Digitizing clinical trials.

Clinical trials are a fundamental tool used to evaluate the efficacy and safety of new drugs and medical devices and other health system interventions. The traditional clinical trials system acts as a quality funnel for the development and implementation of new drugs, devices and health system interventions. The concept of a "digital clinical trial" involves leveraging digital technology to improve participant access, engagement, trial-related measurements, and/or interventions, enable concealed randomized intervention allocation, and has the potential to transform clinical trials and to lower their cost. In April 2019, the US National Institutes of Health (NIH) and the National Science Foundation (NSF) held a workshop bringing together experts in clinical trials, digital technology, and digital analytics to discuss strategies to implement the use of digital technologies in clinical trials while considering potential challenges. This position paper builds on this workshop to describe the current state of the art for digital clinical trials including (1) defining and outlining the composition and elements of digital trials; (2) describing recruitment and retention using digital technology; (3) outlining data collection elements including mobile health, wearable technologies, application programming interfaces (APIs), digital transmission of data, and consideration of regulatory oversight and guidance for data security, privacy, and remotely provided informed consent; (4) elucidating digital analytics and data science approaches leveraging artificial intelligence and machine learning algorithms; and (5) setting future priorities and strategies that should be addressed to successfully harness digital methods and the myriad benefits of such technologies for clinical research.

Granulocytic myeloid-derived suppressor cells (GR-MDSC) accumulate in cord blood of preterm infants and remain elevated during the neonatal period.

Preterm delivery is the leading cause of perinatal morbidity and mortality. Among the most important complications in preterm infants are peri- or postnatal infections. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells. Emerging evidence suggests that granulocytic MDSC (GR-MDSC) play a pivotal role in mediating maternal-fetal tolerance. The role of MDSC for postnatal immune-regulation in neonates is incompletely understood. Until the present time, nothing was known about expression of MDSC in preterm infants. In the present pilot study, we quantified GR-MDSC counts in cord blood and peripheral blood of preterm infants born between 23 + 0 and 36 + 6 weeks of gestation (WOG) during the first 3 months of life and analysed the effect of perinatal infections. We show that GR-MDSC are increased in cord blood independent of gestational age and remain elevated in peripheral blood of preterm infants during the neonatal period. After day 28 they drop to nearly adult levels. In case of perinatal or postnatal infection, GR-MDSC accumulate further and correlate with inflammatory markers C-reactive protein (CRP) and white blood cell counts (WBC). Our results point towards a role of GR-MDSC for immune-regulation in preterm infants and render them as a potential target for cell-based therapy of infections in these patients.

The iTreAD project: a study protocol for a randomised controlled clinical trial of online treatment and social networking for binge drinking and depression in young people.

BACKGROUND: Depression and binge drinking behaviours are common clinical problems, which cause substantial functional, economic and health impacts. These conditions peak in young adulthood, and commonly co-occur. Comorbid depression and binge drinking are undertreated in young people, who are reluctant to seek help via traditional pathways to care. The iTreAD project (internet Treatment for Alcohol and Depression) aims to provide and evaluate internet-delivered monitoring and treatment programs for young people with depression and binge drinking concerns. METHODS: Three hundred sixty nine participants will be recruited to the trial, and will be aged 18-30 years will be eligible for the study if they report current symptoms of depression (score 5 or more on the depression subscale of the Depression Anxiety Stress Scale) and concurrent binge drinking practices (5 or more standard drinks at least twice in the prior month). Following screening and online baseline assessment, participants are randomised to: (a) online monthly self-assessments, (b) online monthly self-assessments + 12-months of access to a 4 week online automated cognitive behaviour therapy program for binge drinking and depression (DEAL); or (c) online monthly assessment + DEAL + 12-months of access to a social networking site (Breathing Space). Independent, blind follow-up assessments occur at 26, 39, 52 and 64-weeks post-baseline. DISCUSSION: The iTreAD project is the first randomised controlled trial combining online cognitive behaviour therapy, social networking and online monitoring for young people reporting concerns with depression and binge drinking. These treatments represent low-cost, wide-reach youth-appropriate treatment, which will have significantly public health implications for service design, delivery and health policy for this important age group. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12614000310662. Date registered 24 March 2014.

Neutrophilic myeloid-derived suppressor cells in cord blood modulate innate and adaptive immune responses.

