Cost-Effectiveness Analysis of a Prescription Digital Therapeutic in Type 2 Diabetes.

INTRODUCTION: BT-001 (AspyreRx™) prescription digital therapy, a form of personalized cognitive behavioral therapy, has demonstrated clinically meaningful and durable hemoglobin A1c reductions in patients with type 2 diabetes (T2D). The current study examined the cost-effectiveness of BT-001 plus standard of care (SoC) versus SoC alone in T2D over a lifetime horizon from a healthcare payer perspective. METHODS: We modeled the T2D pathway using an individual patient-level simulation; clinical data were sourced from the intention-to-treat subset of the BT-001 randomized clinical trial (RCT). SoC across both arms included the composition of oral and injectable treatments for T2D. Events were simulated using the United Kingdom Prospective Diabetes Study Outcomes Model 2 risk equation. A 3-month model cycle length was used in the first year, then annual model cycles were used in line with the original risk engine specifications. Patient characteristics informed event equations and Monte Carlo random sampling was used to assess the occurrence of events within each model cycle. Incidence of hypoglycemic events, drug discontinuation, costs, and health utilities and disutility values were sourced from the literature. RESULTS: From a payer perspective, BT-001 plus SoC versus SoC alone was dominant with a gain in quality-adjusted life years (QALYs) of 0.101 and cost savings of $7343 per patient over the lifetime horizon (i.e., more effective and less costly). BT-001 plus SoC was cost-effective at a willingness-to-pay of $100,000 per QALY (incremental net monetary benefit was $17,443). Savings with BT-001 were primarily driven by a reduction in drug acquisition costs. The reduction in hemoglobin A1c with BT-001 was associated with fewer T2D complications. CONCLUSIONS: BT-001 plus SoC was estimated to dominate SoC alone over the lifetime horizon from a payer perspective, suggesting that using BT-001 can empower patients to better manage their diabetes with the potential for lifelong advantages.

Reduced C-reactive protein level at hospital admission in patients treated with Tocilizumab - An attention may be required.

Background: C-reactive protein (CRP) is a marker of inflammation and infection. The main proinflammatory cytokine that leads to CRP gene expression is IL-6. The study aimed to compare CRP level between patients who were treated with Tocilizumab (TCZ), an il-6 receptor blocker, and other advanced anti-inflammatory treatments (AAIT), as well as with other admitted and non-admitted populations. Methods: A cross-sectional study of all patients (≥18 years) hospitalized at tertiary medical center between December 2009 and February 2020 and treated before hospitalization with (AAIT). Only the first hospitalization of each patient was included. Women admitted to obstetrics department were excluded. Demographic data, first blood tests results, and comorbidities were collected. Results: The study included 563 patients treated with AAIT (2.5% received TCZ). Patients treated with TCZ were older (median 75 vs. 50 years, p < 0.001), had higher Charlson score (median 5 vs. 1, p < 0.001) and more infectious diseases at admission (50% vs. 23.4%, p = 0.05). Patients treated with TCZ had lower CRP levels (median 0.5 vs. 25 mg/l, p < 0.001) and more common normal values (64.3% vs. 20.8%, p < 0.001) compared to patients treated with other AAIT.CRP level in patients treated TCZ (median 0.5 mg/l) was lower than that of 58,548 patients admitted to the hospital between 2010 and 2020 (median 12.55 mg/l, p < 0.001) and not statistically different from 140 non-admitted randomly selected individuals without acute disease (1.33 mg/l, p = 0.294). Conclusion: Tocilizumab is associated with lower levels of CRP in patients admitted to acute care hospital. This finding must be considered by treating physician to avoid misinterpretation of CRP results.

Terahertz reflection hyperspectral 3D imaging using beam scanning.

Terahertz (THz) radiation has the capability to combine spectroscopy and imaging in a single system. The resulting hyperspectral images can reveal concealed objects and identify materials by means of characteristic spectral features. For security applications, THz is attractive for its non-contact and non-destructive measurement capabilities. For such applications, objects may be too absorbing for transmission measurements, or only one side of an object may be accessible, necessitating a reflection measurement configuration. This work details the development and demonstration of a compact fiber-coupled hyperspectral imaging reflection system suited to field use for security and industrial applications. The system uses beam steering to measure objects of up to 150 mm diameter with a depth range of up to 255 mm, allowing for 3-dimensional mapping of objects, while simultaneously acquiring spectral data. Spectral information between 0.2-1.8 THz is extracted from a hyperspectral image and used to identify lactose, tartaric acid, and 4-aminobenzoic acid in high and low humidity environments.

