Publications by authors named "Rebecca Lewis"

143 Publications

Detecting bad actors in value-based payment models.

Health Serv Outcomes Res Methodol 2021 Jun 28:1-20. Epub 2021 Jun 28.

RTI International, 3040 E. Cornwallis Road, P.O. Box 12194, Research Triangle Park, NC 27709 USA.

The U.S. federal government is spending billions of dollars to test a multitude of new approaches to pay for healthcare. Unintended consequences are a major consideration in the testing of these value-based payment (VBP) models. Since participation is generally voluntary, any unintended consequences may be magnified as VBP models move beyond the early testing phase. In this paper, we propose a straightforward unsupervised outlier detection approach based on ranked percentage changes to identify participants (e.g., healthcare providers) whose behavior may represent an unintended consequence of a VBP model. The only data requirements are repeated measurements of at least one relevant variable over time. The approach is generalizable to all types of VBP models and participants and can be used to address undesired behavior early in the model and ultimately help avoid undesired behavior in scaled-up programs. We describe our approach, demonstrate how it can be applied with hypothetical data, and simulate how efficiently it detects participants who are truly bad actors. In our hypothetical case study, the approach correctly identifies a bad actor in the first period in 86% of simulations and by the second period in 96% of simulations. The trade-off is that 9% of honest participants are mistakenly identified as bad actors by the second period. We suggest several ways for researchers to mitigate the rate or consequences of these false positives. Researchers and policymakers can customize and use our approach to appropriately guard VBP models against undesired behavior, even if only by one participant.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10742-021-00253-9.
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http://dx.doi.org/10.1007/s10742-021-00253-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237252PMC
June 2021

Carbon Nanotube-Based Scaffolds for Cardiac Tissue Engineering-Systematic Review and Narrative Synthesis.

Bioengineering (Basel) 2021 Jun 9;8(6). Epub 2021 Jun 9.

School of Veterinary Medicine, University of Surrey, Guildford, Surrey GU2 7AL, UK.

Cardiovascular disease is currently the top global cause of death, however, research into new therapies is in decline. Tissue engineering is a solution to this crisis and in combination with the use of carbon nanotubes (CNTs), which have drawn recent attention as a biomaterial, could facilitate the development of more dynamic and complex in vitro models. CNTs' electrical conductivity and dimensional similarity to cardiac extracellular proteins provide a unique opportunity to deliver scaffolds with stimuli that mimic the native cardiac microenvironment in vitro more effectively. This systematic review aims to evaluate the use and efficacy of CNTs for cardiac tissue scaffolds and was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Three databases were searched: PubMed, Scopus, and Web of Science. Papers resulting from these searches were then subjected to analysis against pre-determined inclusion and quality appraisal criteria. From 249 results, 27 manuscripts met the criteria and were included in this review. Neonatal rat cardiomyocytes were most commonly used in the experiments, with multi-walled CNTs being most common in tissue scaffolds. Immunofluorescence was the experimental technique most frequently used, which was employed for the staining of cardiac-specific proteins relating to contractile and electrophysiological function.
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http://dx.doi.org/10.3390/bioengineering8060080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228669PMC
June 2021

Like Father Like Son: Cultural and Genetic Contributions to Song Inheritance in an Estrildid Finch.

Front Psychol 2021 4;12:654198. Epub 2021 Jun 4.

Department of Earth and Environmental Sciences, University of Manchester, Manchester, United Kingdom.

Social learning of vocalizations is integral to song inheritance in oscine passerines. However, other factors, such as genetic inheritance and the developmental environment, can also influence song phenotype. The relative contributions of these factors can have a strong influence on song evolution and may affect important evolutionary processes such as speciation. However, relative contributions are well-described only for a few species and are likely to vary with taxonomy. Using archived song data, we examined patterns of song inheritance in a domestic population of Java sparrows (), some of which had been cross-fostered. Six-hundred and seventy-six songs from 73 birds were segmented and classified into notes and note subtypes ( = 22,972), for which a range of acoustic features were measured. Overall, we found strong evidence for cultural inheritance of song structure and of the acoustic characteristics of notes; sons' song syntax and note composition were similar to that of their social fathers and were not influenced by genetic relatedness. For vocal consistency of note subtypes, a measure of vocal performance, there was no apparent evidence of social or genetic inheritance, but both age and developmental environment influenced consistency. These findings suggest that high learning fidelity of song material, i.e., song structure and note characteristics, could allow novel variants to be preserved and accumulate over generations, with implications for evolution and conservation. However, differences in vocal performance do not show strong links to cultural inheritance, instead potentially serving as condition dependent signals.
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http://dx.doi.org/10.3389/fpsyg.2021.654198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8213215PMC
June 2021

Hepatitis A Virus Infections Among Men Who Have Sex with Men - Eight U.S. States, 2017-2018.

MMWR Morb Mortal Wkly Rep 2021 Jun 18;70(24):875-878. Epub 2021 Jun 18.

