Longitudinal White and Gray Matter Response to Precision Medicine-Guided Intervention for Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a debilitating condition that is widely known to adversely affect gray matter (GM) and white matter (WM) tracts within the brain. Recently, precision medicine has shown promise in alleviating the clinical and gross morphological trajectories of patients with AD. However, regional morphological changes have not yet been adequately characterized. OBJECTIVE: Investigate regional morphological responses to a precision medicine-guided intervention with regards to white and gray matter in AD and mild cognitive impairment (MCI). METHODS: Clinical and neuroimaging data were compiled over a 9-month period from 25 individuals who were diagnosed with AD or MCI receiving individualized treatment plans. Structural T1-weighted MRI scans underwent segmentation and volumetric quantifications via Neuroreader. Longitudinal changes were calculated via annualized percent change of WM or GM ratios. RESULTS: Montreal Cognitive Assessment scores (p < 0.001) and various domains of the Computerized Neurocognitive Screening Vital Signs significantly improved from baseline to 9-month follow-up. There was regional variability in WM and GM atrophy or hypertrophy, but none of these observed changes were statistically significant after correction for multiple comparisons.

Precision Medicine Approach to Alzheimer's Disease: Rationale and Implications.

The neurodegenerative disease field has enjoyed extremely limited success in the development of effective therapeutics. One potential reason is the lack of disease models that yield accurate predictions and optimal therapeutic targets. Standard clinical trials have pre-determined a single treatment modality, which may be unrelated to the primary drivers of neurodegeneration. Recent proof-of-concept clinical trials using a precision medicine approach suggest a new model of Alzheimer's disease (AD) as a chronic innate encephalitis that creates a network insufficiency. Identifying and addressing the multiple potential contributors to cognitive decline for each patient may represent a more effective strategy. Here we review the rationale for a precision medicine approach in prevention and treatment of cognitive decline associated with AD. Results and implications from recent proof-of-concept clinical trials are presented. Randomized controlled trials, with much larger patient numbers, are likely to be significant to establishing precision medicine protocols as a standard of care for prevention and treatment of cognitive decline. Furthermore, combining this approach with the pharmaceutical approach offers the potential for enhanced outcomes. However, incorporating precision medicine approaches into everyday evaluation and care, as well as future clinical trials, would require fundamental changes in trial design, IRB considerations, funding considerations, laboratory evaluation, personalized treatment plans, treatment teams, and ultimately in reimbursement guidelines. Nonetheless, precision medicine approaches to AD, based on a novel model of AD pathophysiology, offer promise that has not been realized to date with monotherapeutic approaches.

Development and usability testing of an electronic patient-reported outcome (ePRO) solution for patients with inflammatory diseases in an Advanced Therapy Medicinal Product (ATMP) basket trial.

BACKGROUND: Electronic patient-reported outcome (ePRO) systems are increasingly used in clinical trials to provide evidence of efficacy and tolerability of treatment from the patient perspective. The aim of this study is twofold: (1) to describe how we developed an electronic platform for patients to report their symptoms, and (2) to develop and undertake usability testing of an ePRO solution for use in a study of cell therapy seeking to provide early evidence of efficacy and tolerability of treatment and test the feasibility of the system for use in later phase studies. METHODS: An ePRO system was designed to be used in a single arm, multi-centre, phase II basket trial investigating the safety and activity of the use of ORBCEL-C™ in the treatment of patients with inflammatory conditions. ORBCEL-C™ is an enriched Mesenchymal Stromal Cells product isolated from human umbilical cord tissue using CD362+ cell selection. Usability testing sessions were conducted using cognitive interviews and the 'Think Aloud' method with patient advisory group members and Research Nurses to assess the usability of the system. RESULTS: Nine patient partners and seven research nurses took part in one usability testing session. Measures of fatigue and health-related quality of life, the PRO-CTCAE™ and FACT-GP5 global tolerability question were included in the ePRO system. Alert notifications to the clinical team were triggered by PRO-CTCAE™ and FACT-GP5 scores. Patient participants liked the simplicity and responsiveness of the patient-facing app. Two patients were unable to complete the testing session, due to technical issues. Research Nurses suggested minor modifications to improve functionality and the layout of the clinician dashboard and the training materials. CONCLUSION: By testing the effectiveness, efficiency, and satisfaction of our novel ePRO system (PROmicsR), we learnt that most people with an inflammatory condition found it easy to report their symptoms using an app on their own device. Their experiences using the PROmicsR ePRO system within a trial environment will be further explored in our upcoming feasibility testing. Research nurses were also positive and found the clinical dashboard easy-to-use. Using ePROs in early phase trials is important in order to provide evidence of therapeutic responses and tolerability, increase the evidence based, and inform methodology development. TRIAL REGISTRATION: ISRCTN, ISRCTN80103507. Registered 01 April 2022, https://www.isrctn.com/ISRCTN80103507.