Neonates show an impaired anti-microbial host defence, but the underlying immune mechanisms are not understood fully. Myeloid-derived suppressor cells (MDSCs) represent an innate immune cell subset characterized by their capacity to suppress T cell immunity. In this study we demonstrate that a distinct MDSC subset with a neutrophilic/granulocytic phenotype (Gr-MDSCs) is highly increased in cord blood compared to peripheral blood of children and adults. Functionally, cord blood isolated Gr-MDSCs suppressed T cell proliferation efficiently as well as T helper type 1 (Th1), Th2 and Th17 cytokine secretion. Beyond T cells, cord blood Gr-MDSCs controlled natural killer (NK) cell cytotoxicity in a cell contact-dependent manner. These studies establish neutrophilic Gr-MDSCs as a novel immunosuppressive cell subset that controls innate (NK) and adaptive (T cell) immune responses in neonates. Increased MDSC activity in cord blood might serve as key fetomaternal immunosuppressive mechanism impairing neonatal host defence. Gr-MDSCs in cord blood might therefore represent a therapeutic target in neonatal infections.

In vivo high-resolution fluorescence microendoscopy for ovarian cancer detection and treatment monitoring.

BACKGROUND: In patients with advanced ovarian cancer (OvCa), microscopic residual tumour nodules that remain after surgical debulking frequently escape detection by current treatment assessment methods and lead to disease recurrence. The aim of this study was to evaluate the use of high-resolution fibre-optic fluorescence imaging of the clinically approved photodynamic therapy (PDT) agent benzoporphyin-derivative monoacid ring A (BPD-MA) for detection of microscopic OvCa and for monitoring treatment response. METHODS: Our fluorescence microendoscope consists of a flexible imaging fibre coupled to a custom epi-fluorescence system optimised for imaging BPD-MA, which, after a single administration, serves as both an imaging agent and a light-activated therapeutic agent. After characterisation in an in vitro OvCa 3D model, we used the flexible imaging fibre to minimally invasively image the peritoneal cavity of a disseminated OvCa murine model using BPD-MA administered intraperitoneally (i.p.). To evaluate longitudinal changes in response to treatment, we compared sets of images obtained before and after PDT with those from untreated mice imaged at the same time points. RESULTS: By comparison with histopathology, we report an 86% sensitivity for tumour detection in vivo using the microendoscope. Using a custom routine to batch process-image data in the monitoring study, treated mice exhibited an average decrease of 58.8% in tumour volumes compared with an increase of 59.3% in untreated controls (P<0.05). CONCLUSIONS: Our findings indicate the potential of this approach as a reporter of treatment outcome that could aid in the rational design of strategies to mitigate recurrent OvCa.

[Role of endovascular therapy for redo surgery in patients after aortoiliac aneurysm exclusion]. / Stellenwert der endovaskulären Therapie bei Reeingriffen nach Ausschaltung aortoiliakaler Aneurysmata.

INTRODUCTION: Redo surgery or reintervention following conventional or endovascular aortoiliac reconstruction often requires exclusion of new aneurysms. In the present study the potentials of endovascular management of such lesions are investigated. METHODS: All patients with endovascular reoperation for of newly developed aortoiliac aneurysms were identified from a prospectively run data-base. The indications and results of endovascular therapy were analysed retrospectively. In detail, data were analysed for the type of original operation, interval until and kind of reoperation, and results concerning survival, technical success and complications. RESULTS: From 12 / 2003 through 3 / 2007 195 patients with aortoiliac aneurysms were operated. Endovascular repair was performed in 15 cases of previously excluded aneurysms. Mean age of these 15 patients (12 men) was 73 (64-85) years. Ten patients had a primary conventional (group A) and 5 patients had a primary endovascular (group B) aneurysm repair. The mean time interval between the first and second operation was 8.9 (1-26) years. The secondary endovascular therapy in group A was successful in all cases. In group B endoleaks type I a (n = 1), I a / b (n = 1), II (n = 2) and III (n = 1) were treated. One type II endoleak could only be treated successfully by conversion to open repair, the other one was successfully treated by reintervention. All but one patient are alive and -remained free of pathological findings during a median follow-up of 13 (2-39) months. DISCUSSION: Because of the clearly elevated operation risk of redo surgery after conventional or endovascular aneurysm repair, endovascular aneurysm exclusion represents the method of first choice. The reasonable selection and combination of procedures allows for an optimal adaptation of therapy to the individual case.