During 1995-2011, the overall incidence of hepatitis A decreased by 95% in the United States from 12 cases per 100,000 population during 1995 to 0.4 cases per 100,000 population during 2011, and then plateaued during 2012─2015. The incidence increased by 294% during 2016-2018 compared with the incidence during 2013-2015, with most cases occurring among populations at high risk for hepatitis A infection, including persons who use illicit drugs (injection and noninjection), persons who experience homelessness, and men who have sex with men (MSM) (1-3). Previous outbreaks among persons who use illicit drugs and MSM led to recommendations issued in 1996 by the Advisory Committee on Immunization Practices (ACIP) for routine hepatitis A vaccination of persons in these populations (4). Despite these long-standing recommendations, vaccination coverage rates among MSM remain low (5). In 2017, the New York City Department of Health and Mental Hygiene contacted CDC after public health officials noted an increase in hepatitis A infections among MSM. Laboratory testing* of clinical specimens identified strains of the hepatitis A virus (HAV) that subsequently matched strains recovered from MSM in other states. During January 1, 2017-October 31, 2018, CDC received reports of 260 cases of hepatitis A among MSM from health departments in eight states, a substantial increase from the 16 cases reported from all 50 states during 2013-2015. Forty-eight percent (124 of 258) of MSM patients were hospitalized for a median of 3 days. No deaths were reported. In response to these cases, CDC supported state and local health departments with public health intervention efforts to decrease HAV transmission among MSM populations. These efforts included organizing multistate calls among health departments to share information, providing guidance on developing targeted outreach and managing supplies for vaccine campaigns, and conducting laboratory testing of clinical specimens. Targeted outreach for MSM to increase awareness about hepatitis A infection and improve access to vaccination services, such as providing convenient locations for vaccination, are needed to prevent outbreaks among MSM.
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http://dx.doi.org/10.15585/mmwr.mm7024a2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220954PMC
June 2021

The long lives of primates and the 'invariant rate of ageing' hypothesis.

Nat Commun 2021 06 16;12(1):3666. Epub 2021 Jun 16.

Dian Fossey Gorilla Fund International, Atlanta, GA, USA.

Is it possible to slow the rate of ageing, or do biological constraints limit its plasticity? We test the 'invariant rate of ageing' hypothesis, which posits that the rate of ageing is relatively fixed within species, with a collection of 39 human and nonhuman primate datasets across seven genera. We first recapitulate, in nonhuman primates, the highly regular relationship between life expectancy and lifespan equality seen in humans. We next demonstrate that variation in the rate of ageing within genera is orders of magnitude smaller than variation in pre-adult and age-independent mortality. Finally, we demonstrate that changes in the rate of ageing, but not other mortality parameters, produce striking, species-atypical changes in mortality patterns. Our results support the invariant rate of ageing hypothesis, implying biological constraints on how much the human rate of ageing can be slowed.
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http://dx.doi.org/10.1038/s41467-021-23894-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209124PMC
June 2021

Transcriptome-based screening of ion channels and transporters in a migratory chondroprogenitor cell line isolated from late-stage osteoarthritic cartilage.

J Cell Physiol 2021 May 18. Epub 2021 May 18.

Department of Regenerative Medicine, State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.

Chondrogenic progenitor cells (CPCs) may be used as an alternative source of cells with potentially superior chondrogenic potential compared to mesenchymal stem cells (MSCs), and could be exploited for future regenerative therapies targeting articular cartilage in degenerative diseases such as osteoarthritis (OA). In this study, we hypothesised that CPCs derived from OA cartilage may be characterised by a distinct channelome. First, a global transcriptomic analysis using Affymetrix microarrays was performed. We studied the profiles of those ion channels and transporter families that may be relevant to chondroprogenitor cell physiology. Following validation of the microarray data with quantitative reverse transcription-polymerase chain reaction, we examined the role of calcium-dependent potassium channels in CPCs and observed functional large-conductance calcium-activated potassium (BK) channels involved in the maintenance of the chondroprogenitor phenotype. In line with our very recent results, we found that the KCNMA1 gene was upregulated in CPCs and observed currents that could be attributed to the BK channel. The BK channel inhibitor paxilline significantly inhibited proliferation, increased the expression of the osteogenic transcription factor RUNX2, enhanced the migration parameters, and completely abolished spontaneous Ca events in CPCs. Through characterisation of their channelome we demonstrate that CPCs are a distinct cell population but are highly similar to MSCs in many respects. This study adds key mechanistic data to the in-depth characterisation of CPCs and their phenotype in the context of cartilage regeneration.
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http://dx.doi.org/10.1002/jcp.30413DOI Listing
May 2021

Effects of electromagnetic fields on neuronal ion channels: a systematic review.

Ann N Y Acad Sci 2021 May 4. Epub 2021 May 4.

Leverhulme Quantum Biology Doctoral Training Centre, University of Surrey, Guildford, Surrey, UK.

Many aspects of chemistry and biology are mediated by electromagnetic field (EMF) interactions. The central nervous system (CNS) is particularly sensitive to EMF stimuli. Studies have explored the direct effect of different EMFs on the electrical properties of neurons in the last two decades, particularly focusing on the role of voltage-gated ion channels (VGCs). This work aims to systematically review published evidence in the last two decades detailing the effects of EMFs on neuronal ion channels as per the PRISM guidelines. Following a predetermined exclusion and inclusion criteria, 22 papers were included after searches on three online databases. Changes in calcium homeostasis, attributable to the voltage-gated calcium channels, were found to be the most commonly reported result of EMF exposure. EMF effects on the neuronal landscape appear to be diverse and greatly dependent on parameters, such as the field's frequency, exposure time, and intrinsic properties of the irradiated tissue, such as the expression of VGCs. Here, we systematically clarify how neuronal ion channels are particularly affected and differentially modulated by EMFs at multiple levels, such as gating dynamics, ion conductance, concentration in the membrane, and gene and protein expression. Ion channels represent a major transducer for EMF-related effects on the CNS.
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http://dx.doi.org/10.1111/nyas.14597DOI Listing
May 2021

Patterns of surveillance for late effects of BCR-ABL tyrosine kinase inhibitors in survivors of pediatric Philadelphia chromosome positive leukemias.

