatologie préhospitalière n'a pas eu d'effet significatif sur la mortalité à 24 heures, mais a entraîné une réduction significative du temps nécessaire à l'intervention d'urgence, à la tomodensitométrie et à la transfusion sanguine, ainsi que de la durée de séjour dans les services d'urgence.

Natural history and variability in albuminuria in pediatric and murine sickle cell anemia.

It is critical to characterize the natural history of albuminuria in patients with sickle cell anemia (SCA); however, these data are currently lacking and affecting evidence-based guidelines. We performed a natural history study of the development of pediatric albuminuria. We identified participants with hemoglobin SS/SB0 thalassemia ≥5 years with albumin to creatinine ratio (ACR) measurements performed at a steady-state clinic visit. Participants were characterized as either persistent, intermittent, or never albuminuria. We determined the prevalence of persistent albuminuria, use of ACR ≥100 mg/g as a predictor, and variation in ACR measurements. We mirrored this study to determine the variation in albuminuria measurements in the SCA murine model. Among 355 participants with HbSS/SB0 thalassemia with 1728 ACR measurements, we identified 17% with persistent and 13% with intermittent albuminuria. Thirteen percent of participants with persistent albuminuria developed an abnormal ACR before 10 years of age. A single ACR measurement ≥100 mg/g was associated with 55.5 times (95% confidence interval, 12.3-527) higher odds of having persistent albuminuria. Among participants with ACR ≥100 mg/g, we identified significant variability in the results of repeated measurements. The median ACR at the initial and next measurements were 175.8 mg/g (interquartile range [IQR], 135-242) and 117.3 mg/g (IQR, 64-292). The human variability in ACR was mirrored by ∼20% variability in albuminuria in murine model. This evidence suggests adopting standards for repeating ACR measurements, consider screening for ACR before 10 years of age, and using an ACR >100 mg/g as a risk factor for progression. Pediatric and murine renoprotective clinical trials need to consider the high variability in repeated ACR measurements.

Factors associated with oral anticoagulant prescription status among patients with a new diagnosis of atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and increases stroke risk. Treatment with oral anticoagulants (OACs) may reduce this risk however many patients do not receive OAC therapy. This study aimed to use electronic health record data to identify newly diagnosed AF patients at high risk for stroke and not anticoagulated as well as factors associated with OAC prescription. HYPOTHESIS: Timely prescription of OACs among patients with newly diagnosed AF is poor. METHODS: We performed a retrospective study of patients with a new diagnosis of AF. We assessed stroke risk with the CHA2 DS2 -VASc score. The primary outcome was prescription of an OAC within 6 months following diagnosis. We used logistic regression to see how the odds of being prescribed an OAC differs for 17 independent variables. RESULTS: We identified 18 404 patients with a new diagnosis of AF. Among patients at high risk for stroke, 41.3% received an OAC prescription within 6 months. Male sex, Caucasian compared to African American race, stroke, obesity, congestive heart failure, vascular disorder, current antiplatelet, beta blocker, or calcium channel blocker prescription, and increasing CHA2 DS2 -VASc score were positively associated with receiving an OAC. Whereas anemia, renal dysfunction, liver dysfunction, antiarrhythmic drug use and increasing HAS-BLED score were negatively associated. CONCLUSIONS: Most newly diagnosed AF patients at high stroke risk do not receive an OAC prescription in the first 6 months following diagnosis. Our analysis suggests that patient sex, race, comorbidities, and additional prescriptions are associated with rates of OAC prescribing.

Transcranial Photobiomodulation Treatment: Significant Improvements in Four Ex-Football Players with Possible Chronic Traumatic Encephalopathy.