Image analysis for denoising full-field frequency-domain fluorescence lifetime images.

Video-rate fluorescence lifetime-resolved imaging microscopy (FLIM) is a quantitative imaging technique for measuring dynamic processes in biological specimens. FLIM offers valuable information in addition to simple fluorescence intensity imaging; for instance, the fluorescence lifetime is sensitive to the microenvironment of the fluorophore allowing reliable differentiation between concentration differences and dynamic quenching. Homodyne FLIM is a full-field frequency-domain technique for imaging fluorescence lifetimes at every pixel of a fluorescence image simultaneously. If a single modulation frequency is used, video-rate image acquisition is possible. Homodyne FLIM uses a gain-modulated image intensified charge-coupled device (ICCD) detector, which unfortunately is a major contribution to the noise of the measurement. Here we introduce image analysis for denoising homodyne FLIM data. The denoising routine is fast, improves the extraction of the fluorescence lifetime value(s) and increases the sensitivity and fluorescence lifetime resolving power of the FLIM instrument. The spatial resolution (especially the high spatial frequencies not related to noise) of the FLIM image is preserved, because the denoising routine does not blur or smooth the image. By eliminating the random noise known to be specific to photon noise and from the intensifier amplification, the fidelity of the spatial resolution is improved. The polar plot projection, a rapid FLIM analysis method, is used to demonstrate the effectiveness of the denoising routine with exemplary data from both physical and complex biological samples. We also suggest broader impacts of the image analysis for other fluorescence microscopy techniques (e.g. super-resolution imaging).

Phagocytosis and postphagocytic reaction of cord blood and adult blood monocyte after infection with green fluorescent protein-labeled Escherichia coli and group B Streptococci.

BACKGROUND: Neonatal sepsis is characterized by an excessive inflammatory response induced by immune cells (monocytes). We investigated the initial stage of monocyte-pathogen interaction, i.e. bacterial ingestion and degradation at the single-cell level, by comparing a new flow cytometric procedure with culture methods. We also examined the hypothesis that, in terms of phagocytosis-induced cell death (PICD), phenotype, or cytokine production, cord blood monocytes (CBMO) differ from monocytes derived from adults (peripheral blood monocytes, PBMO). METHODS: Phagocytosis and intracellular degradation were assessed by means of flow cytometry and bacterial cultures of green fluorescent protein-labeled group B Streptococci (GBS) and Escherichia coli. The production of reactive oxygen species (ROS) was measured through luminol-enhanced chemiluminescence. Apoptosis, phenotype, and cytokine production were assessed through flow cytometry. RESULTS: Flow cytometry and bacterial cultures showed no difference between phagocytosis and degradation of GBS and E. coli by PBMO and CBMO. A high correlation between both methods was observed. No difference in ROS production was evident. In comparison with PBMO, CBMO apoptosis was lower after exposure to GBS and E. coli. Similarities were found between nonapoptotic monocytes and pro-inflammatory monocytes. CONCLUSIONS: PICD is lower in CBMO during the early stages of monocyte-pathogen interaction. Our results emphasize that monocyte apoptosis has a potential role in tailoring the immune response in neonatal sepsis.

[Endovascular therapy of an abdominal aortic aneurysm in a renal transplant recipient]. / Endovaskuläre Therapie eines infrarenalen Aortenaneurysmas bei heterotopem Nierentransplantat.

INTRODUCTION: The indications for endovascular aortic aneurysm repair (EVAR) are mainly established in hostile abdomen, in patients with significant comorbidities which affect the general operability of the patient and, given the necessary infrastructure, also in ruptured aneurysm. Along to those, we present another possible indication in the presence of a kidney allograft in patients with aortic aneurysm. METHODS: Based on a case report of aorto-biiliac stent-graft repair of an infrarenal aortic aneurysm in a patient with renal allograft, a systematic review of the literature was performed of all similar cases concerning surgical therapy in this constellation. RESULTS: EVAR was performed using an aorto-biiliac system (Zenith) Trifab, COOK) in a 61-year-old male patient 11 years after heterotopic renal allotransplantation in the right iliac fossa. Preoperative renal function was normal. Because the donor renal artery was anastomosed to the recipient's external iliac artery the stent-graft was implanted from the left common femoral artery to minimize temporary allograft ischemia. The intra- and postoperative course was uneventful with a follow-up of presently 12 months. A primary type-II endoleak (retroleak from a lumbar artery) is being treated conservatively so far with embolization being a future option. At present there are 15 cases of EVAR in renal allograft patients that have been reported, all of them being successful. DISCUSSION: All data existing in the literature reported to date as well as our own experience justify the first choice of EVAR in morphologically suitable cases. One major advantage of EVAR in this constellation is the avoidance of aortic cross clamping which poses the graft at risk of ischemia. Long-term results will be most important for definite assessment of EVAR. However, contrast media application during the operation and for CT surveillance should be considered as a major disadvantage.