BMC Cancer 2021 Apr 29;21(1):474. Epub 2021 Apr 29.

Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplantation, Emory University, Atlanta, GA, USA.

Background: Targeted anticancer therapies such as BCR-ABL tyrosine kinase inhibitors (TKIs) have improved outcomes for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, little is known about long-term risks of TKIs in children. Exposure-based survivorship guidelines do not include TKIs, thus surveillance practices may be variable.

Methods: We retrospectively examined surveillance for cardiac and endocrine late effects in children receiving TKIs for Ph + leukemias, diagnosed at < 21 years between 2000 and 2018. Frequency of echocardiogram (ECHO), electrocardiogram (EKG), thyroid stimulating hormone (TSH), dual-energy x-ray absorptiometry (DXA), and bone age testing were abstracted. Descriptive statistics were stratified by leukemia type.

Results: 66 patients (CML n = 44; Ph + ALL n = 22) met inclusion criteria. Among patients with CML, ≥1 evaluation was done: ECHO (50.0%), EKG (48.8%), TSH (43.9%), DXA (2.6%), bone age (7.4%). Among patients with Ph + ALL, ≥1 evaluation was done: ECHO (86.4%), EKG (68.2%), TSH (59.1%), DXA (63.6%), bone age (44.4%). Over a median 6.3 and 5.7 years of observation, respectively, 2% of patients with CML and 57% with Ph + ALL attended a survivorship clinic.

Conclusions: Despite common exposure to TKIs in survivors of Ph + leukemias, patterns of surveillance for late effects differed in CML and Ph + ALL, with the latter receiving more surveillance likely due to concomitant chemotherapy exposures. Targeted therapies such as TKIs are revolutionizing cancer treatment, but surveillance for late effects and referral to survivorship clinics are variable despite the chronicity of exposure. Evidence based guidelines and longer follow-up are needed.
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http://dx.doi.org/10.1186/s12885-021-08182-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082962PMC
April 2021

Letter to the editor regarding 'six-year experience of oncoplastic volume replacement using local perforator flaps' by Quinn et al.

J Plast Reconstr Aesthet Surg 2021 Apr 2. Epub 2021 Apr 2.

The Royal Marsden Hospital NHS Trust, Downs Road, Sutton, SM2 5PT UK.

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http://dx.doi.org/10.1016/j.bjps.2021.03.052DOI Listing
April 2021

Transitioning a home-based, motivational interviewing intervention among families to remote delivery during the COVID-19 pandemic: Key lessons learned.

Patient Educ Couns 2021 Feb 25. Epub 2021 Feb 25.

Department of Family Relations and Applied Nutrition, University of Guelph, Guelph, Canada.

Objective: This study examined the experiences, learnings, and strategies of Health Educators (HE) as they transitioned from a home-based model for motivational interviewing (MI) to remote delivery during COVID-19. The overall goal of this paper is to identify key lessons learned to help inform future delivery of remote MI delivery.

Methods: HE perceptions and experiences regarding the transition from in-person to remote delivery of MI for 21 families were captured through a video recorded discussion. Thematic analysis was used to identify themes and subthemes and key learnings from the transition experience.

Results: Five themes were identified including: 1) Impact of COVID-19 on families; 2) Scheduling, no-shows, and cancellations; 3) Preference of online video versus phone; 4) Building rapport with remote delivery; 5) HE work satisfaction. Based on these results, several key learnings were identified to improve remote MI-counseling, including using online video platforms versus phone calls, providing families the necessary information and technical support to improve acceptability, using specific strategies to enhance rapport and child engagement, and asking probing questions to elicit deeper reflection.

Conclusion: Specific considerations regarding rapport building including more frequent check-ins to demonstrate commitment to the family's success, and effective communication strategies including asking more probing questions that elicit complex reflection can support successful transition of MI-counseling from in-person to remote delivery among families with young children.

Practice Implications: Our practice recommendations based on key learnings from MI practitioners during the transition from in-person to remote MI-counseling can support healthcare professionals looking to transition MI-counseling services to remote delivery.
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http://dx.doi.org/10.1016/j.pec.2021.02.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906506PMC
February 2021

Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials.

Lancet Oncol 2021 02;22(2):246-255

Division of Cancer Sciences, University of Manchester, Manchester, UK; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Mount Vernon Cancer Centre, Northwood, UK.

Background: Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer.

Methods: We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2-T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors.

Findings: 782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99-159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52-0·96]). Both schedules had similar toxicity profiles (adjusted RD -3·37% [95% CI -11·85 to 5·10]).

Interpretation: A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S1470-2045(20)30607-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851111PMC
February 2021

Protocol for tumour-focused dose-escalated adaptive radiotherapy for the radical treatment of bladder cancer in a multicentre phase II randomised controlled trial (RAIDER): radiotherapy planning and delivery guidance.

BMJ Open 2020 12 31;10(12):e041005. Epub 2020 Dec 31.

Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.

Introduction: Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused 'plan of the day' radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity.

Methods And Analysis: Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes.

Ethics And Dissemination: This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities.

Trial Registration Number: NCT02447549; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-041005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780718PMC
December 2020

Clinical Outcomes of a Randomized Trial of Adaptive Plan-of-the-Day Treatment in Patients Receiving Ultra-hypofractionated Weekly Radiation Therapy for Bladder Cancer.

Int J Radiat Oncol Biol Phys 2021 Jun 11;110(2):412-424. Epub 2020 Dec 11.

The Institute of Cancer Research, London, United Kingdom.