More and more patients tell clinicians how they feel by completing questionnaires electronically. Therefore, it is important to assess how easy it is for patients to do this. In this study, we describe how we developed an electronic platform for patients to report their symptoms and how we tested the usability of this platform with patient partners and research nurses. Once the electronic platform was developed, quality of life and symptoms questionnaires were programmed onto it. Alerts were sent to the clinical team if specific scores were obtained on the symptoms questionnaires. Although two patient partners were not able to finish the testing session because of technical issues, the ones who completed the session liked its simplicity and responsiveness. The research nurses also liked the system and only suggested minor modifications. Following this testing, we refined the electronic platform to test it further in a larger study which investigates the safety and use of a drug. We hope that thanks to this electronic platform, we will obtain useful information on the safety and efficacy of treatment.

An online implementation of a measure of spectro-temporal processing by cochlear-implant listeners.

The spectro-temporal ripple for investigating processor effectiveness (STRIPES) test is a psychophysical measure of spectro-temporal resolution in cochlear-implant (CI) listeners. It has been validated using direct-line input and loudspeaker presentation with listeners of the Advanced Bionics CI. This article investigates the suitability of an online application using wireless streaming (webSTRIPES) as a remote test. It reports a strong across-listener correlation between STRIPES thresholds obtained using laboratory testing with loudspeaker presentation vs remote testing with streaming presentation, with no significant difference in STRIPES thresholds between the two measures. WebSTRIPES also produced comparable and robust thresholds with users of the Cochlear CI.

Perceived Stress, Grit, and Self-Care Behaviors in First-Year Medical Students.

Medical students experience more stress than the general population, which over time can cause mental and physical disease, including burnout. Identifying factors impacting stress during early medical training could inform strategies to minimize its impacts throughout training and in clinical practice. This study surveyed 238 first-year osteopathic medical students to assess stress (Perceived Stress Scale; PSS), grit, sleep quality (Pittsburgh Sleep Quality Index; PSQI), physical activity (Godin-Shephard Leisure-Time Physical Activity Score; LTPA), and nutrition habits (Rapid Eating Assessment for Participants; REAP) within the first 2 weeks of starting medical school and again 10 weeks later. Incomplete responses were removed, leaving 204 study participants. We observed statistically significant decreases in grittiness (∆grit = -2.230%, P = .002) and physical activity (∆LTPA = -22.147%, P < .0001), while perceived stress (∆PSS = 34.548%, P < .0001) and poor sleep quality (∆PSQI% = 19.853, P < .0001) increased. Correlation analyses identified the strongest relationships were between ∆PSS vs ∆PSQI (r = .47, P < .0001) and ∆PSS vs ∆LTPA (r = -.20, P < .01). Multivariable linear regression analysis isolated ∆PSQI (P < .0001) and ∆LTPA (P = .012) as statistically significant predictors of ∆PSS. These results suggest early, repeated curricular interventions focused on physical activity and sleep hygiene may help students better manage stress during medical education.

Precision Medicine Approach to Alzheimer's Disease: Successful Pilot Project.

