Are large randomised controlled trials in severe sepsis and septic shock statistically disadvantaged by repeated inadvertent underestimates of required sample size?

OBJECTIVES: We sought to understand why randomised controlled trials in septic shock have failed to demonstrate effectiveness in the face of improving overall outcomes for patients and seemingly promising results of early phase trials of interventions. DESIGN: We performed a retrospective analysis of large critical care trials of severe sepsis and septic shock. Data were collected from the primary trial manuscripts, prepublished statistical plans or by direct communication with corresponding authors. SETTING: Critical care randomised control trials in severe sepsis and septic shock. PARTICIPANTS: 14 619 patients randomised in 13 trials published between 2005 and 2015, enrolling greater than 500 patients and powered to a primary outcome of mortality. INTERVENTION: Multiple interventions including the evaluation of treatment strategies and novel therapeutics. PRIMARY AND SECONDARY OUTCOME MEASURES: Our primary outcome measure was the difference between the anticipated and actual control arm mortality. Secondary analysis examined the actual effect size and the anticipated effect size employed in sample size calculation. RESULTS: In this post hoc analysis of 13 trials with 14 619 patients randomised, we highlight a global tendency to overestimate control arm mortality in estimating sample size (absolute difference 9.8%, 95% CI -14.7% to -5.0%, p<0.001). When we compared anticipated and actual effect size of a treatment, there was also a substantial overestimation in proposed values (absolute difference 7.4%, 95% CI -9.0% to -5.8%, p<0.0001). CONCLUSIONS: An interpretation of our results is that trials are consistently underpowered in the planning phase by employing erroneous variables to calculate a satisfactory sample size. Our analysis cannot establish if, given a larger sample size, a trial would have had a positive result. It is disappointing so many promising phase II results have not translated into durable phase III outcomes. It is possible that our current framework has biased us towards discounting potentially life-saving treatments

Dose de-escalation of intrapleural tissue plasminogen activator therapy for pleural infection. The alteplase dose assessment for Pleural infection Therapy project

Rationale: Intrapleural therapy with a combination of tissue plasminogen activator (tPA) 10 mg and DNase 5 mg administered twice daily has been shown in randomized and open-label studies to successfully manage over 90% of patients with pleural infection without surgery. Potential bleeding risks associated with intrapleural tPA and its costs remain important concerns. The aim of the ongoing Alteplase Dose Assessment for Pleural infection Therapy (ADAPT) project is to investigate the efficacy and safety of dose de-escalation for intrapleural tPA. The first of several planned studies is presented here. Objectives: To evaluate the efficacy and safety of a reduced starting dose regimen of 5 mg of tPA with 5 mg of DNase administered intrapleurally for pleural infection. Methods: Consecutive patients with pleural infection at four participating centers in Australia, the United Kingdom, and New Zealand were included in this observational, open-label study. Treatment was initiated with tPA 5 mg and DNase 5 mg twice daily. Subsequent dose escalation was permitted at the discretion of the attending physician. Data relating to treatment success, radiological and systemic inflammatory changes (blood C-reactive protein), volume of fluid drained, length of hospital stay, and treatment complications were extracted retrospectively from the medical records. Results: We evaluated 61 patients (41 males; age, 57 ± 16 yr). Most patients (n = 58 [93.4%]) were successfully treated without requiring surgery for pleural infection. Treatment success was corroborated by clearance of pleural opacities visualized by chest radiography (from 42% [interquartile range, 22–58] to 16% [8–31] of hemithorax; P &lt; 0.001), increase in pleural fluid drainage (from 175 ml in the 24 h preceding treatment to 2,025 ml [interquartile range, 1,247–2,984] over 72 h of therapy; P &lt;  0.05) and a reduction in blood C-reactive protein (P &lt; 0.05). Seven patients (11.5%) had dose escalation of tPA to 10 mg. Three patients underwent surgery. Three patients (4.9%) received blood transfusions for gradual pleural blood loss; none were hemodynamically compromised. Pain requiring escalation of analgesia affected 36% of patients; none required cessation of therapy. Conclusions: These pilot data suggest that a starting dose of 5 mg of tPA administered intrapleurally twice daily in combination with 5 mg of DNase for the treatment of pl