Purpose: Hypofractionated radiation therapy can be used to treat patients with muscle-invasive bladder cancer unable to have radical therapy. Toxicity is a key concern, but adaptive plan-of the day (POD) image-guided radiation therapy delivery could improve outcomes by minimizing the volume of normal tissue irradiated. The HYBRID trial assessed the multicenter implementation, safety, and efficacy of this strategy.

Methods: HYBRID is a Phase II randomized trial that was conducted at 14 UK hospitals. Patients with T2-T4aN0M0 muscle-invasive bladder cancer unsuitable for radical therapy received 36 Gy in 6 weekly fractions, randomized (1:1) to standard planning (SP) or adaptive planning (AP) using a minimization algorithm. For AP, a pretreatment cone beam computed tomography (CT) was used to select the POD from 3 plans (small, medium, and large). Follow-up included standard cystoscopic, radiologic, and clinical assessments. The primary endpoint was nongenitourinary Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 (≥G3) toxicity within 3 months of radiation therapy. A noncomparative single stage design aimed to exclude ≥30% toxicity rate in each planning group in patients who received ≥1 fraction of radiation therapy. Local control at 3-months (both groups combined) was a key secondary endpoint.

Results: Between April 15, 2014, and August 10, 2016, 65 patients were enrolled (SP, n = 32; AP, n = 33). The median follow-up time was 38.8 months (interquartile range [IQR], 36.8-51.3). The median age was 85 years (IQR, 81-89); 68% of participants (44 of 65) were male; and 98% of participants had grade 3 urothelial cancer. In 63 evaluable participants, CTCAE ≥G3 nongenitourinary toxicity rates were 6% (2 of 33; 95% confidence interval [CI], 0.7%-20.2%) for the AP group and 13% (4 of 30; 95% CI, 3.8%-30.7%) for the SP group. Disease was present in 9/48 participants assessed at 3 months, giving a local control rate of 81.3% (95% CI, 67.4%-91.1%).

Conclusions: POD adaptive radiation therapy was successfully implemented across multiple centers. Weekly ultrahypofractionated 36 Gy/6 fraction radiation therapy is safe and provides good local control rates in this older patient population.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114997PMC
June 2021

Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Neoadjuvant Chemotherapy Followed by (Chemo)radiotherapy in the BC2001 Trial.

Eur Urol 2021 02 6;79(2):307-315. Epub 2020 Dec 6.

The Institute of Cancer Research, London, UK.

Background: BC2001 demonstrated improved local control with the addition of chemotherapy to radiotherapy in 360 patients with muscle-invasive bladder cancer.

Objective: To establish whether such benefit remained in BC2001 patients who received prior neoadjuvant chemotherapy.

Design, Setting, And Participants: A total of 117 patients (33%) received neoadjuvant chemotherapy and were randomised to radiotherapy with (48%) or without (52%) concomitant chemotherapy. Patients were recruited between August 2001 and April 2008 from 28 UK centres.

Intervention: Platinum-based neoadjuvant chemotherapy, followed by radiotherapy with (cRT) or without (RT) synchronous 5-fluorouracil and mitomycin-C.

Outcome Measurements And Statistical Analysis: Toxicity, locoregional control (LRC), overall survival (OS), and quality of life (QoL) were measured.

Results And Limitations: Of the patients, 74% received gemcitabine plus cisplatin or carboplatin. Compliance rates with full-dose radiotherapy were cRT 93% and RT 92%. An excess of grade ≥3 toxicities while on (chemo)radiation occurred for cRT 33% versus RT 22%, although nonstatistically significant (p = 0.16). With 110 mo median follow-up for survival (interquartile range 96-123), cRT showed improved LRC though not statistically significant (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] 0.33-1.23, p = 0.18). No differences in OS (aHR = 0.95, 95% CI 0.57-1.57, p = 0.8) were observed. No significant detriment in QoL was observed between cRT and RT in this subgroup of patients.

Conclusions: Neoadjuvant chemotherapy does not compromise the delivery of radical curative treatment. Although underpowered due to a small sample size, the benefit of chemoradiotherapy to improve local control in this group of patients receiving neoadjuvant chemotherapy is consistent with that observed in the main trial. Although a nonsignificant excess of toxicity was observed, there was no evidence of impaired QoL.

Patient Summary: Chemotherapy before radical chemo(radiotherapy) is feasible and well tolerated.
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http://dx.doi.org/10.1016/j.eururo.2020.11.036DOI Listing
February 2021

Rapid deployment of virtual ICU support during the COVID-19 pandemic.

Future Healthc J 2020 Oct;7(3):181-184

Royal Brompton & Harefield NHS Foundation Trust, London, UK.

The COVID-19 pandemic brought many serious challenges to the clinical workplace, and was a catalyst to novel approaches to the way in which we practice medicine. These challenges include extreme numbers of critically ill patients overwhelming many intensive care units, how to maintain the flow of communication between clinicians, patients and their families, and how to prevent the spread of infection working on quarantined units in personal protective equipment. The Royal Brompton and Harefield Hospitals deployed a series of digital solutions to try to address some of those challenges and a series of case studies describes their clinical application in three clinical domains: communicating with families, clinical communication between clinicians and the delivery of clinical education.
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http://dx.doi.org/10.7861/fhj.2020-0157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571721PMC
October 2020

Polyandry provides reproductive and genetic benefits in colonising populations.

Ecol Evol 2020 Oct 12;10(19):10851-10857. Epub 2020 Sep 12.

School of Biological Sciences Norwich Research Park University of East Anglia Norwich UK.

