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.

Outcomes after kidney transplantation of patients previously diagnosed with atrial fibrillation.

Little is known about the prevalence and outcomes of patients with atrial fibrillation/flutter (AF) who receive a kidney transplant. We identified all patients who had >1 year of uninterrupted Medicare A+B coverage before receiving their first kidney transplant (1997-2009). The presence of pretransplant AF was ascertained from diagnosis codes in Medicare physician claims. We studied the posttransplant outcomes of death, all-cause graft failure, death-censored graft failure and stroke using multivariable Cox regression. Of 62 706 eligible first kidney transplant recipients studied, 3794 (6.4%) were diagnosed with AF prior to kidney transplant. Over a mean follow up of 4.9 years, 40.6% of AF patients and 24.9% without AF died. All-cause and death-censored graft failure were 46.8% and 16.5%, respectively, in the AF group and 36.4% and 19.5%, respectively, in those without AF. Ischemic stroke occurred in 2.8% of patients with and 1.6% of patients without AF. In patients with AF, multivariable-adjusted hazard ratios (95% confidence intervals) for death, graft failure, death-censored graft failure and ischemic stroke were 1.46 (1.38-1.54), 1.41 (1.34-1.48), 1.26 (1.15-1.37) and 1.36 (1.10-1.68), respectively. Pre-existing AF is associated with poor posttransplant outcomes. Special attention should be paid to AF in pretransplant evaluation, counseling and risk stratification of kidney transplant candidates.

Epidural anesthesia reduces the gain and maximum intensity of shivering.

BACKGROUND: Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase), and maximum intensity. The gain of shivering might be preserved during epidural or spinal anesthesia if control mechanisms compensate for lower-body paralysis by augmenting the activity of upper-body muscles. Conversely, gain will be reduced approximately by half if the thermoregulatory system fails to compensate. Similarly, appropriate regulatory feedback might maintain maximum shivering intensity during regional anesthesia. Accordingly, the gain and maximum intensity of shivering during epidural anesthesia were determined. METHODS: Seven volunteers participated on two randomly ordered study days. On one day (control), no anesthesia was administered; on the other, epidural anesthesia was maintained at a T8 sensory level. Shivering, at a mean skin temperature near 33 degrees C, was provoked by central-venous infusion of cold fluid; core cooling continued until shivering intensity no longer increased. Shivering was evaluated by systemic oxygen consumption and electromyography of two upper-body and two lower-body muscles. The core temperature triggering an increase in oxygen consumption identified the shivering threshold. The slopes of the oxygen consumption versus core temperature and electromyographic intensity versus core temperature regressions identified systemic and regional shivering gains, respectively. RESULTS: The shivering threshold was reduced by epidural anesthesia by approximately 0.4 degrees C, from 36.7 +/- 0.6 to 36.3 +/- 0.5 degrees C (means +/- SD; P < 0.05). Systemic gain, as determined by oxygen consumption, was reduced from -581 +/- 186 to -215 +/- 154 ml x min(-1) x degrees C(-1) (P < 0.01). Lower-body gain, as determined electromyographically, was essentially obliterated by paralysis during epidural anesthesia, decreasing from -0.73 +/- 0.85 to -0.04 +/- 0.06 intensity units/degrees C (P < 0.01). However, upper-body gain had no compensatory increase: -1.3 +/- 1.1 units/degrees C control versus 2.0 +/- 2.1 units/degrees C epidural. Maximum oxygen consumption was decreased by one third during epidural anesthesia: 607 +/- 82 versus 412 +/- 50 ml/min (P < 0.05). CONCLUSIONS: These results confirm that regional anesthesia reduces the shivering threshold. Epidural anesthesia reduced the gain of shivering by 63% because upper-body muscles failed to compensate for lower-body paralysis. The thermoregulatory system thus fails to recognize that regional anesthesia reduces metabolic heat production, instead responding as if lower-body muscular activity remained intact.

Meperidine and alfentanil do not reduce the gain or maximum intensity of shivering.