Background: Chronic traumatic encephalopathy, diagnosed postmortem (hyperphosphorylated tau), is preceded by traumatic encephalopathy syndrome with worsening cognition and behavior/mood disturbances, over years. Transcranial photobiomodulation (tPBM) may promote improvements by increasing ATP in compromised/stressed cells and increasing local blood, lymphatic vessel vasodilation. Objective: Aim 1: Examine cognition, behavior/mood changes Post-tPBM. Aim 2: MRI changes - resting-state functional-connectivity MRI: salience, central executive, default mode networks (SN, CEN, DMN); magnetic resonance spectroscopy, cingulate cortex. Methods: Four ex-players with traumatic encephalopathy syndrome/possible chronic traumatic encephalopathy, playing 11- 16 years, received In-office, red/near-infrared tPBM to scalp, 3x/week for 6 weeks. Two had cavum septum pellucidum. Results: The three younger cases (ages 55, 57, 65) improved 2 SD (p < 0.05) on three to six neuropsychological tests/subtests at 1 week or 1 month Post-tPBM, compared to Pre-Treatment, while the older case (age 74) improved by 1.5 SD on three tests. There was significant improvement at 1 month on post-traumatic stress disorder (PTSD), depression, pain, and sleep. One case discontinued narcotic pain medications and had reduced tinnitus. The possible placebo effect is unknown. At 2 months Post-tPBM, two cases regressed. Then, home tPBM was applied to only cortical nodes, DMN (12 weeks); again, significant improvements were seen. Significant correlations for increased SN functional connectivity (FC) over time, with executive function, attention, PTSD, pain, and sleep; and CEN FC, with verbal learning/memory, depression. Increased n-acetyl-aspartate (NAA) (oxygen consumption, mitochondria) was present in anterior cingulate cortex (ACC), parallel to less pain and PTSD. Conclusion: After tPBM, these ex-football players improved. Significant correlations of increased SN FC and CEN FC with specific cognitive tests and behavior/mood ratings, plus increased NAA in ACC support beneficial effects from tPBM.

Machine learning methods applied to audit of surgical margins after curative surgery for facial (non-melanoma) skin cancer.

We aimed to build a model to predict positive margin status after curative excision of facial non-melanoma skin cancer based on known risk factors that contribute to the complexity of the case mix. A pathology output of consecutive histology reports was requested from three oral and maxillofacial units in the south east of England. The dependent variable was a deep margin with peripheral margin clearance at a 0.5 mm threshold. A total of 3354 cases were analysed. Positivity of either the peripheral or deep margin for both squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) was 15.4% at Unit 1, 21.1% at Unit 2, and 15.4% at Unit 3. Predictive models accounting for patient and tumour factors were developed using automated machine learning methods. The champion models demonstrated good discrimination for predicting margin status after excision of BCCs (AUROC = 0.67) and SCCs (AUROC = 0.71). We demonstrate that rates of positive excision margins of facial non-melanoma skin cancer (fNMSC), when adjusted by the risk prediction model, can be used to compare unit performance fairly once variations in tumour factors and patient factors are accounted for.

Differences in cardiac testing resource utilization using two different risk stratification schemes.

OBJECTIVE: Assess whether changing an emergency department (ED) chest pain pathway from utilizing the Thrombolysis in Myocardial Infarction (TIMI) score for risk stratification to an approach utilizing the History, EKG, Age, Risk, Troponin (HEART) score was associated with reductions in healthcare resource utilization. METHODS: A retrospective, quasi-experimental study using difference-in-differences and interrupted time series specifications evaluated all ED patients with a chest pain encounter from 8/2015 to 7/2019 at a large academic medical center. We included patients age ≥ 18 with negative troponin testing discharged from the ED. Our standardized care pathway utilized TIMI for risk stratification until 09/2017 and HEART thereafter. We evaluated patients undergoing hospital-based cardiac diagnostic testing (CDT), length of stay (LOS), and 30-day Major Adverse Cardiovascular Events (MACE) at the intervention site before and after the pathway change and compared these outcomes to a similar control site within the health system for the difference-in-differences specification. RESULTS: During the study period, 6.3% (450 of 7117) of patients in the TIMI cohort and 7.2% (546 of 7623) in the HEART cohort among 400,965 total ED visits underwent CDT. In a multivariable analysis, transition to the HEART pathway was associated with greater odds of receiving CDT (odds ratio 2.88 [95% CI 1.21 to 6.86]), a reduction in LOS of 34 min (95% CI 2.2 to 67.6), and no significant difference in 30-day MACE. CONCLUSION: The transition from TIMI to HEART was associated with mixed consequences for healthcare resource utilization, including increased CDT but reduced length of stay.

Machine learning methods applied to risk adjustment of cumulative sum chart methodology to audit free flap outcomes after head and neck surgery.