BACKGROUND: Effective therapeutics for Alzheimer's disease are needed. However, previous clinical trials have pre-determined a single treatment modality, such as a drug candidate or therapeutic procedure, which may be unrelated to the primary drivers of the neurodegenerative process. Therefore, increasing data set size to include the potential contributors to cognitive decline for each patient, and addressing the identified potential contributors, may represent a more effective strategy. OBJECTIVE: To determine whether a precision medicine approach to Alzheimer's disease and mild cognitive impairment is effective enough in a proof-of-concept trial to warrant a larger, randomized, controlled clinical trial. METHODS: Twenty-five patients with dementia or mild cognitive impairment, with Montreal Cognitive Assessment (MoCA) scores of 19 or higher, were evaluated for markers of inflammation, chronic infection, dysbiosis, insulin resistance, protein glycation, vascular disease, nocturnal hypoxemia, hormone insufficiency or dysregulation, nutrient deficiency, toxin or toxicant exposure, and other biochemical parameters associated with cognitive decline. Brain magnetic resonance imaging with volumetrics was performed at baseline and study conclusion. Patients were treated for nine months with a personalized, precision medicine protocol, and cognition was assessed at t = 0, 3, 6, and 9 months. RESULTS: All outcome measures revealed improvement: statistically significant improvement in MoCA scores, CNS Vital Signs Neurocognitive Index, and Alzheimer's Questionnaire Change score were documented. No serious adverse events were recorded. MRI volumetrics also improved. CONCLUSION: Based on the cognitive improvements observed in this study, a larger, randomized, controlled trial of the precision medicine therapeutic approach described herein is warranted.

Protocol for a randomised controlled trial investigating an intervention to boost decentering in response to distressing mental experiences during adolescence: the decentering in adolescence study (DECADES).

INTRODUCTION: Decentering describes the ability to voluntarily adopt an objective self-perspective from which to notice internal, typically distressing, stressors (eg, difficult thoughts, memories and feelings). The reinforcement of this skill may be an active ingredient through which different psychological interventions accrue reductions in anxiety and/or depression. However, it is unclear if decentering can be selectively trained at a young age and if this might reduce psychological distress. The aim of the current trial is to address this research gap. METHODS AND ANALYSIS: Adolescents, recruited from schools in the UK and Ireland (n=57 per group, age range=16-19 years), will be randomised to complete 5 weeks of decentering training, or an active control group that will take part in a combination of light physical exercise and cognitive training. The coprimary training outcomes include a self-reported decentering inventory (ie, the Experiences Questionnaire) and the momentary use of decentering in response to psychological stressors, using experience sampling. The secondary mental health outcomes will include self-reported inventories of depression and anxiety symptoms, as well as psychological well-being. Initial statistical analysis will use between-group analysis of covariance to estimate the effect of training condition on self-rated inventories, adjusted for baseline scores. Additionally, experience sampling data will be examined using hierarchical linear models. ETHICS AND DISSEMINATION: This study was approved by the Cambridge Psychology Research Ethics Committee, University of Cambridge (PRE.2019.109). Findings will be disseminated through typical academic routes including poster/paper presentations at (inter)national conferences, academic institutes and through publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN14329613.

Antiadenovirus Antibodies Predict Response Durability to Nadofaragene Firadenovec Therapy in BCG-unresponsive Non-muscle-invasive Bladder Cancer: Secondary Analysis of a Phase 3 Clinical Trial.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec.

The relationship between environmental context and attentional engagement in podcast listening experiences.