BACKGROUND: Thermoregulatory shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core temperature deviation), and maximum intensity. Meperidine (a combined mu- and kappa-agonist) treats shivering better than equianalgesic doses of pure mu-opioid agonists. Meperidine's special antishivering action is mediated, at least in part, by a disproportionate decrease in the shivering threshold. That is, meperidine decreases the shivering threshold twice as much as the vasoconstriction threshold, whereas alfentanil (a pure mu-agonist) decreases the vasoconstriction and shivering thresholds comparably. However, reductions in the gain or maximum shivering intensity might also contribute to the clinical efficacy of meperidine. Accordingly, we tested the hypothesis that meperidine reduces the gain and maximum intensity of shivering much more than alfentanil does. METHODS: Ten volunteers were each studied on three separate days: (1) control (no drug); (2) a target total plasma meperidine concentration of 1.2 microg/ml; and (3) a target plasma alfentanil concentration of 0.2 microg/ml. Skin temperatures were maintained near 31 degrees C, and core temperatures were decreased by central-venous infusion of cold lactated Ringer's solution until maximum shivering intensity was observed. Shivering was evaluated using oxygen consumption and electromyography. A sustained increase in oxygen consumption identified the shivering threshold. The gain of shivering was calculated as the slope of the oxygen consumption versus core temperature regression, and as the slope of electromyographic intensity versus core temperature regression. RESULTS: Meperidine and alfentanil administration significantly decreased the shivering thresholds. However, neither meperidine nor alfentanil reduced the gain of shivering, as determined by either oxygen consumption or electromyography. Opioid administration also failed to significantly decrease the maximum intensity of shivering. CONCLUSIONS: The authors could not confirm the hypothesis that meperidine reduces the gain or maximum intensity of shivering more than alfentanil does. These results suggest that meperidine's special antishivering effect is primarily mediated by a disproportionate reduction in the shivering threshold.

Isoflurane alters shivering patterns and reduces maximum shivering intensity.

BACKGROUND: Shivering can be characterized by its threshold (triggering core temperature), gain (incremental intensity increase with further core hypothermia), and maximum response intensity. Isoflurane produces a clonic muscular activity that is not a component of normal shivering. To the extent that clonic activity is superimposed on normal thermoregulatory shivering, the gain of shivering might be increased during isoflurane anesthesia. Conversely, volatile anesthetics decrease systemic oxygen consumption and peripherally inhibit skeletal muscle strength, which might limit maximum intensity despite central activation. The purpose of the present study was, therefore, to evaluate the effect of isoflurane shivering patterns and the gain and maximum intensity of shivering. METHODS: Ten volunteers were each studied in two separate protocols: (1) control (no drug) and (2) 0.7% end-tidal isoflurane. On each day, the mean skin temperature was maintained at 31 degrees C. Core temperature was then reduced by infusion of cold fluid until shivering intensity no longer increased. The core temperature triggering the initial increase in oxygen consumption defined the shivering threshold. The gain of shivering was defined by the slope of the core temperature versus oxygen consumption regression. Pectoralis and quadriceps electromyography was used to evaluate anesthetic-induced facilitation of clonic (5-7 Hz) muscular activity. RESULTS: Isoflurane significantly decreased the shivering threshold from 36.4 +/- 0.3 to 34.2 +/- 0.8 degrees C. The increase in oxygen consumption was linear on the control day and was followed by sustained high-intensity activity. During isoflurane administration, shivering was characterized by bursts of intense shivering separated by quiescent periods. Isoflurane significantly increased the gain of shivering (as calculated from the initial increase), from -684 +/- 266 to -1483 +/- 752 ml x min(-1) x degrees C(-1). However, isoflurane significantly decreased the maximum intensity of shivering, from 706 +/- 144 to 489 +/- 80 ml/min. Relative electromyographic power in frequencies associated with clonus increased significantly when the volunteers were given isoflurane. CONCLUSIONS: These data indicate that isoflurane anesthesia markedly changes the overall pattern of shivering during progressive hypothermia from a linear increase to an unusual saw-tooth pattern. They further suggest that clonic muscular activity combines with shivering to increase the initial gain of shivering during isoflurane anesthesia, but that isoflurane peripherally inhibits the maximum expression of shivering.

Postanesthetic vasoconstriction slows peripheral-to-core transfer of cutaneous heat, thereby isolating the core thermal compartment.