Synovial monocytes from psoriatic and rheumatoid arthritis patients are modulated differently by TNF inhibitors and glucocorticoids: an ex-vivo study.

OBJECTIVES: Synovial monocytes (expressing CD14+CD16+) affect pro-inflammatory responses in the synovium microenvironment of psoriatic arthritis (PsA) and rheumatoid arthritis (RA). The effect of various drugs on those cells was evaluated. METHODS: Synovial fluid mononuclear cells (SFMCs) from PsA (n=29) and RA (n=11) patients were cultured with biologics or glucocorticoids (GCs). CD14+CD16+ cells were analysed by flow cytometry. TNF secretion was assessed by ELISA and changes in cytokine and matrix metalloproteinase-9 (MMP-9) mRNA by qPCR. RESULTS: TNF inhibitors (i) [adalimumab (ADA) and infliximab (IFX)] significantly reduced the %CD14+CD16+ cells (p<0.04 and p<0.02, respectively) compared to IL-17Ai, IL-12/23i, and GCs in PsA patients' SFMCs. Similarly, those TNFi reduced the %CD14+CD16+ cells (p<0.05 and p<0.02, respectively) compared to IL-6Ri, CD20i and GCs in RA patients' SFMCs. TNFi (ADA p<0.01, IFX p=0.0003), and GCs (p<0.05) reduced TNF levels in PsA patients SFMCs supernatants. IFX down-regulated IL-1ß mRNA (p<0.005) while GCs betamethasone (BET) (p<0.01) and methylprednisolone acetate (MPA) (p<0.005) led to IL-1ß up-regulation. IFX down-regulated IL-8 and MMP-9 (p<0.01) and up-regulated IL-10 (p<0.005), and GCs did so to a greater extent (for IL-8, BET p<0.0001 and MPA p<0.005, for MMP-9, BET and MPA p<0.0001 and for IL-10, BET and MPA p<0.0001). CONCLUSIONS: TNFi but not GCs reduced the inflammatory monocytes. Both TNFi and GCs inhibited TNF secretion but differently modulated IL-1ß, IL-8, MMP-9 and IL-10 gene expression. Our data point to TNFi as a modulator of synovial monocytes.

Randomized, Controlled Trial of a Digital Behavioral Therapeutic Application to Improve Glycemic Control in Adults With Type 2 Diabetes.

OBJECTIVE: To evaluate the efficacy and safety of a digital therapeutic application (app) delivering cognitive behavioral therapy (CBT) designed to improve glycemic control in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes and an HbA1c of 7 to <11% were randomly assigned to receive access to a digital therapeutic app delivering CBT (BT-001) or a control app, both on top of standard of care management. CBT is an established form of psychological treatment that endeavors to identify and change unhelpful thinking patterns. The primary study end point was treatment group difference in mean HbA1c change from baseline to 90 days. RESULTS: Among 669 randomly assigned subjects who completed app onboarding, the mean age was 58 years, BMI 35 kg/m2, 54% were female, 28% Black, and 16% Latino. Baseline HbA1c was 8.2 and 8.1% in the BT-001 and control groups, respectively. After 90 days of app access, change in HbA1c was -0.28% (95% CI -0.41, -0.15) in the BT-001 group and +0.11% (95% CI -0.02, 0.23) in the control group (treatment group difference 0.39%; P < 0.0001). HbA1c reduction paralleled exposure to the therapeutic intervention, assessed as the number of modules completed on the app (P for trend <0.0001). No adverse events in either group were attributed to app use and no adverse device effects reported. CONCLUSIONS: Patients randomly assigned to the BT-001 arm relative to the control arm had significantly lower HbA1c at 90 days. The digital therapeutic may provide a scalable treatment option for patients with type 2 diabetes.

Cognitive behavioral therapy delivered via digital mobile application for the treatment of type 2 diabetes: Rationale, design, and baseline characteristics of a randomized, controlled trial.