Polyandry, when females mate with more than one male, is theorised to play an important role in successful colonisation of new habitats. In addition to possible benefits from sexual selection, even mild polyandry could facilitate colonisation by protecting against inbreeding and reducing the costs of mating with incompatible or infertile males. Here, we measure the importance of mild polyandry for population viability and reproductive fitness following experimental founder events into a higher-temperature regime. Using colonisation experiments with the model beetle , in which females can produce offspring for up to 140 days following a single mating, we founded more than 100 replicate populations using single females that had been given the opportunity to mate with either one or two males and then tracked their subsequent population dynamics. Following population viability and fitness across 10 generations, we found that extinction rates were significantly lower in populations founded by females given polyandrous opportunities to mate with two males (9%) compared to populations founded by monogamous females (34%). In addition, populations founded by females that had been provided with opportunities to store sperm from two different males showed double the median productivity following colonisation compared to monogamous-founded populations. Notably, we identified short-term and longer-term benefits to post-colonisation populations from double-mating, with results suggesting that polyandry acts to both protect against mating with incompatible males through the founder event, and reduce inbreeding depression as the colonisation proceeds for 10 generations. Our results therefore show that even mild polyandry provides both reproductive and genetic benefits for colonising populations.
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http://dx.doi.org/10.1002/ece3.6742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548180PMC
October 2020

Life After COVID-19 for Cancer Clinical Trials.

Int J Radiat Oncol Biol Phys 2020 Oct;108(2):486-488

Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom.

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http://dx.doi.org/10.1016/j.ijrobp.2020.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462772PMC
October 2020

The effect of visitors on the behavior of zoo-housed western lowland gorillas (Gorilla gorilla gorilla).

Zoo Biol 2020 Sep 19;39(5):283-296. Epub 2020 Aug 19.

Pathobiology and Population Sciences, Royal Veterinary College, London, UK.

Primates, especially apes, are popular with the public, often attracting large crowds. These crowds could cause behavioral change in captive primates, whether positive, neutral, or negative. We examined the impact of visitors on the behavior of six western lowland gorillas (Gorilla gorilla gorilla), observing the troop over 6 weeks during high season (4.5 hr/day, 35 days, May-July 2016). We used focal scan sampling to determine activity budget and enclosure usage, and focal continuous sampling to identify bouts of anxiety-related behavior (visitor-directed vigilance, self-scratching, and aggression). Both daily zoo-entry numbers (V ) and instantaneous crowds at the exhibit (V ) were measured. Overall, V had little effect across behaviors. However, consistent with the more acute time frame of measurement, V was a better predictor of behavior; at high crowd volumes, we observed significant group-level changes in activity budget (increased inactivity, increased locomotion, and decreased environment-related behaviors), increase in some anxiety-related behaviors, and decreased enclosure usage. Although contributing similar effects, it could not be determined if crowd numbers, composition, or noise most affected the troop, nor any chronic effects of exposure to large crowds. Nevertheless, our findings suggest that measures to minimize the impacts of large crowds at the exhibit would be beneficial. Furthermore, we highlight potential discrepancies between common methods for measuring visitor numbers: V is less sensitive to detecting visitor effects on behavioral indices than V . Future studies should appropriately match the biological time frame of welfare indicators and visitor measures used to ensure the reliability of findings.
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http://dx.doi.org/10.1002/zoo.21552DOI Listing
September 2020

Hearing Vital Signs: Mobile Audiometry in the Emergency Department for Evaluation of Sudden Hearing Loss.

Otolaryngol Head Neck Surg 2020 11 28;163(5):1025-1028. Epub 2020 Jul 28.

Department of Otolaryngology, Massachusetts Eye and Ear, Boston, Massachusetts, USA.

Emergency departments (EDs) are a common location for patients to present with sudden hearing loss (SHL). Unfortunately, high-quality, rapid quantitative measurement of hearing loss is challenging. Herein, we aim to evaluate the accuracy of tablet-based audiometry in patients complaining of SHL. Prospective tablet-based testing was completed in the ED in patients complaining of SHL. Air conduction thresholds (ACTs) obtained via tablet-based audiometry were compared to same-day measurements with a clinical-grade audiometer. Hearing loss (HL) was defined as >20 dB ACT for any frequency. In participant-level analysis, 30+ dB HL in 3 consecutive frequencies was used to define SHL. In the ED, mobile audiogram ACTs were within 5 dB (77%) and 10 dB (89.6%) of those determined by conventional audiometry. The sensitivity and specificity for mobile audiometry to detect 3 or more consecutive thresholds with 30+ dB HL were 100% and 62.5%, respectively. Findings have implications for increasing access to high-quality audiometry.
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http://dx.doi.org/10.1177/0194599820935420DOI Listing
November 2020

The implementation and utility of patient screening logs in a multicentre randomised controlled oncology trial.

Trials 2020 Jul 8;21(1):629. Epub 2020 Jul 8.

Clinical Trials and Statistics Unit at the Institute of Cancer Research (ICR-CTSU), London, SM2 5NG, UK.

Background: The utility of patient screening logs and their impact on improving trial recruitment rates are unclear. We conducted a retrospective exploratory analysis of screening data collected within a multicentre randomised controlled trial investigating chemotherapy for upper tract urothelial carcinoma.

Methods: Participating centres maintained a record of patients meeting basic screening criteria stipulated in the trial protocol, submitting logs regularly to the clinical trial coordinating centre (CTC). Sites recorded the number of patients ineligible, not approached, declined and randomised. The CTC monitored proportions of eligible patients, approach rate (proportion of eligible patients approached) and acceptance rate (proportion recruited of those approached). Data were retrospectively analysed to identify patterns of screening activity and correlation with recruitment.