We describe a risk adjustment algorithm to benchmark and report free flap failure rates after immediate reconstruction of head and neck defects. A dataset of surgical care episodes for curative surgery for head and neck cancer and immediate reconstruction (n = 1593) was compiled from multiple NHS hospitals (n = 8). The outcome variable was complete flap failure. Classification models using preoperative patient demographic data, operation data, functional status data and tumour stage data, were built. Machine learning processes are described to model free flap failure. Overall complete flap failure was uncommon (4.7%) with a non-statistical difference seen between hospitals. The champion predictive model had acceptable discrimination (AUROC 0.66). This model was used to risk-adjust cumulative sum (CuSUM) charts. The use of CuSUM charts is a viable way to monitor in a 'Live Dashboard' this quality metric as part of the quality outcomes in oral and maxillofacial surgery audit.

Pathways for the rehabilitation of resection defects in the maxilla.

Oral rehabilitation of head and neck cancer patients is an integral component of the care pathway. Maxillectomy procedures can cause significant defects, such as oronasal fistulas, loss of support for the cheek and lip, aesthetic defects in the middle third of the face and functional impairments. Orofacial rehabilitation plays a fundamental role in restoring aesthetics and functional capabilities, such as speech, mastication and deglutition.Rehabilitation of maxillectomy patients poses a challenge for both clinicians and patients. This paper utilises case examples to demonstrate the treatment options for the oral rehabilitation of these patients. We will summarise the treatment pathways for conventional obturators, delayed (secondary) implant retained fixed rehabilitation following composite free flap and early rehabilitation using a zygomatic implant perforated flap technique. This paper aims to highlight the challenges in treatment planning and the importance of a multidisciplinary approach in improving patient outcomes.

The association between non-ventilator associated hospital acquired pneumonia and patient outcomes among U.S. Veterans.

BACKGROUND: Non-ventilator associated hospital acquired pneumonia (NV-HAP) affects approximately 1 in 100 hospitalized patients yet risk-adjusted outcomes associated with developing NV-HAP are unknown. METHODS: Retrospective cohort study with propensity score matched populations (NV-HAP vs no NV-HAP), using ICD-10 codes for bacterial pneumonia not present on admission. Outcomes included the patient level probability of NV-HAP developing among acute care non-transfer admissions in 133 Veterans Affairs hospitals and subsequent mortality, length of stay, inpatient sepsis, and 12-month costs. RESULTS: NV-HAP occurred in 0.6% of Veteran admissions. Among admissions that developed NV-HAP, the mean length of stay of 26.3 days (6.72 days among non-NV-HAP), 30-day mortality was 18.4% (4.5% among non-NV-HAP), 1-year mortality was 47.8% (21.4% among non-NV-HAP), and total median 12-month direct medical costs were $138,136.32 ($64,357.21 among non-NV-HAP). Inpatient sepsis occurred in approximately 20% of NV-HAP admissions (0.7% among non-NV-HAP). Data available at admission was insufficient to identify high and low risk patient groups. CONCLUSIONS: NV-HAP is associated with severely worse patient outcomes and increased costs of care up to 12 months post-episode. Since population risk stratification is not feasible, prevention efforts should be directed at the full population of hospitalized Veterans.

Interscalene Brachial Plexus Block with Liposomal Bupivacaine versus Standard Bupivacaine with Perineural Dexamethasone: A Noninferiority Trial.

BACKGROUND: The interscalene nerve block provides analgesia for shoulder surgery. To extend block duration, provide adequate analgesia, and minimize opioid consumption, the use of adjuvants such as dexamethasone as well as the application of perineural liposomal bupivacaine have been proposed. This randomized, double-blinded, noninferiority trial hypothesized that perineural liposomal bupivacaine is noninferior to standard bupivacaine with perineural dexamethasone in respect to average pain scores in the first 72 h after surgery. METHODS: A total of 112 patients undergoing ambulatory shoulder surgery were randomized into two groups. The liposomal bupivacaine group received a 15-ml premixed admixture of 10 ml of 133 mg liposomal bupivacaine and 5 ml of 0.5% bupivacaine (n = 55), while the bupivacaine with dexamethasone group received an admixture of 15 ml of 0.5% standard bupivacaine with 4 mg dexamethasone (n = 56), respectively. The primary outcome was the average numerical rating scale pain scores at rest over 72 h. The mean difference between the two groups was compared against a noninferiority margin of 1.3. Secondary outcomes were analgesic block duration, motor and sensory resolution, opioid consumption, numerical rating scale pain scores at rest and movement on postoperative days 1 to 4 and again on postoperative day 7, patient satisfaction, readiness for postanesthesia care unit discharge, and adverse events. RESULTS: A liposomal bupivacaine group average numerical rating scale pain score over 72 h was not inferior to the bupivacaine with dexamethasone group (mean [SD], 2.4 [1.9] vs. 3.4 [1.9]; mean difference [95% CI], -1.1 [-1.8, -0.4]; P < 0.001 for noninferiority). There was no significant difference in duration of analgesia between the groups (26 [20, 42] h vs. 27 [20, 39] h; P = 0.851). Motor and sensory resolutions were similar in both groups: 27 (21, 48) h versus 27 (19, 40) h (P = 0.436) and 27 [21, 44] h versus 31 (20, 42) h (P = 0.862), respectively. There was no difference in opioid consumption, readiness for postanesthesia care unit discharge, or adverse events. CONCLUSIONS: Interscalene nerve blocks with perineural liposomal bupivacaine provided effective analgesia similar to the perineural standard bupivacaine with dexamethasone. The results show that bupivacaine with dexamethasone can be used interchangeably with liposomal bupivacaine for analgesia after shoulder surgery.