BACKGROUND: The prevalence of type 2 diabetes (T2D) continues to rise in the United States and worldwide. Cognitive behavioral therapy (CBT) has been shown to improve glycemic control in patients with T2D, but broad implementation has been limited by inherent access and resource constraints. Digital therapeutics have the potential to overcome these obstacles. HYPOTHESIS: To describe the rationale and design of a trial evaluating the efficacy and safety of a digital therapeutic providing CBT to improve glycemic control in adults with T2D. METHODS: This randomized, controlled, multicenter, Phase 3 trial evaluates the hypothesis that BT-001, an investigational digital therapeutic intended to help patients with T2D improve their glycemic control, on top of standard of care therapy, will lower hemoglobin A1c (HbA1c) compared to a control app across a broad range of patients in a real-world setting. The study is designed to provide evidence to support FDA review of this device as a digital therapeutic. The intervention is provided within the digital application (app) and includes no person-to-person coaching. The primary endpoint is the difference in HbA1c change from baseline to 90 days for BT-001-allocated subjects compared with those assigned to the control app. Safety assessment includes adverse events and adverse device effects. The study incorporates pragmatic features including entirely remote conduct with at-home visits for physical measures and blood sample collection. CONCLUSIONS: This randomized, controlled trial evaluates a cognitive behavioral intervention delivered via smartphone app which has the potential to provide a scalable treatment option for patients with T2D.

Ultrasound, magnetic resonance imaging and radiography of the finger joints in psoriatic arthritis patients.

OBJECTIVES: To report the discrepancies and agreements between US, MRI and radiography of the hand in PsA, and to compare the sensitivity and specificity of US and radiography to MRI as the gold standard imaging study in PsA. METHODS: All of the 100 prospectively recruited consecutive PsA patients underwent clinical assessment and concomitant radiographic, US and MRI studies of the MCP, PIP and DIP joints of one hand. Synovitis, flexor tenosynovitis, extensor paratenonitis, erosions and bone proliferations were identified and scored. All readers were blinded to clinical data, and agreement was calculated based on prevalence-adjusted bias-adjusted kappa (PABAK). RESULTS: The prevalence of synovitis, flexor tenosynovitis, extensor paratenonitis and erosions was similar for US and MRI, while that of bone proliferation was significantly increased in US and radiography compared with MRI (P < 0.001). The absolute agreement between US and MRI was good-to-very good for synovitis (85-96%, PABAK = 0.70-0.92), flexor tenosynovitis (93-98%, PABAK = 0.87-0.96) and extensor paratenonitis (95-98%, PABAK = 0.90-0.97). Agreement between US, MRI and radiography was 96-98% (PABAK = 0.92-0.97) for erosions and 71-93% (PABAK = 0.47-0.87) for bone proliferations. Sensitivity of US with MRI as gold standard was higher for synovitis (0.5-0.86) and extensor paratenonitis (0.63-0.85) than for flexor tenosynovitis (0.1-0.75), while the specificity was high for each pathology (0.89-0.98). CONCLUSION: There is very good agreement between US and MRI for the detection of inflammatory changes in finger joints in PsA. US, radiography and MRI have a good-to-very good agreement for destructive changes.

Treatment with Ixekizumab Following Secukinumab Failure in Patients with Psoriatic Arthritis: Real-Life Experience from a Resistant Population.

OBJECTIVE: To assess the clinical response to ixekizumab following secukinumab failure in patients with psoriatic arthritis. METHODS: A retrospective multi-center observational study included psoriatic arthritis (PsA) patients with a history of treatment with secukinumab, further treated with ixekizumab. Primary endpoint was primary response to treatment (drug survival > 6 months); secondary endpoints were changes in disease activity indices from initiation of ixekizumab to 6 and 12 months later and overall drug survival. RESULTS: Of 23 PsA patients, 86% (n = 20) received more than two TNF inhibitors (TNFi). Median secukinumab treatment time was 15 months (IQR 10-21.5 months). Subsequently, 19 patients (83%) had a primary response to ixekizumab. Overall treatment duration during follow-up period for primary responders was 14 months (IQR 10-20.5). Reasons for ixekizumab cessation were worsening psoriasis (27%), peripheral arthritis (27%), both (47%), worsening of axial disease (13%), and adverse events (6%). Articular disease indices including Disease Activity Index for Psoriatic Arthritis (DAPSA), tender joints count (TJC) and Simplified Disease Activity Index (SDAI) were significantly lower at 6 and 12 months (DAPSA 1.5-2 levels reduction; p = 0.018 and 1-1.5 levels reduction; p = 0.031, respectively; TJC -2.16 [-4.0, -0.3]; p = 0.025 and -1.69 [-3.09, -0.28]; p = 0.022, respectively; SDAI -10.13 [-16.4, -3.8], p = 0.003 and -12.2 [-17.1, -7.2], p = 0.0002, respectively). PASI75 at 6 and 12 months was achieved by 63% and 57%, respectively, and PASI100 at 6 and 12 months by 31% and 21%, respectively. CONCLUSION: Patients with resistant PsA, including inadequate response to secukinumab, demonstrated a good response to ixekizumab, albeit limited on time. Within class switch from secukinumab to ixekizumab may be a plausible therapeutic option in PsA patients following secukinumab failure.