Results: Data were collected between May 2012 and August 2016, during which time 71 sites were activated-a recruitment period of 2768 centre months. A total of 1138 patients were reported on screening logs, with 2300 requests for logs sent by the CTC and 47% of expected logs received. A total of 758 patients were reported as ineligible, 36 eligible patients were not approached and 207 declined trial participation. The approach rate was 91% (344/380), and the acceptance rate was 40% (137/344); these rates remained consistent throughout the data collection. The main reason patients provided for declining (99/207, 48%) was not wanting to receive chemotherapy. There was a moderately strong correlation (r = 0.47) between the number reported on screening logs and the number recruited per site. Considerable variation in data between centres was observed, and 54/191 trial participants (28%) enrolled during this period were not reported on logs.

Conclusions: Central collection of screening logs can identify reasons for patients declining trial participation and help monitor trial activity at sites; however, obtaining complete data can be challenging. There was a correlation between the number of patients reported on logs and recruitment; however, this was likely confounded by sites' available patient population. The use of screening logs may not be appropriate for all trials, and their use should be carefully considered in relation to the associated workload. No evidence was found that central collection of screening logs improved recruitment rates in this study, and their continued use warrants further investigation.

Trial Registration: ISRCTN98387754 . Registered on 31 January 2012.
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http://dx.doi.org/10.1186/s13063-020-04559-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346417PMC
July 2020

Bioacoustics in cognitive research: Applications, considerations, and recommendations.

Wiley Interdiscip Rev Cogn Sci 2020 Sep 16;11(5):e1538. Epub 2020 Jun 16.

Department of Integrative Biology, Oklahoma State University, Stillwater, Oklahoma, USA.

The multifaceted ability to produce, transmit, receive, and respond to acoustic signals is widespread in animals and forms the basis of the interdisciplinary science of bioacoustics. Bioacoustics research methods, including sound recording and playback experiments, are applicable in cognitive research that centers around the processing of information from the acoustic environment. We provide an overview of bioacoustics techniques in the context of cognitive studies and make the case for the importance of bioacoustics in the study of cognition by outlining some of the major cognitive processes in which acoustic signals are involved. We also describe key considerations associated with the recording of sound and its use in cognitive applications. Based on these considerations, we provide a set of recommendations for best practices in the recording and use of acoustic signals in cognitive studies. Our aim is to demonstrate that acoustic recordings and stimuli are valuable tools for cognitive researchers when used appropriately. In doing so, we hope to stimulate opportunities for innovative cognitive research that incorporates robust recording protocols. This article is categorized under: Neuroscience > Cognition Psychology > Theory and Methods Neuroscience > Behavior Neuroscience > Cognition.
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http://dx.doi.org/10.1002/wcs.1538DOI Listing
September 2020

Protocol for hypofractionated adaptive radiotherapy to the bladder within a multicentre phase II randomised trial: radiotherapy planning and delivery guidance.

BMJ Open 2020 05 26;10(5):e037134. Epub 2020 May 26.

Radiotherapy and Imaging, The Institute of Cancer Research, London, UK.

Introduction: Patients with muscle invasive bladder cancer (MIBC) who are unfit and unsuitable for standard radical treatment with cystectomy or daily radiotherapy present a large unmet clinical need. Untreated, they suffer high cancer specific mortality and risk significant disease-related local symptoms. Hypofractionated radiotherapy (delivering higher doses in fewer fractions/visits) is a potential treatment solution but could be compromised by the mobile nature of the bladder, resulting in target misses in a significant proportion of fractions. Adaptive 'plan of the day' image-guided radiotherapy delivery may improve the precision and accuracy of treatment. We aim to demonstrate within a randomised multicentre phase II trial feasibility of plan of the day hypofractionated bladder radiotherapy delivery with acceptable rates of toxicity.

Methods And Analysis: Patients with T2-T4aN0M0 MIBC receiving 36 Gy in 6-weekly fractions are randomised (1:1) between treatment delivered using a single-standard plan or adaptive radiotherapy using a library of three plans (small, medium and large). A cone beam CT taken prior to each treatment is used to visualise the anatomy and select the most appropriate plan depending on the bladder shape and size. A comprehensive radiotherapy quality assurance programme has been instituted to ensure standardisation of radiotherapy planning and delivery. The primary endpoint is to exclude 30% acute grade 3 non-genitourinary toxicity at 3 months for adaptive radiotherapy in patients who received 1 fraction (p0=0.7, p1=0.9, α=0.05, β=0.2). Secondary endpoints include local disease control, symptom control, late toxicity, overall survival, patient-reported outcomes and proportion of fractions benefiting from adaptive planning. Target recruitment is 62 patients.

Ethics And Dissemination: The trial is approved by the London-Surrey Borders Research Ethics Committee (13/LO/1350). The results will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities.

Trial Registration Number: NCT01810757.
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http://dx.doi.org/10.1136/bmjopen-2020-037134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259864PMC
May 2020

Outbreaks of Adenovirus-associated Respiratory Illness on 5 College Campuses in the United States, 2018-2019.

Clin Infect Dis 2021 06;72(11):1992-1999

Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.

Background: Human adenoviruses (HAdVs) are commonly associated with acute respiratory illness. HAdV outbreaks are well documented in congregate military training settings, but less is known about outbreaks on college campuses. During fall 2018 and spring 2019, 5 United States (US) colleges reported increases in HAdV-associated respiratory illness. Investigations were performed to better understand HAdV epidemiology in this setting.