Comparison of electrodiagnosis, neurosonography and MR neurography in localization of ulnar neuropathy at the elbow.

INTRODUCTION: In patients with ulnar neuropathy at the elbow (UNE) the precise determination of the site of lesion is important for subsequent differential diagnostic considerations and therapeutic management. Due to a paucity of comparable data, to better define the role of different diagnostic tests, we performed the first prospective study comparing the diagnostic accuracy of short segment nerve stimulation, nerve ultrasonography, MR neurography (MRN), and diffusion tensor imaging (DTI) in patients with UNE. METHODS: UNE was clinically diagnosed in 17 patients with 18 affected elbows. For all 18 affected elbows in patients and 20 elbows in 10 healthy volunteers, measurements of all different diagnostic tests were performed at six anatomical positions across the elbow with measuring points from distal (D4) to proximal (P6) in relation to the medial epicondyle (P0). Additional qualitative assessment regarding structural changes of surrounding nerve anatomy was conducted. RESULTS: The difference between affected arms of patients and healthy control arms were most frequently the largest at measure intervals D2 to P0 and P0 to P2 for electrophysiological testing, or measure points P0 and P2 for all other devices, respectively. At both levels P0 and at P2, T2 contrast-to-noise ratio (CNR) of MRN and mean diffusivity (MD) of DTI-based MRN showed best accuracies. DISCUSSION: This study revealed differences in diagnostic performance of tests concerning a specific location of UNE, with better results for T2 contrast to noise ratio (CNR) in MRN and mean diffusivity of DTI-based MRN. Additional testing with MRN and nerve ultrasonography is recommended to uncover anatomical changes.

Loss of FANCD2 and related proteins may predict malignant transformation in oral epithelial dysplasia.

OBJECTIVE: Predicting malignant transformation (MT) in oral epithelial dysplasia (OED) is challenging. The higher rate of MT reported in nonsmokers suggests an endogenous etiology in oncogenesis. We hypothesize that loss of FANCD2 and associated proteins could influence genomic instability and MT in the absence of environmental carcinogens. STUDY DESIGN: Longitudinal archival samples were obtained from 40 individuals with OED: from diagnosis to the most recent review in 23 patients with stable OED or until excision of the squamous cell carcinoma in 17 patients with unstable OED undergoing MT. Histopathological reassessment, immunohistochemistry for FANCD2, and Western blotting for phosphorylation/monoubiquitylation status of ATR, CHK1, FANCD2, and FANCG were undertaken on each tissue sample. RESULTS: Decreased expression of FANCD2 was observed in the diagnostic biopsies of OED lesions that later underwent MT. Combining the FANCD2 expression scores with histologic grading more accurately predicted MT (P = .005) than histology alone, and it correctly predicted MT in 10 of 17 initial biopsies. Significantly reduced expression of total FANCD2, pFANCD2, pATR, pCHK-1, and pFANCG was observed in unstable OED. CONCLUSIONS: There is preliminary evidence that defects in the DNA damage sensing/signaling/repair cascade are associated with MT in OED. Loss of expression of FANCD2 protein in association with a higher histologic grade of dysplasia offered better prediction of MT than clinicopathologic parameters alone.

Advancing diagnostic performance and clinical usability of neural networks via adversarial training and dual batch normalization.