Role of ultrasound for assessment of psoriatic arthritis patients with fibromyalgia.

OBJECTIVE: To investigate whether ultrasonography (US), as an objective imaging modality, can optimise the evaluation of disease activity in psoriatic arthritis (PsA) patients with concomitant fibromyalgia syndrome (FMS). METHODS: The study population included 156 consecutive PsA patients who were recruited prospectively and fulfilled the ClASsification criteria for Psoriatic ARthritis criteria. The patients underwent complete clinical evaluation including assessment of fulfilment of the 2016 fibromyalgia classification criteria. All of the patients underwent US evaluation including 52 joints, 40 tendons and 14 entheses. The US score was based on the summation of a semiquantitative score (including synovitis, tenosynovitis and enthesitis). Scoring was performed by a sonographer blinded to the clinical data. Spearman's correlation coefficient and multivariate linear regression models were used to examine the association of FMS with clinical and the US scores. RESULTS: Forty-two patients (26.9%) with coexisting PsA and FMS were compared with 114 (73.1%) PsA patients without FMS. Patients with PsA and FMS had significantly increased scores for clinical composite indices, including non-Minimal Disease Activity, Composite Psoriatic Disease Activity Index (CPDAI), Disease Activity for Psoriatic Arthritis (DAPSA) and Psoriatic Arthritis Disease Activity Score (PASDAS) (p<0.001). In contrast, the total US score and its subcategories were similar for those with and without FMS. The total US score significantly correlated with CPDAI, DAPSA and PASDAS (p<0.001) in the PsA without FMS but not in the PsA with FMS group. FMS was significantly associated with higher clinical scores (p<0.001) but not with the US score (multivariable linear regression models). CONCLUSIONS: US has significantly greater value than composite clinical scores in the assessment of disease activity in PsA patients with FMS.

The Effect of Tocilizumab on Inflammatory Markers in Patients Hospitalized with Serious Infections. Case Series and Review of Literature.

BACKGROUND: The human anti-IL-6 receptor antibody tocilizumab (TCZ) has been approved for the treatment of rheumatoid arthritis (RA) and giant cell arteritis (GCA). It is observed that CRP levels drop quickly after starting TCZ treatment. This may lead to misinterpretation of laboratory results when accessing the patient with infectious disease while on TCZ. We conducted this study to report cases treated with tocilizumab who developed serious infections with special reference to levels of CRP and to review the literature on the effect of tocilizumab on acute phase response (APR) during infections. METHODS: The files of RA and GCA patients hospitalized in the Tel Aviv medical center between 2009-2019 were reviewed. Cases of patients with RA and GCA treated with tocilizumab who were hospitalized due to severe infections were reviewed with special emphasis on the duration of treatment, type of infection, and APR. RESULTS: We identified nine admissions. Seven patients were treated with tocilizumab for RA, two for GCA. The diagnosis was pneumonia in three cases, osteomyelitis in one, cellulitis in one, endocarditis due to Whipple disease in one, abscess of cervix uteri in one, meningitis in one, and perforated diverticulitis in one. The mean CRP levels on admission were 4.75 mg/L (normal range, up to 5 mg/L). All cases were diagnosed correctly on admission. CONCLUSIONS: CRP levels may not correctly reflect the severity of infectious diseases during tocilizumab treatment. Increased awareness of the masking effect of tocilizumab on the APR during infection is needed in order to avoid a delay in the diagnosis.

Prevalence of Nonradiographic Sacroiliitis in Patients With Psoriatic Arthritis: A Real-life Observational Study.