Rumination and cigarette smoking: a bad combination for depressive outcomes?

Ruminative coping has been shown to heighten the risk and severity of depression. The authors hypothesized that ruminators who smoke would experience greater depressive symptoms than ruminators who do not. The rationale is that, by heightening attentional focus, nicotine may increase ruminators' ability to focus on negative thoughts, augmenting depressed mood. Participants (N = 145) self-reported smoking status, rumination, and current and lifetime depressive symptoms, including depressed mood. Results showed that rumination accounted for a larger amount of variance in current and past depressed mood and severity of lifetime depressive symptoms among smokers than nonsmokers. Noncorrelational, experimental research should directly test whether nicotine worsens depressed mood among ruminative smokers. Such evidence would be surprising because it would contradict the assumption that nicotine dispels negative moods.

Influences of gender and weight gain on short-term relapse to smoking in a cessation trial.

Few researchers have studied whether weight gain has an impact on short-term relapse to smoking. The authors of this study investigated predictors of relapse among 989 participants (60% women) in a randomized, double-blind, 10-week multicenter trial to determine the effect of fluoxetine (30 or 60 mg) versus placebo in combination with behavioral counseling for smoking cessation. Medication compliance and smoking status were biochemically verified. At Visit 2, participants were asked to set a quit date within the subsequent 2 visits. A proportional hazards regression model was used to predict risk of relapse within the first 3 months of quitting. Weight gain predicted relapse, but for men only. Female gender also predicted relapse. The results led the authors to question whether postcessation weight gain interventions should be restricted to women smokers.

Influence of antidepressant pharmacotherapy on behavioral treatment adherence and smoking cessation outcome in a combined treatment involving fluoxetine.

The authors examined whether serum fluoxetine levels influence behavioral treatment adherence and smoking cessation outcome. Nondepressed smokers (N = 989) from 16 centers were randomized on a double-blind basis to receive either fluoxetine (30 or 60 mg) or placebo plus 9 sessions of behavioral smoking cessation treatment. Fluoxetine and norfluoxetine blood levels were assayed 1 week after the quit date. Logistic regression was used to predict treatment completion and cessation outcome, controlling for gender, age, treatment site, and degree of nicotine dependence. Higher steady-state fluoxetine blood levels (fluoxetine + norfluoxetine) predicted less likelihood of dropping out, chi2(1, N = 820) = 3.9, p < .05, and more likelihood of being abstinent, chi2(1, N = 513) = 18.1, p < .001. Attaining a higher fluoxetine blood level improved the likelihood of completing behavioral treatment and increased the probability of achieving abstinence.

Individual differences among cocaine users.

The present study examined whether individual differences in personality could differentiate two types of cocaine users. We hypothesized that self-medicators (SM) use cocaine as a way to alleviate their dysphoric moods, whereas sensation seekers (SS), in contrast, use cocaine primarily to engender positive mood states. Eighteen male cocaine users were classified based on two dimensions of the Tridimensional Personality Questionnaire. SM were defined by having high harm avoidance (>17) and low novelty-seeking scores (<18), and SS by high novelty-seeking (>18) and low harm-avoidance scores (<17). It was predicted that SM would report higher depression and anxiety than would SS, and would also exhibit a brain activity pattern similar to that found in clinical depression. The results showed that SM reported higher anxiety than SS, F(1, 8) = 27.5, p < .001, but did not differ in depression. SM exhibited decreased blood flow within the left frontal lobes, F(1, 10) = 6.78, p < .05, similar to what has been observed in major depressive disorder. These findings suggest the importance of attending to individual differences in the motivation for cocaine use so that treatment can be targeted more effectively.

Re-formation of the coracoacromial ligament after open resection or arthroscopic release.