UNLABELLED: Forced-air warming during anesthesia increases core temperature comparably with and without thermoregulatory vasoconstriction. In contrast, postoperative forced-air warming may be no more effective than passive insulation. Nonthermoregulatory anesthesia-induced vasodilation may thus influence heat transfer. We compared postanesthetic core rewarming rates in volunteers given cotton blankets or forced air. Additionally, we compared increases in peripheral and core heat contents in the postanesthetic period with data previously acquired during anesthesia to determine how much vasomotion alters intercompartmental heat transfer. Six men were anesthetized and cooled passively until their core temperatures reached 34 degrees C. Anesthesia was then discontinued, and shivering was prevented by giving meperidine. On one day, the volunteers were covered with warmed blankets for 2 h; on the other, volunteers were warmed with forced air. Peripheral tissue heat contents were determined from intramuscular and skin thermocouples. Predicted changes in core temperature were calculated assuming that increases in body heat content were evenly distributed. Predicted changes were thus those that would be expected if vasomotor activity did not impair peripheral-to-core transfer of applied heat. These results were compared with those obtained previously in a similar study of anesthetized volunteers. Body heat content increased 159 +/- 35 kcal (mean +/- SD) more during forced-air than during blanket warming (P < 0.001). Both peripheral and core temperatures increased significantly faster during active warming: 3.3 +/- 0.7 degrees C and 1.1 +/- 0.4 degrees C, respectively. Nonetheless, predicted core temperature increase during forced-air warming exceeded the actual temperature increase by 0.8 +/- 0.3 degree C (P < 0.001). Vasoconstriction thus isolated core tissues from heat applied to the periphery, with the result that core heat content increased 32 +/- 12 kcal less than expected after 2 h of forced-air warming (P < 0.001). In contrast, predicted and actual core temperatures differed only slightly in the anesthetized volunteers previously studied. In contrast to four previous studies, our results indicate that forced-air warming increases core temperature faster than warm blankets. Postanesthetic vasoconstriction nonetheless impeded peripheral-to-core heat transfer, with the result that core temperatures in the two groups differed less than might be expected based on systemic heat balance estimates. IMPLICATIONS: Comparing intercompartmental heat flow in our previous and current studies suggests that anesthetic-induced vasodilation influences intercompartmental heat transfer and distribution of body heat more than thermoregulatory shunt vasomotion.

Rapid core-to-peripheral tissue heat transfer during cutaneous cooling.

Perioperative thermal manipulations are usually directed at the skin surface because methods of directly warming the core are invasive or ineffective. However, inadequate heat flow between peripheral and core compartments will decrease the rate at which core temperature changes. We therefore determined whether core hypothermia is delayed after initiation of surface cooling. Six volunteers were anesthetized with propofol and midazolam, and maintained under three layers of passive insulation for 2.5-4 h. Subsequently, the skin surface was cooled using forced air, 1000 L/min, at 10 degrees C. Isoflurane was added as necessary to maintain arteriovenous shunt vasodilation. Overall heat balance was determined from the difference between cutaneous heat loss (thermal flux transducers) and metabolic heat production (oxygen consumption). Average arm and leg (peripheral) tissue temperatures were determined from 19 intramuscular needle thermocouples, 10 skin temperatures, and "deep" foot temperature. Overall body heat content decreased approximately 234 kcal during 2.5 h of active cooling. Core temperature, which was nearly constant before active cooling, decreased approximately 1.3 degrees C/h. There was no delay between initiation of active cooling and the decrease in core temperature. Furthermore, peripheral (arm and leg) and core (trunk and head) tissue heat contents decreased at virtually the same rates: approximately 50 kcal/h and approximately 47 kcal/h, respectively. These data indicate that there is little restriction of heat flow between peripheral and core tissues in vasodilated, anesthetized subjects.

Activity of Pseudomonas aeruginosa in biofilms: effect of calcium.

Aerobic glucose metabolism by Pseudomonas aeruginosa biofilms at various calcium loading rates was investigated. The influence of calcium on specific growth rate, extracellular polymeric substance (EPS) formation rate, biofilm detachment rate, and biofilm calcium concentrations was determined. Calcium accumulated in the biofilm in proportion to the liquid phase concentration. Increasing calcium concentration increased the cohesiveness of the biofilm as indicated by a lower relative detachment rate. Specific activity in the biofilm was the same as that measured in a chemostat and was not influenced by changing calcium concentration. EPS formation rate in the biofilm was unaffected by calcium concentration but was higher than that observed in a chemostat.

Influence of a calcium-specific chelant on biofilm removal.

This paper describes the influence of ethylene glycol-bisbeta-aminoethyl ether)- N, N-tetraacetic acid (EGTA) on biofilm removal. The addition of EGTA resulted in the immediate detachment of biofilm which suggests that the chelant removed essential calcium from the biofilm, causing it to detach.