OBJECTIVE: To establish the prevalence of nonradiographic sacroiliitis within a real-life sample of patients with psoriatic arthritis (PsA), using pelvic radiographs and magnetic resonance imaging (MRI) of sacroiliac joints (SIJs). METHODS: This cross-sectional study included 107 consecutive adults with PsA (Classification Criteria for Psoriatic Arthritis criteria). Participants completed clinical and laboratory evaluation, pelvic radiographs scored for radiographic sacroiliitis according to the modified New York (mNY) criteria, and noncontrast MRI of SIJs, scored by the Berlin score and categorized into active sacroiliitis using the 2016 Assessment of Spondyloarthritis international Society (ASAS) criteria and the presence of structural sacroiliitis. RESULTS: Radiographic sacroiliitis/mNY criteria were detected in 28.7% (n = 29), confirmed by MRI-detected structural lesions in 72.4% (n = 21). Active sacroiliitis was detected by MRI in 26% (n = 28) of patients, with 11% (n = 11) qualifying for nonradiographic sacroiliitis. Patients with radiographic and nonradiographic sacroiliitis had similar clinical characteristics, except for a longer duration of psoriasis (PsO) and PsA in the radiographic subgroup (PsO: 23.8 ± 12.5 vs 14.1 ± 11.7 yrs, P = 0.03; PsA: 12.3 ± 9.8 vs 4.7 ± 4.5 yrs, P = 0.02, respectively). Inflammatory back pain (IBP) was reported in 46.4% (n = 13) with active sacroiliitis and 27% (n = 3) with nonradiographic sacroiliitis. The sensitivity of IBP for detection of nonradiographic sacroiliitis was low (27%) and moderate for radiographic sacroiliitis (52%), whereas specificity ranged from 72% to 79% for radiographic and nonradiographic sacroiliitis, respectively. CONCLUSION: The prevalence of active sacroiliitis among a real-life population of patients with PsA was 26%. However, the prevalence of nonradiographic sacroiliitis was low (11%) compared to the radiographic sacroiliitis (28.7%) seen in patients with longer disease duration. IBP was not a sensitive indicator for the presence of early-stage sacroiliitis that was commonly asymptomatic.

Rituximab for refractory manifestations of the antiphospholipid syndrome: a multicentre Israeli experience.

OBJECTIVES: The clinical manifestations of the antiphospholipid syndrome (APS) are heterogeneous and related to anti-phospholipid antibodies (aPL). There is some evidence that B cells are involved in the pathogenesis of this condition. Thus the ability of rituximab (RTX) to deplete B cells makes it an appealing potential therapy for refractory antiphospholipid syndrome (APS). Real world data on RTX treatment of APS are still lacking. This study was conducted to report outcomes of RTX administration in the treatment of different aspects of APS. METHODS: This is a retrospective case series study on APS patients from 3 medical centres in Israel who were treated with RTX during 2010-2019 for refractory manifestations of APS including diffuse alveolar haemorrhage, recurrent thrombosis, cytopenia, neurological and skin manifestations. Medical records were reviewed regarding the clinical indication for RTX treatment, concomitant medications, RTX protocol, aPL status and response to treatment. Outcomes were defined as complete response if full resolution of the "indicated manifestation" was achieved and maintained for at least 12 months, partial response or no response. RESULTS: We identified 40 APS patients who were treated with RTX for refractory manifestations of this condition, of whom, 24 patients (60%) were female with a mean age of 40 years, and 31 patients (78%) were diagnosed with primary APS. A favourable response to RTX was documented in 32 patients (80%) including a complete response in 22 patients (55%). Response to RTX treatment was associated with a rituximab protocol of 375mg/m2 x 4 compared to a fixed dose of 1000 mg x2 (100% vs. 65%; p=0.01). Complete response was associated with a decrease in aPL titres within 4-6 months post treatment, whereas no significant change in aPL titres was observed in patients with partial or no response. CONCLUSIONS: Consistent with previous small case series, we report a good therapeutic response to RTX in patients with difficult to treat manifestations of APS. In this cohort, treatment protocols were associated with outcomes. Although further studies are required to verify our observations, our data support a plausible role for B cell depletion in refractory APS.

Immunogenicity and safety of vaccination against seasonal influenza vaccine in patients with psoriatic arthritis treated with secukinumab.