Introduction: Previous research has shown that podcasts are most frequently consumed using mobile listening devices across a wide variety of environmental, situational, and social contexts. To date, no studies have investigated how an individual's environmental context might influence their attentional engagement in podcast listening experiences. Improving understanding of the contexts in which episodes of listening take place, and how they might affect listener engagement, could be highly valuable to researchers and producers working in the fields of object-based and personalized media. Methods: An online questionnaire on listening habits and behaviors was distributed to a sample of 264 podcast listeners. An exploratory factor analysis was run to identify factors of environmental context that influence attentional engagement in podcast listening experiences. Five aspects of podcast listening engagement were also defined and measured across the sample. Results: The exploratory factor analysis revealed five factors of environmental context labeled as: outdoors, indoors & at home, evenings, soundscape & at work, and exercise. The aspects of podcast listening engagement provided a comprehensive quantitative account of contemporary podcast listening experiences. Discussion: The results presented support the hypothesis that elements of a listener's environmental context can influence their attentional engagement in podcast listening experiences. The soundscape & at work factor suggests that some listeners actively choose to consume podcasts to mask disturbing stimuli in their surrounding soundscape. Further analysis suggested that the proposed factors of environmental context were positively correlated with the measured aspects of podcast listening engagement. The results are highly pertinent to the fields of podcast studies, mobile listening experiences, and personalized media, and provide a basis for researchers seeking to explore how other forms of listening context might influence attentional engagement.

Case Report: Infantile Urticaria as a Herald of Neonatal Onset Multisystem Inflammatory Disease With a Novel Mutation in NLRP3.

Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1ß. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant's diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.

Further simulations of the effect of cochlear-implant pre-processing and head movement on interaural level differences.

We simulated the effect of several automatic gain control (AGC) and AGC-like systems and head movement on the output levels, and resulting interaural level differences (ILDs) produced by bilateral cochlear-implant (CI) processors. The simulated AGC systems included unlinked AGCs with a range of parameter settings, linked AGCs, and two proprietary multi-channel systems used in contemporary CIs. The results show that over the range of values used clinically, the parameters that most strongly affect dynamic ILDs are the release time and compression ratio. Linking AGCs preserves ILDs at the expense of monaural level changes and, possibly, comfortable listening level. Multichannel AGCs can whiten output spectra, and/or distort the dynamic changes in ILD that occur during and after head movement. We propose that an unlinked compressor with a ratio of approximately 3:1 and a release time of 300-500 ms can preserve the shape of dynamic ILDs, without causing large spectral distortions or sacrificing listening comfort.

National accreditation programmes for hospitals in the Eastern Mediterranean Region: Case studies from Egypt, Jordan, and Lebanon.

BACKGROUND: Many countries use external evaluation programmes such as accreditation in order to improve quality and safety in their healthcare settings. Hospital accreditation has developed in many low-and-middle-income countries (LMICs); however, the implementation and sustainability of these programmes vary in each country. This study addresses design and implementation issues of national hospital accreditation programmes. It identifies factors which may explain why programmes can be implemented successfully in one country but not in another and derives lessons for the design and implementation of national accreditation programmes in poor-resource settings. METHODS: A multiple case study design was used, comprising three countries in the Eastern Mediterranean Region: Egypt, Lebanon and Jordan. In-depth semi-structured interviews were conducted with 27 key stakeholders in the three countries and experts from international organisations concerned with accreditation activities in LMICs. RESULTS: The hospital accreditation programme was successful and sustainable in Jordan but experienced some difficulties in Egypt and Lebanon. The premature end of external funding and devastating political instability after the Arab Spring were problematic for the programmes in Egypt and Lebanon, but continuous funding and strong political will supported the implementation and sustainability of the programme in Jordan. CONCLUSIONS: LMICs striving to improve their hospitals' performance through accreditation programmes should consider their vulnerability to a scarcity of financial resources and political instability. An important factor underpinning sustainability is recognising that the accreditation programme is an ongoing and developing quality improvement process that needs continuing and careful attention from funders and political systems if it is to survive and thrive.

Vinpocetine, cognition, and epilepsy.

