BackgroundExcellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.Methods and findingsWe evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2–3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18–80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [−1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid rem...

Summary Background The malignant mechanisms that control the development of cutaneous T‐cell lymphoma (CTCL) are beginning to be identified. Recent evidence suggests that disturbances in specific intracellular signalling pathways, such as RAS–mitogen‐activated protein kinase, T‐cell receptor (TCR)–phospholipase C gamma 1 (PLCG1)–nuclear factor of activated T cells (NFAT) and Janus kinase (JAK)–signal transducer and activator of transcription (STAT), may play an essential role in the pathogenesis of CTCL. Objectives To investigate the mechanisms controlling disease development and progression in mycosis fungoides (MF), the most common form of CTCL. Methods We collected 100 samples that were submitted for diagnosis of, or a second opinion regarding, MF between 2001 and 2018, 80% of which were in the early clinical stages of the disease. Formalin‐fixed paraffin‐embedded tissues were used for histological review and to measure the expression by immunohistochemistry of surrogate markers of activation of the TCR–PLCG1–NFAT, JAK–STAT and NF‐κB pathways. Folliculotropism and large‐cell transformation were also examined. Results NFAT and nuclear factor kappa B (NF‐κB) markers showed a comparable activation status in early and advanced stages, while STAT3 activation was more frequent in advanced stages and was associated with large‐cell transformation. Consistently with this observation, STAT3 activation occurred in parallel with MF progression in two initially MF‐negative cases. A significant association of NFAT with NF‐κB markers was also found, reflecting a common mechanism of activation in the two pathways. Genomic studies identified nine mutations in seven genes known to play a potential role in tumorigenesis in T‐cell leukaemia/lymphoma, including PLCG1, JAK3 and STAT3, which underlies the activation of these key cell‐survival pathways. A higher mutational allele frequency was detected in advanced stages. Conclusions Our results show that STAT3 is activated in advanced cases and is associated with large‐cell transformation, while the activation of NFAT and NF‐κB is maintained throughout the disease. These findings could have important diagnostic and therapeutic implications. What's already known about this topic? Mycosis fungoides is characterized by a clonal expansion of T cells in the skin. The mechanisms controlling disease development and progression are not fully understood. What does this study add? An association of the nuclear factor of activated T cells and nuclear factor kappa B pathways was found, which could reflect a common mechanism of activation. These pathways were activated in early and advanced stages at the same level. Signal transducer and activator of transcription 3 activation was associated with large‐cell transformation and was more frequent in advanced stages. A genomic analysis of cutaneous T‐cell lymphoma‐associated genes was performed. Nine mutations were detected. What is the translational message? These results could have important implications for the treatment of MF in ...

Background Millions of smartphones contain a photoplethysmography (PPG) bio-sensor (Maxim Integrated, San Jose CA) that accurately measures pulse oximetry. No clinical use of these embedded sensors is currently being made, despite the relevance of remote clinical pulse oximetry to the management of chronic cardiopulmonary disease, and the triage, initial management and remote monitoring of persons effected by respiratory viral pandemics, such as SARS-CoV-2 or Influenza. To be used for clinical pulse oximetry the embedded PPG system must be paired with an App and meet FDA and ISO requirements. Research Question We evaluated whether this smartphone sensor with App met FDA/ISO requirements and how measurements obtained using this system compared to hospital reference devices across a wide range of persons. Study Design and Methods We performed laboratory testing addressing ISO and FDA requirements in ten participants using the smartphone sensor with App. Subsequently, we performed an open label clinical study on 320 participants with widely varying characteristics, to compare accuracy and precision of readings obtained by patients, to hospital reference devices using a rigorous statistical methodology. Results ‘Breathe Down’ testing in the laboratory showed that the total Root Mean Square Deviation (RSMD) of SpO 2 measurement was 2.02%, meeting FDA/ISO standards. Clinical comparison of the smartphone sensor with App versus hospital reference devices determined SpO 2 and heart rate (HR) accuracy was 0.48 % points (CI 0.38 to 0.58; p<0.001) and 0.73 bpm (CI 0.33 to 1.14; p<0.001) respectively; with SpO 2 and HR precision 1.25 versus reference 0.95 points (p< 0.001) and 5.99 versus reference 3.80 bpm (p<0.001), respectively. These small differences were similar to the variation found between two FDA approved reference instruments for SpO 2 : accuracy 0.52 points (CI 0.41 to 0.64; p<0.001) and precision 1.01 versus 0.86 (p<0.001). Interpretation Our findings support the application for full FDA/ISO approval of the smartphone sensor with App tested for use in clinical pulse oximetry. Given the immense and immediate practical medical importance of remote intermittent clinical pulse oximetry to both chronic disease management and the global ability to respond to respiratory viral pandemics, the smartphone sensor with APP should be prioritized and fast tracked for FDA/ ISO approval to allow clinical use.

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