OBJECTIVE: To assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) patients treated with secukinumab versus healthy controls (HC). METHODS: PsA patients administered secukinumab for ≥3 months and HC received the Sanofi Pasteur vaccine composed of 3 antigens (H3N3, H1N1, and B) and underwent clinical and laboratory assessments on the day of vaccination and 4-6 weeks later. Immunogenicity of the vaccine was evaluated by hemagglutination inhibition assay against those 3 antigens. Responders to each antigen were defined by a 4-fold increase in the antigen titer or by seroconversion in patients whose baseline level was <1/40. RESULTS: Thirty-two consecutive PsA patients treated with secukinumab for ≥3 months comprised the study group, 10 of whom received concomitant conventional synthetic disease-modifying drugs, mostly methotrexate. There were 17 age- and gender-matched HC (median age 48.5 years, 6 females). The geometric mean titers of each antigen increased significantly in both groups. The number of responders in each group was similar for H3N2 and H1N1, and significantly higher for B/Brisbane in the PsA group. The proportion of patients with a seroprotective level (a titer >1/40) was high and similar in both groups. There was no correlation between the response rate and age, gender, or selected parameters of disease activity (tender/swollen joint counts, Leeds enthesitis index, physician and patient global assessment, psoriasis area severity index, and C-reactive protein). No disease exacerbation was observed following the vaccination. No serious adverse effects were observed in both groups during the study period. CONCLUSION: Secukinumab treatment does not affect the humoral response to influenza vaccine of patients with PsA.

Achieving Rapid Blood Pressure Control With Digital Therapeutics: Retrospective Cohort and Machine Learning Study.

BACKGROUND: Behavioral therapies, such as electronic counseling and self-monitoring dispensed through mobile apps, have been shown to improve blood pressure, but the results vary and long-term engagement is a challenge. Machine learning is a rapidly advancing discipline that can be used to generate predictive and responsive models for the management and treatment of chronic conditions and shows potential for meaningfully improving outcomes. OBJECTIVE: The objectives of this retrospective analysis were to examine the effect of a novel digital therapeutic on blood pressure in adults with hypertension and to explore the ability of machine learning to predict participant completion of the intervention. METHODS: Participants with hypertension, who engaged with the digital intervention for at least 2 weeks and had paired blood pressure values, were identified from the intervention database. Participants were required to be ≥18 years old, reside in the United States, and own a smartphone. The digital intervention offers personalized behavior therapy, including goal setting, skill building, and self-monitoring. Participants reported blood pressure values at will, and changes were calculated using averages of baseline and final values for each participant. Machine learning was used to generate a model of participants who would complete the intervention. Random forest models were trained at days 1, 3, and 7 of the intervention, and the generalizability of the models was assessed using leave-one-out cross-validation. RESULTS: The primary cohort comprised 172 participants with hypertension, having paired blood pressure values, who were engaged with the intervention. Of the total, 86.1% participants were women, the mean age was 55.0 years (95% CI 53.7-56.2), baseline systolic blood pressure was 138.9 mmHg (95% CI 136.6-141.3), and diastolic was 86.2 mmHg (95% CI 84.8-87.7). Mean change was -11.5 mmHg for systolic blood pressure and -5.9 mmHg for diastolic blood pressure over a mean of 62.6 days (P<.001). Among participants with stage 2 hypertension, mean change was -17.6 mmHg for systolic blood pressure and -8.8 mmHg for diastolic blood pressure. Changes in blood pressure remained significant in a mixed-effects model accounting for the baseline systolic blood pressure, age, gender, and body mass index (P<.001). A total of 43% of the participants tracking their blood pressure at 12 weeks achieved the 2017 American College of Cardiology/American Heart Association definition of blood pressure control. The 7-day predictive model for intervention completion was trained on 427 participants, and the area under the receiver operating characteristic curve was .78. CONCLUSIONS: Reductions in blood pressure were observed in adults with hypertension who used the digital therapeutic. The degree of blood pressure reduction was clinically meaningful and achieved rapidly by a majority of the studied participants. Greater improvement was observed in participants with more severe hypertension at baseline. A successful proof of concept for using machine learning to predict intervention completion was presented.

Estimating the Impact of Novel Digital Therapeutics in Type 2 Diabetes and Hypertension: Health Economic Analysis.