Color-Octet Fraction in J/Psi Production and Absorption

The cross section between a $c \bar c$ pair and a nucleon is small and sensitive to the $c - \bar c$ separation if the pair is in a color-singlet state, but very large and insensitive to the separation if it is in a color-octet state. We use this property in an absorption model involving both color components to deduce the color structure of $c \bar c$ pairs produced in $p(B)A \to \psi X$ reactions. Our analysis shows that the NA3, NA38 and E772 data are not inconsistent with the theoretical picture that color-octet and color-singlet precursors are produced in roughly equal proportions if the produced color-singlet precursors are pointlike and transparent. However, if the color-singlet precursors are not transparent but have a cross section of a few mb, these data do show a definite preference for a larger fraction of color-singlet precursors. In either case, the color-octet fraction increases with $x_F$, approaching unity as $x_F$ becomes large.Comment: 9 pages, updated to include new result

Metropolitan quantum key distribution with silicon photonics

Photonic integrated circuits (PICs) provide a compact and stable platform for quantum photonics. Here we demonstrate a silicon photonics quantum key distribution (QKD) transmitter in the first high-speed polarization-based QKD field tests. The systems reach composable secret key rates of 950 kbps in a local test (on a 103.6-m fiber with a total emulated loss of 9.2 dB) and 106 kbps in an intercity metropolitan test (on a 43-km fiber with 16.4 dB loss). Our results represent the highest secret key generation rate for polarization-based QKD experiments at a standard telecom wavelength and demonstrate PICs as a promising, scalable resource for future formation of metropolitan quantum-secure communications networks

The use of smart phones and their mobile applications among older adults in Hong Kong: An exploratory study

The purpose of this study was to explore social participation using smart phones by the older population in Hong Kong. The present study was conducted from 10-June-2013 to 16-August-2013. It was a cross-sectional survey study, and data were collected from street interviews. Potential participants were approached and invited to respond to a questionnaire. The locations for collecting data were evenly distributed on Hong Kong Island, Kowloon, and the New Territories. The size of the samples for Hong Kong Island, Kowloon, and the New Territories were calculated based on their respective proportion of the Hong Kong population in 2011. The estimated time to complete the questionnaire was approximately 10 minutes. The questionnaire included questions on demographic data and the use of smart phones and their related features. A total of 982 participants were interviewed, 46% of whom were male and 54% female. The participants were divided into the following two groups: the young-old (age 50-69) and the old-old (age 70 or above). The mean age was 67.93±10.386. The findings showed that, in comparison with the young-old group (age 50 to 69), a smaller percentage of the old-old group (70 and over) used smart phones and mobile messaging applications to communicate with others. There were no differences in patterns with regard to the type and frequency of the mobile applications being used. However, a smaller percentage of the old-old group had installed the mobile app by themselves and introduced the mobile app to others. This study reveals the behavioral patterns of the young-old and the old-old groups in the use of mobile devices to communicate. The young-old and old-old groups exhibited the same patterns in terms of the types and frequency of the mobile apps used; however, a smaller percentage of the old-old group used mobile apps to communicate. Different educational programs on the importance of social support should be established, and the promotional strategies for these programs need to be tailored to older adults

Relationships between Irritable Bowel Syndrome Pain, Skin Temperature Indices of Autonomic Dysregulation, and Sensitivity to Thermal Cutaneous Stimulation

This study evaluated relationships between irritable bowel syndrome (IBS) pain, sympathetic dysregulation, and thermal pain sensitivity. Eight female patients with diarrhea-predominant IBS and ten healthy female controls were tested for sensitivity to thermal stimulation of the left palm. A new method of response-dependent thermal stimulation was used to maintain pain intensity at a predetermined level (35%) by adjusting thermal stimulus intensity as a function of pain ratings. Clinical pain levels were assessed prior to each testing session. Skin temperatures were recorded before and after pain sensitivity testing. The temperature of palmar skin dropped (1.5°C) when the corresponding location on the opposite hand of control subjects was subjected to prolonged thermal stimulation, but this response was absent for IBS pain patients. The patients also required significantly lower stimulus temperatures than controls to maintain a 35% pain rating. Baseline skin temperatures of patients were significantly correlated with thermode temperatures required to maintain 35% pain ratings. IBS pain intensity was not significantly correlated with skin temperature or pain sensitivity. The method of response-dependent stimulation revealed thermal hyperalgesia and increased sympathetic tone for chronic pain patients, relative to controls. Similarly, a significant correlation between resting skin temperatures and thermal pain sensitivity for IBS but not control subjects indicates that tonic sympathetic activation and a thermal hyperalgesia were generated by the chronic presence of visceral pain. However, lack of a significant relationship between sympathetic tone and ratings of IBS pain casts doubt on propositions that the magnitude of IBS pain is determined by psychological stress