Methods: A case was defined as a student at one of the 5 colleges, with acute respiratory illness and laboratory-confirmed HAdV infection during October 2018-December 2018 or March-May 2019. Available respiratory specimens were typed by HAdV type-specific real-time polymerase chain reaction assays, and for a subset, whole genome sequencing was performed. We reviewed available medical records and cases were invited to complete a questionnaire, which included questions on symptom presentation, social history, and absenteeism.

Results: We identified 168 HAdV cases. Median age was 19 (range, 17-22) years and 102 cases (61%) were male. Eleven cases were hospitalized, 10 with pneumonia; 2 cases died. Among questionnaire respondents, 80% (75/94) missed ≥ 1 day of class because of their illness. Among those with a type identified (79%), HAdV types 4 and 7 were equally detected, with frequency of each varying by site. Genome types 4a1 and 7d were identified, respectively, by whole genome sequence analysis.

Conclusions: HAdV respiratory illness was associated with substantial morbidity and missed class time among young, generally healthy adults on 5 US college campuses. HAdVs should be considered a cause of respiratory illness outbreaks in congregate settings such as college campuses.
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http://dx.doi.org/10.1093/cid/ciaa465DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315123PMC
June 2021

Data-driven segmentation of audiometric phenotypes across a large clinical cohort.

Sci Rep 2020 04 21;10(1):6704. Epub 2020 Apr 21.

Eaton-Peabody Laboratories, Department of Otolaryngology - Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, 02114, USA.

Pure tone audiograms are used to assess the degree and underlying source of hearing loss. Audiograms are typically categorized into a few canonical types, each thought to reflect distinct pathologies of the ear. Here, we analyzed 116,400 patient records from our clinic collected over a 24-year period and found that standard categorization left 46% of patient records unclassified. To better account for the full spectrum of hearing loss profiles, we used a Gaussian Mixture Model (GMM) to segment audiograms without any assumptions about frequency relationships, interaural symmetry or etiology. The GMM converged on ten types, featuring varying degrees of high-frequency hearing loss, flat loss, mixed loss, and notched profiles, with predictable relationships to patient age and sex. A separate GMM clustering of 15,380 audiograms from the National Health and Nutrition Examination Survey (NHANES) identified six similar types, that only lacked the more extreme hearing loss configurations observed in our patient cohort. Whereas traditional approaches distill hearing loss configurations down to a few canonical types by disregarding much of the underlying variability, an objective probabilistic model that accounted for all of the data identified an organized, but more heterogenous set of audiogram types that was consistent across two large clinical databases.
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http://dx.doi.org/10.1038/s41598-020-63515-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174357PMC
April 2020

Audiometric Predictors of Bothersome Tinnitus in a Large Clinical Cohort of Adults With Sensorineural Hearing Loss.

Otol Neurotol 2020 04;41(4):e414-e421

Eaton-Peabody Laboratories, Massachusetts Eye and Ear Infirmary.

Objective: To identify demographic and audiometric predictors of bothersome tinnitus within a large clinical cohort.

Study Design: Retrospective chart review.

Setting: Tertiary care hospital.

Patients: 51,989 English-speaking patients between 18 and 80 years of age that received initial audiometric evaluations at the Massachusetts Eye and Ear Infirmary between the years 2000 and 2016.

Main Outcome Measures: Patients were categorized according to whether or not tinnitus was the primary reason for their visit. The likelihood of tinnitus as a primary complaint (TPC) was evaluated as a function of age, sex, and audiometric configuration. Patient-reported tinnitus percepts were qualitatively assessed in relation to audiometric configuration.

Results: Approximately 20% of adults who presented for an initial hearing evaluation reported TPC. The prevalence of TPC increased with advancing age until approximately 50 to 54 years, and then declined thereafter. In general, men were significantly more likely to report TPC than women. TPC was statistically associated with specific audiogram configurations. In particular, TPC was most prevalent for notched and steeply sloping hearing losses, but was relatively uncommon in adults with flat losses. Patients with frequency-restricted threshold shifts often reported tonal tinnitus percepts, while patients with asymmetric configurations tended to report broadband percepts.

Conclusions: The probability of seeking audiological evaluation for bothersome tinnitus is highest for males, middle-aged patients, and those with notched or high-frequency hearing losses. These findings support the theory that tinnitus arises from sharp discontinuities in peripheral afferent innervation and cochlear amplification, which may induce topographically restricted changes in the central auditory pathway.
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http://dx.doi.org/10.1097/MAO.0000000000002568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366362PMC
April 2020

Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial.

Lancet 2020 04 5;395(10232):1268-1277. Epub 2020 Mar 5.

The Institute of Cancer Research, Clinical Trials and Statistics Unit, London, UK.

Background: Urothelial carcinomas of the upper urinary tract (UTUCs) are rare, with poorer stage-for-stage prognosis than urothelial carcinomas of the urinary bladder. No international consensus exists on the benefit of adjuvant chemotherapy for patients with UTUCs after nephroureterectomy with curative intent. The POUT (Peri-Operative chemotherapy versus sUrveillance in upper Tract urothelial cancer) trial aimed to assess the efficacy of systemic platinum-based chemotherapy in patients with UTUCs.

Methods: We did a phase 3, open-label, randomised controlled trial at 71 hospitals in the UK. We recruited patients with UTUC after nephroureterectomy staged as either pT2-T4 pN0-N3 M0 or pTany N1-3 M0. We randomly allocated participants centrally (1:1) to either surveillance or four 21-day cycles of chemotherapy, using a minimisation algorithm with a random element. Chemotherapy was either cisplatin (70 mg/m) or carboplatin (area under the curve [AUC]4·5/AUC5, for glomerular filtration rate <50 mL/min only) administered intravenously on day 1 and gemcitabine (1000 mg/m) administered intravenously on days 1 and 8; chemotherapy was initiated within 90 days of surgery. Follow-up included standard cystoscopic, radiological, and clinical assessments. The primary endpoint was disease-free survival analysed by intention to treat with a Peto-Haybittle stopping rule for (in)efficacy. The trial is registered with ClinicalTrials.gov, NCT01993979. A preplanned interim analysis met the efficacy criterion for early closure after recruitment of 261 participants.