OBJECTIVE: Vinpocetine has been shown to enhance memory in animal models, with possible cognitive benefit in humans. The present study sought to demonstrate if vinpocetine can enhance cognition in healthy volunteers or patients with epilepsy. In addition, we compare blood levels of vinpocetine and its active metabolite (apovincaminic acid; AVA) in humans and animals to further characterize factors related to possible therapeutic benefit. METHODS: The cognitive effects of vinpocetine were assessed in healthy adult volunteers (n = 8) using a double-blind, randomized, crossover design at single doses (placebo, 10, 20, and 60 mg oral). Cognitive effects of vinpocetine in patients with focal epilepsy (n = 8) were tested using a double-blind, randomized, crossover design at single doses (placebo, 20 mg oral) followed by one-month open label at 20 mg oral three times a day. The neuropsychological battery included both computerized and non-computerized tests. Levels of vinpocetine and AVA in the human studies were compared to levels in 45 mice across time dosed at 5-20 mg/kg intraperitoneal of vinpocetine. RESULTS: No significant cognitive benefits were seen in healthy volunteers or patients with epilepsy. No appreciable side effects occurred. Vinpocetine and AVA levels were lower in humans than animals. CONCLUSIONS: Vinpocetine was well tolerated, but was not associated with positive cognitive effects. However, blood levels obtained in humans were substantially less than levels in animals obtained from dosages known to be effective in one model. This suggests that higher dosages are needed in humans to assess vinpocetine's cognitive efficacy.

Clinical and Histopathologic Characteristics of Metastatic and Locally Advanced Cutaneous Basal Cell Carcinomas.

ABSTRACT: Locally advanced or metastatic basal cell carcinomas (laBCCs or mBCCs) are rare, with few case series providing information on their epidemiology. We aimed to describe the clinical and histologic features of locally advanced and metastatic basal cell carcinomas. Forty cases of laBCC or mBCC were identified by searching Vanderbilt's database from 1984 to January 2019. A retrospective chart review was performed. Pathology slides were available for 23 cases (13 mBCCs and 10 laBCCs). Twenty-one of 23 cases were Clark level IV or V, with a mean depth of invasion of >7 mm for both types. The mean mitotic rate was 4.4 mitoses/mm2 for laBCCs and 3.3 mitoses/mm2 for mBCCs. Ulceration was identified in 7 laBCC and 8 mBCC cases. Perineural invasion was present in 2 laBCC and 6 mBCC cases, with 3 mBCCs invading nerves >0.1 mm. Of 13 mBCC cases, histologic subtypes included infiltrative (n = 9), nodular (n = 7), morpheaform (n = 4), and superficial (n = 2), with multiple patterns present in some specimens. 10 of 13 patients with mBCC had local recurrence before metastasis. In summary, we identified several potential markers of high-risk BCC, including perineural invasion, deep invasion, elevated mitotic rate, and local recurrence of the primary tumor.

The effect of increased channel interaction on speech perception with cochlear implants.

Cochlear implants (CIs) are neuroprostheses that partially restore hearing for people with severe-to-profound hearing loss. While CIs can provide good speech perception in quiet listening situations for many, they fail to do so in environments with interfering sounds for most listeners. Previous research suggests that this is due to detrimental interaction effects between CI electrode channels, limiting their function to convey frequency-specific information, but evidence is still scarce. In this study, an experimental manipulation called spectral blurring was used to increase channel interaction in CI listeners using Advanced Bionics devices with HiFocus 1J and MS electrode arrays to directly investigate its causal effect on speech perception. Instead of using a single electrode per channel as in standard CI processing, spectral blurring used up to 6 electrodes per channel simultaneously to increase the overlap between adjacent frequency channels as would occur in cases with severe channel interaction. Results demonstrated that this manipulation significantly degraded CI speech perception in quiet by 15% and speech reception thresholds in babble noise by 5 dB when all channels were blurred by a factor of 6. Importantly, when channel interaction was increased just on a subset of electrodes, speech scores were mostly unaffected and were only significantly degraded when the 5 most apical channels were blurred. These apical channels convey information up to 1 kHz at the apical end of the electrode array and are typically located at angular insertion depths of about 250 up to 500°. These results confirm and extend earlier findings indicating that CI speech perception may not benefit from deactivating individual channels along the array and that efforts should instead be directed towards reducing channel interaction per se and in particular for the most-apical electrodes. Hereby, causal methods such as spectral blurring could be used in future research to control channel interaction effects within listeners for evaluating compensation strategies.

Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial.

BACKGROUND: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer. METHODS: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 1011 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849. FINDINGS: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths. INTERPRETATION: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state. FUNDING: FKD Therapies Oy.