In 21 (91%) of 23 shoulder revisions after primary surgery involving resection or release of the coracoacromial ligament, there was evidence of a reattached or re-formed coracoacromial ligament. In 9 cases there was no other obvious explanation for symptom recurrence, and in 7 cases the coracoacromial ligament might have influenced progression of rotator cuff pathosis. Electron micrographs of a re-formed ligament showed a substantially large amount of large-diameter (> 100 microns) collagen fibrils resembling those of a normal ligament. We conclude that the coracoacromial ligament has an ability to re-form or reattach, whether primarily resected or released, and that this might account for recurrent symptoms.

Inferior capsular shift procedure in athletes with multidirectional instability based on isolated capsular and ligamentous redundancy.

Twenty-five athletes (26 shoulders) who underwent an inferior capsular shift procedure for multidirectional glenohumeral instability based on isolated capsular and ligamentous redundancy were evaluated at a median of 54 months (range, 25 to 113) after the operation. Twenty-one athletes (84%) returned to their preinjury activity level at a median of 5 months after surgery. Of 21 athletes involved in sports using overhead motions, 16 (76%) returned to their previous sport after the operation, and 12 (57%) were still active in this sport at the preinjury level at follow-up. According to the Rowe score, 23 shoulders (88%) were excellent or good. The University of California at Los Angeles score for 24 shoulders (92%) was excellent or good. The operations on two shoulders (8%) failed. One patient had a spontaneous redislocation, and one had recurrent subluxations. Nine contralateral shoulders had a history of significant instability; four of these had undergone Bankart repair. We concluded that athletes who have multidirectional instability based on isolated capsular and ligamentous redundancy can be successfully treated by an inferior capsular shift preserving the subscapularis tendon insertion. We found a high rate of return to demanding upper extremity sports in our patients, range of motion was restored in the majority of shoulders, and the failure rate after a median of 54 months was acceptable.

Antidepressant pharmacotherapy helps some cigarette smokers more than others.

Adult smokers (N = 253) without clinically significant depression were randomized on a double-blind basis to receive fluoxetine (30 or 60 mg daily) or a placebo for 10 weeks in combination with cognitive-behavioral therapy (CBT). It was predicted that fluoxetine would selectively benefit smokers with higher baseline depression, nicotine dependence, and weight concern and lower self-efficacy about quitting smoking. Among those who completed the prescribed treatment regimen, baseline depression scores moderated the treatment response. Logistic regression analyses showed that 1 and 3 months after the quit date, fluoxetine increased the likelihood of abstinence, as compared with placebo, among smokers with minor depression but not among those with little or no depression. Results suggests that, as an adjunct to CBT, fluoxetine enhances cessation by selectively benefiting medication-compliant smokers who display even subclinical levels of depression.

Schizophrenia, monoamine oxidase activity, and cigarette smoking.

Reduced monoamine oxidase activity has been proposed as a marker for vulnerability to schizophrenia. Reduced monamine oxidase activity has also been shown to occur in cigarette smokers. This study compared monamine oxidase activity level in a matched group of patients with schizophrenia who smoked with a group who did not. Lower levels of monoamine oxidase activity were found in the smokers and this is the likely explanation for the low levels hypothesized as a marker for schizophrenia.

Weight suppression and weight rebound in ex-smokers treated with fluoxetine.

Fluoxetine's effect (30 mg, 60 mg, and placebo) on postcessation weight gain was studied among participants from a randomized, double-blind 10-week smoking cessation trial who met strict criteria for abstinence and drug levels. It was hypothesized that (a) fluoxetine would dose-dependently suppress postcessation weight gain and (b) drug discontinuation would produce dose-dependent weight rebound. During the on-drug phase, placebo participants gained weight linearly (M = 2.61 kg). exceeding both fluoxetine groups (30-mg group M = 1.33 kg, 60-mg group M = 1.25 kg). Weight suppression was initially greater for 60 mg than 30 mg, but both were followed by weight gain. Six months off drug produced greater dose-dependent weight rebound for 60 mg than 30 mg or placebo. Considering both on- and off-drug phases, weight gain for 60 mg of fluoxetine (M = 6.5 kg) was comparable with that for placebo (M = 4.7 kg) but greater than that for 30 mg (M = 3.6 kg). Fluoxetine appears to forestall postcessation weight gain, allowing time for the weight-conscious smoker to focus on quitting smoking rather than on preventing weight gain.