BACKGROUND: Behavioral interventions can meaningfully improve cardiometabolic conditions. Digital therapeutics (DTxs) delivering these interventions may provide benefits comparable to pharmacologic therapies, displacing medications for some patients. OBJECTIVE: Our objective was to estimate the economic impact of a digital behavioral intervention in type 2 diabetes mellitus (T2DM) and hypertension (HTN) and estimate the impact of clinical inertia on deprescribing medications. METHODS: Decision analytic models estimated health resource savings and cost effectiveness from a US commercial payer perspective. A 3-year time horizon was most relevant to the intervention and payer. Effectiveness of the DTx in improving clinical outcomes was based on cohort studies and published literature. Health resource utilization (HRU), health state utilities, and costs were drawn from the literature with costs adjusted to 2018 dollars. Future costs and quality-adjusted life years (QALYs) were discounted at 3%. Sensitivity analyses assessed uncertainty. RESULTS: Average HRU savings ranged from $97 to $145 per patient per month, with higher potential benefits in T2DM. Cost-effectiveness acceptability analyses using a willingness-to-pay of $50,000/QALY indicated that the intervention would be cost effective at total 3-year program costs of $6468 and $6620 for T2DM and HTN, respectively. Sensitivity analyses showed that reduced medication costs are a primary driver of potential HRU savings, and the results were robust within values tested. A resistance to deprescribe medications when a patient's clinical outcomes improve can substantially reduce the estimated economic benefits. Our models rely on estimates of clinical effectiveness drawn from limited cohort studies with DTxs and cannot account for other disease management programs that may be implemented. Performance of DTxs in real-world settings is required to further validate their economic benefits. CONCLUSIONS: The DTxs studied may provide substantial cost savings, in part by reducing the use of conventional medications. Clinical inertia may limit the full cost savings of DTxs.

Personal cell therapy for interstitial cystitis with autologous stromal vascular fraction stem cells.

BACKGROUND: The objective of this study was to evaluate whether autologous stem-cell-based therapy may mitigate the symptoms of interstitial cystitis. METHODS: Stromal vascular fraction (SVF) rich in stem cells and derived from autologous adipose tissue was deployed into 109 men and women with interstitial cystitis/painful bladder syndrome as a surgical procedure. This stem-cell-rich biologic product was injected both systemically and regionally into pelvic floor targets. Patients were queried about quality of life and symptom and bother subjective outcomes tests every 3 months for 2 years. RESULTS: A total of 78 patients reported a positive response at 1 year. Symptom and bother metrics were statistically improved at 1 year. There were minimal adverse events associated with the harvesting, procurement, and clinical deployment of SVF. CONCLUSION: Interstitial cystitis is a complex clinical problem that is known for its resistance to conventional therapies. SVF as an autologous personalized regenerative strategy shows good safety and efficacy and may potentially have a role in the mitigation of interstitial cystitis.

First-in-human study of TK-positive oncolytic vaccinia virus delivered by adipose stromal vascular fraction cells.

BACKGROUND: ACAM2000, a thymidine kinase (TK)-positive strain of vaccinia virus, is the current smallpox vaccine in the US. Preclinical testing demonstrated potent oncolytic activity of ACAM2000 against several tumor types. This Phase I clinical trial of ACAM2000 delivered by autologous adipose stromal vascular fraction (SVF) cells was conducted to determine the safety and feasibility of such a treatment in patients with advanced solid tumors or acute myeloid leukemia (AML). METHODS: Twenty-four patients with solid tumors and two patients with AML participated in this open-label, non-randomized dose-escalation trial. All patients were treated with SVF derived from autologous fat and incubated for 15 min to 1 h with ACAM2000 before application. Six patients received systemic intravenous application only, one patient received intra-tumoral application only, 15 patients received combination intravenous with intra-tumoral deployment, 3 patients received intravenous and intra-peritoneal injection and 1 patient received intravenous, intra-tumoral and intra-peritoneal injections. Safety at each dose level of ACAM2000 (1.4 × 106 plaque-forming units (PFU) to 1.8 × 107 PFU) was evaluated. Blood samples for PK assessments, flow cytometry and cytokine analysis were collected at baseline and 1 min, 1 h, 1 day, 1 week, 1 month, 3 months and 6 months following treatment. RESULTS: No serious toxicities (> grade 2) were reported. Seven patients reported an adverse event (AE) in this study: self-limiting skin rashes, lasting 7 to 18 days-an expected adverse reaction to ACAM2000. No AEs leading to study discontinuation were reported. Viral DNA was detected in all patients' blood samples immediately following treatment. Interestingly, in 8 patients viral DNA disappeared 1 day and re-appeared 1 week post treatment, suggesting active viral replication at tumor sites, and correlating with longer survival of these patients. No major increase in cytokine levels or correlation between cytokine levels and skin rashes was noted. We were able to assess some initial efficacy signals, especially when the ACAM2000/SVF treatment was combined with checkpoint inhibition. CONCLUSIONS: Treatment with ACAM2000/SVF in patients with advanced solid tumors or AML is safe and well tolerated, and several patients had signals of an anticancer effect. These promising initial clinical results merit further investigation of therapeutic utility. Trial registration Retrospectively registered (ISRCTN#10201650) on October 22, 2018.