Unmasking the decision making process of machine learning models is essential for implementing diagnostic support systems in clinical practice. Here, we demonstrate that adversarially trained models can significantly enhance the usability of pathology detection as compared to their standard counterparts. We let six experienced radiologists rate the interpretability of saliency maps in datasets of X-rays, computed tomography, and magnetic resonance imaging scans. Significant improvements are found for our adversarial models, which are further improved by the application of dual-batch normalization. Contrary to previous research on adversarially trained models, we find that accuracy of such models is equal to standard models, when sufficiently large datasets and dual batch norm training are used. To ensure transferability, we additionally validate our results on an external test set of 22,433 X-rays. These findings elucidate that different paths for adversarial and real images are needed during training to achieve state of the art results with superior clinical interpretability.

SAVER: sodium valproate for the epigenetic reprogramming of high-risk oral epithelial dysplasia-a phase II randomised control trial study protocol.

BACKGROUND: Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study. METHODS: One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial. DISCUSSION: The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial. TRIAL REGISTRATION: The trial is registered with the European Clinical Trials Database ( Eudra-CT 2018-000197-30 ). ( http://www.isrctn.com/ISRCTN12448611 ). The trial was prospectively registered on 24/04/2018.

Improving quality of life through the routine use of the patient concerns inventory for head and neck cancer patients: main results of a cluster preference randomised controlled trial.

PURPOSE: The patient concerns inventory (PCI) is a prompt list allowing head and neck cancer (HNC) patients to discuss issues that otherwise might be overlooked. This trial evaluated the effectiveness of using the PCI at routine outpatient clinics for one year after treatment on health-related QOL (HRQOL). METHODS: A pragmatic cluster preference randomised control trial with 15 consultants, 8 'using' and 7 'not using' the PCI intervention. Patients treated with curative intent (all sites, disease stages, treatments) were eligible. RESULTS: Consultants saw a median (inter-quartile range) 16 (13-26) patients, with 140 PCI and 148 control patients. Of the pre-specified outcomes, the 12-month results for the mean University of Washington Quality of Life (UW-QOLv4) social-emotional subscale score suggested a small clinical effect of intervention of 4.6 units (95% CI 0.2, 9.0), p = 0.04 after full adjustment for pre-stated case-mix. Results for UW-QOLv4 overall quality of life being less than good at 12 months (primary outcome) also favoured the PCI with a risk ratio of 0.83 (95% CI 0.66, 1.06) and absolute risk 4.8% (- 2.9%, 12.9%) but without achieving statistical significance. Other non-a-priori analyses, including all 12 UWQOL domains and at consultant level also suggested better HRQOL with PCI. Consultation times were unaffected and the number of items selected decreased over time. CONCLUSION: This novel trial supports the integration of the PCI approach into routine consultations as a simple low-cost means of benefiting HNC patients. It adds to a growing body of evidence supporting the use of patient prompt lists more generally.

UK consensus recommendations on the management of oral epithelial dysplasia during COVID-19 pandemic outbreaks.

OBJECTIVES: Oral Epithelial Dysplasia (OED) is associated with an increased risk of oral cancer development. The SARS-CoV-2 pandemic is necessitating the suspension or dramatic reduction of face-to-face non-urgent elective services, including OED clinics. Little is known regarding the potential impact of elective services suspension upon the risk of OED progression, and whether alternative strategies (e.g. remote consultations) may be introduced to ensure OED surveillance. The aim of this paper is to provide expert-opinion consensus recommendations for the management of OED during the current and future pandemic outbreaks. MATERIALS AND METHODS: A working group of nine UK-based senior clinicians and academics in Oral and Maxillofacial Surgery and Oral Medicine was created and twelve consensus statements were developed using a modified-Delphi process. Greater than 80% agreement was considered a consensus. RESULTS: Consensus was achieved for all twelve statements (89-100% agreement). The group agreed that, during the temporary suspension of elective services associated with COVID-19 pandemic outbreaks, patients with OED can be risk stratified to determine the length of accepted delay in face-to-face consultation. Remote consultations with patient-provided clinical photographs may be a useful way of maintaining a level of surveillance in this group of patients. CONCLUSIONS: Using an expert working group methodology, we have developed consensus recommendations for the monitoring of individuals with OED during pandemic outbreaks associated with temporary suspension of elective services. This has identified areas of future research and highlighted the need for a stronger evidence base to inform the set-up and delivery of surveillance regimens for patients with OED.