Findings: Between June 19, 2012, and Nov 8, 2017, we enrolled 261 participants from 57 of 71 open study sites. 132 patients were assigned chemotherapy and 129 surveillance. One participant allocated chemotherapy withdrew consent for data use after randomisation and was excluded from analyses. Adjuvant chemotherapy significantly improved disease-free survival (hazard ratio 0·45, 95% CI 0·30-0·68; p=0·0001) at a median follow-up of 30·3 months (IQR 18·0-47·5). 3-year event-free estimates were 71% (95% CI 61-78) and 46% (36-56) for chemotherapy and surveillance, respectively. 55 (44%) of 126 participants who started chemotherapy had acute grade 3 or worse treatment-emergent adverse events, which accorded with frequently reported events for the chemotherapy regimen. Five (4%) of 129 patients managed by surveillance had acute grade 3 or worse emergent adverse events. No treatment-related deaths were reported.

Interpretation: Gemcitabine-platinum combination chemotherapy initiated within 90 days after nephroureterectomy significantly improved disease-free survival in patients with locally advanced UTUC. Adjuvant platinum-based chemotherapy should be considered a new standard of care after nephroureterectomy for this patient population.

Funding: Cancer Research UK.
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http://dx.doi.org/10.1016/S0140-6736(20)30415-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181180PMC
April 2020

CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin-C vs surgical management in low-risk non-muscle-invasive bladder cancer.

BJU Int 2020 06 3;125(6):817-826. Epub 2020 Apr 3.

Institute of Cancer Research, London, UK.

Objectives: To evaluate the activity of intravesical mitomycin-C (MMC) to ablate recurrent low-risk non-muscle-invasive bladder cancer (NMIBC) and assess whether it may enable patients to avoid surgical intervention for treatment of recurrence.

Patients And Methods: CALIBER is a phase II feasibility study. Participants were randomized (2:1) to treatment with four once-weekly MMC 40-mg intravesical instillations (chemoablation arm) or to surgical management. The surgical group was included to assess the feasibility of randomization. The primary endpoint was complete response to intravesical MMC in the chemoablation arm at 3 months, reported with exact 95% confidence intervals (CIs). Secondary endpoints included time to subsequent recurrence, summarized by Kaplan-Meier methods.

Results: Between February 2015 and August 2017, 82 patients with visual diagnosis of recurrent low-risk NMIBC were enrolled from 24 UK hospitals (chemoablation, n = 54; surgical management, n =28). The median follow-up was 24 months. Complete response at 3 months was 37.0% (20/54; 95% CI 24.3-51.3) with chemoablation and 80.8% (21/26; 95% CI 60.6-93.4) with surgical management. Amongst patients with complete response at 3 months, a similar proportion was recurrence-free by 12 months in both groups (84%). Amongst those with residual disease at 3 months, the 12-month recurrence-free proportion was lower in the surgical management group (40.0%) than in the chemoablation group (84%). Recruitment stopped early as chemoablation did not meet the prespecified threshold of 45% complete responses at 3 months.

Conclusion: Intravesical chemoablation in low-risk NMIBC is feasible and safe, but did not demonstrate sufficient response in the present trial. After chemoablation there may be a reduction in recurrence rate, even in non-responders, that is greater than with surgery alone. Further research is required to investigate the role and optimal schedule of neoadjuvant intravesical chemotherapy prior to surgery for NMIBC.
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http://dx.doi.org/10.1111/bju.15038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318672PMC
June 2020

Intracochlear Perfusion of Tumor Necrosis Factor-Alpha Induces Sensorineural Hearing Loss and Synaptic Degeneration in Guinea Pigs.

Front Neurol 2019 10;10:1353. Epub 2020 Feb 10.

Eaton Peabody Laboratories, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA, United States.

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine that plays a prominent role in the nervous system, mediating a range of physiologic and pathologic functions. In the auditory system, elevated levels of TNF-α have been implicated in several types of sensorineural hearing loss, including sensorineural hearing loss induced by vestibular schwannoma, a potentially fatal intracranial tumor that originates from the eighth cranial nerve; however, the mechanisms underlying the tumor's deleterious effects on hearing are not well-understood. Here, we investigated the effect of acute elevations of TNF-α in the inner ear on cochlear function and morphology by perfusing the cochlea with TNF-α in guinea pigs. TNF-α perfusion did not significantly change thresholds for compound action potential (CAP) responses, which reflect cochlear nerve activity, or distortion product otoacoustic emissions, which reflect outer hair cell integrity. However, intracochlear TNF-α perfusion reduced CAP amplitudes and increased the number of inner hair cell synapses without paired post-synaptic terminals, suggesting a pattern of synaptic degeneration that resembles that observed in primary cochlear neuropathy. Additionally, etanercept, a TNF-α blocker, protected against TNF-α-induced synaptopathy when administered systemically prior to intracochlear TNF-α perfusion. Findings motivate further investigation into the harmful effects of chronically elevated intracochlear levels of TNF-α, and the potential for etanercept to counter these effects.
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http://dx.doi.org/10.3389/fneur.2019.01353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025643PMC
February 2020
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