Emergence of digital biomarkers to predict and modify treatment efficacy: machine learning study.

OBJECTIVES: Development of digital biomarkers to predict treatment response to a digital behavioural intervention. DESIGN: Machine learning using random forest classifiers on data generated through the use of a digital therapeutic which delivers behavioural therapy to treat cardiometabolic disease. Data from 13 explanatory variables (biometric and engagement in nature) generated in the first 28 days of a 12-week intervention were used to train models. Two levels of response to treatment were predicted: (1) systolic change ≥10 mm Hg (SC model), and (2) shift down to a blood pressure category of elevated or better (ER model). Models were validated using leave-one-out cross validation and evaluated using area under the curve receiver operating characteristics (AUROC) and specificity- sensitivity. Ability to predict treatment response with a subset of nine variables, including app use and baseline blood pressure, was also tested (models SC-APP and ER-APP). SETTING: Data generated through ad libitum use of a digital therapeutic in the USA. PARTICIPANTS: Deidentified data from 135 adults with a starting blood pressure ≥130/80, who tracked blood pressure for at least 7 weeks using the digital therapeutic. RESULTS: The SC model had an AUROC of 0.82 and a sensitivity of 58% at a specificity of 90%. The ER model had an AUROC of 0.69 and a sensitivity of 32% at a specificity at 91%. Dropping explanatory variables related to blood pressure resulted in an AUROC of 0.72 with a sensitivity of 42% at a specificity of 90% for the SC-APP model and an AUROC of 0.53 for the ER-APP model. CONCLUSIONS: Machine learning was used to transform data from a digital therapeutic into digital biomarkers that predicted treatment response in individual participants. Digital biomarkers have potential to improve treatment outcomes in a digital behavioural intervention.

Human intracerebroventricular (ICV) injection of autologous, non-engineered, adipose-derived stromal vascular fraction (ADSVF) for neurodegenerative disorders: results of a 3-year phase 1 study of 113 injections in 31 patients.

We have chosen to test the safety of human intracerebroventricular (ICV) brain injections of autologous non-genetically-modified adipose-derived stromal vascular fraction (ADSVF). In this IRB-approved trial, 24 patients received ICV ADSVF via an implanted reservoir between 5/22/14 and 5/22/17. Seven others were injected via their ventriculo-peritoneal shunts. Ten patients had Alzheimer's disease (AD), 6 had amyotrophic lateral sclerosis (ALS), 6 had progressive multiple sclerosis (MS-P), 6 had Parkinson's "Plus" (PD+), 1 had spinal cord injury, 1 had traumatic brain injury, and 1 had stroke. Median age was 74 (range 41-83). Injections were planned every 2-3 months. Thirty-one patients had 113 injections. Patients received SVF injection volumes of 3.5-20 cc (median:4 cc) containing 4.05 × 105 to 6.2 × 107 cells/cc, which contained an average of 8% hematopoietic and 7.5% adipose stem cells. Follow-up ranged from 0 to 36 months (median: 9.2 months). MRIs post injection(s) were unchanged, except for one AD patient whose hippocampal volume increased from < 5th percentile to 48th percentile (NeuroQuant® volumetric MRI). Of the 10 AD patients, 8 were stable or improved in tests of cognition. Two showed improvement in P-tau and ß-amyloid levels. Of the 6 MS-P patients all are stable or improved. Four of 6 ALS patients died of disease progression. Twelve of 111 injections (11%) led to 1-4 days of transient meningismus, and mild temperature elevation, which resolved with acetaminophen and/or dexamethasone. Two (1.8% of injections) required hospitalization for these symptoms. One patient (0.9% of injections) had his reservoir removed and later replaced for presumed infection. In this Phase 1 safety trial, ADSVF was safely injected into the human brain ventricular system in patients with no other treatment options. Secondary endpoints of clinical improvement or stability were particularly promising in the AD and MS-P groups. These results will be submitted for a Phase 2 FDA-approved trial.