Experimental Treatment of Ebola Virus Disease with TKM-130803: A Single-Arm Phase 2 Clinical Trial.

BACKGROUND: TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. METHODS AND FINDINGS: In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. CONCLUSIONS: Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201501000997429

Behaviour of reinforced concrete frames with lightweight blockwork infill panels.

The current investigation concerns the behaviour of lightweight blockork infill panels bounded by reinforced concrete frames. A detailed and comprehensive review of the literature on different frame-inf ill combinations is presented. Details are given of tests on sixteen third-scale infilled frames and four open frames. These were tested under two types of loading: horizontal racking loading only and combined vertical loads on columns and racking loading. The complete load-deflection response is considered in detail including. initial elastic behaviour, influence of cracking and the formation of collapse mechanisms after the attainment of peak load. The variables investigated include the overall effects of the infill, the infill thickness, the vertical loads, the amount of reinforcement, the change in stiffness and strength of beams and of columns and the effect of reinforcement detailing. Those found to have a major influence are the vertical loads, the infill thickness, the reinforcement detailing particularly in the opening corners of the frame, and the workmanship. The principal parameters obtained from the tests are the initial racking stiffness, the infill cracking strength, the ultimate load and the plastic collapse load. Their values are compared to the available empirical and theoretical methods. None of these methods is found to safely predict the initial racking stiffness and the ultimate carrying capacity of this type of structure. A plastic analysis is presented to predict the two plastic collapse mechanisms identified in the tests. The penalty factor to allow for idealization of plasticity of the infill is found as part of the solution. A second penalty factor is introduced to allow for the limited ductility of the frame. The proposed method is found to yield satisfactory and safe predictions for the plastic resistance of these infilled frames. In conclusion some design recommendations are proposed for the initial racking stiffness and the cracking infill strength

Met and unmet needs for surgery in Sierra Leone: A comprehensive, retrospective, countrywide survey from all health care facilities performing operations in 2012

BackgroundUnderstanding a country's baseline operative actors and capacity is critical to improving the quality of services and outcomes. The aim of this study was to describe all operative providers and national operative production, to evaluate district and nationwide population rates for operations, and to estimate unmet operative need in Sierra Leone.MethodsA nationwide, exhaustive, retrospective, facility-based study of operative actors and surgical procedures was performed in Sierra Leone. Between January and May 2013, 4 teams of 12 medical students collected data on the characteristics of the institutions and of the operations performed in 2012. Data were retrieved from the log books of operations, anesthesia, and delivery.ResultsA total of 24,152 operative procedures were identified, equal to a national rate of 400 operative procedures per 100,000 inhabitants (district range 32–909/100,000, interquartile range 95–502/100,000). Hernia repair was the most common operative procedure at 86.1 per 100,000 inhabitants (22.4% of the total national volume) followed by cesarean delivery at 80.6 per 100,000 (21.0% of the total). Private, nonprofit facilities performed 54.0% of the operations, compared with 39.6% by governmental and 6.4% by private for-profit facilities. More than 90% of the estimated operative need in Sierra Leone was unmet in 2012.ConclusionThe unmet operative need in Sierra Leone is very high. The 30-fold difference in operative output between districts also is very high. As the main training institution, operative services within the governmental sector need to be strengthened. An understanding of the existing operative platform is a good start for expanding operative services

Admissions and surgery as indicators of hospital functions in Sierra Leone during the west-African Ebola outbreak

Abstract Background In an attempt to assess the effects of the Ebola viral disease (EVD) on hospital functions in Sierra Leone, the aim of this study was to evaluate changes in provisions of surgery and non-Ebola admissions during the first year of the EVD outbreak. Methods All hospitals in Sierra Leone known to perform inpatient surgery were assessed for non-Ebola admissions, volume of surgery, caesarean deliveries and inguinal hernia repairs between January 2014 and May 2015, which was a total of 72 weeks. Accumulated weekly data were gathered from readily available hospital records at bi-weekly visits during the peak of the outbreak from September 2014 to May 2015. The Mann-Whitney U test was used to compare weekly median admissions during the first year of the EVD outbreak, with the 20 weeks before the outbreak, and weekly median volume of surgeries performed during the first year of the EVD outbreak with identical weeks of 2012. The manuscript is prepared according to the STROBE checklist for cross-sectional studies. Results Of the 42 hospitals identified, 40 had available data for 94% (2719/2880) of the weeks. There was a 51% decrease in weekly median non-Ebola admissions and 41% fewer weekly median surgeries performed compared with the 20 weeks before the outbreak (admission) and 2012 (volume of surgery). Governmental hospitals experienced a smaller reduction in non-Ebola admissions (45% versus 60%) and surgeries (31% versus 53%) compared to private non-profit hospitals. Governmental hospitals realized an increased volume of cesarean deliveries by 45% during the EVD outbreak, thereby absorbing the 43% reduction observed in the private non-profit hospitals. Conclusions Both non-Ebola admissions and surgeries were severely reduced during the EVD outbreak. In addition to responding to the EVD outbreak, governmental hospitals were able to maintain certain core health systems functions. Volume of surgery is a promising indicator of hospital functions that should be further explored

Admissions and surgery as indicators of hospital functions in Sierra Leone during the west-African Ebola outbreak

Background In an attempt to assess the effects of the Ebola viral disease (EVD) on hospital functions in Sierra Leone, the aim of this study was to evaluate changes in provisions of surgery and non-Ebola admissions during the first year of the EVD outbreak. Methods All hospitals in Sierra Leone known to perform inpatient surgery were assessed for non-Ebola admissions, volume of surgery, caesarean deliveries and inguinal hernia repairs between January 2014 and May 2015, which was a total of 72 weeks. Accumulated weekly data were gathered from readily available hospital records at bi-weekly visits during the peak of the outbreak from September 2014 to May 2015. The Mann-Whitney U test was used to compare weekly median admissions during the first year of the EVD outbreak, with the 20 weeks before the outbreak, and weekly median volume of surgeries performed during the first year of the EVD outbreak with identical weeks of 2012. The manuscript is prepared according to the STROBE checklist for cross-sectional studies. Results Of the 42 hospitals identified, 40 had available data for 94% (2719/2880) of the weeks. There was a 51% decrease in weekly median non-Ebola admissions and 41% fewer weekly median surgeries performed compared with the 20 weeks before the outbreak (admission) and 2012 (volume of surgery). Governmental hospitals experienced a smaller reduction in non-Ebola admissions (45% versus 60%) and surgeries (31% versus 53%) compared to private non-profit hospitals. Governmental hospitals realized an increased volume of cesarean deliveries by 45% during the EVD outbreak, thereby absorbing the 43% reduction observed in the private non-profit hospitals. Conclusions Both non-Ebola admissions and surgeries were severely reduced during the EVD outbreak. In addition to responding to the EVD outbreak, governmental hospitals were able to maintain certain core health systems functions. Volume of surgery is a promising indicator of hospital functions that should be further explored

Survival plot with futility boundary for TKM-130803 recipients.

<p>The red line denotes the futility boundary. The points and dashed line denote the number of survivors at day 14 plotted against the number of day 14 reports.</p

Box and whisker plot of vital signs in TKM-130803 recipients, before, during, and after TKM-130803 infusions.

<p>Heart rate, respiratory rate, mean arterial blood pressure, and tympanic temperature in patients administered TKM-130803 at the following time points: immediately prior to TKM-130803 infusion (PRE), during the infusion, immediately at the end of the infusion (END), and at 1, 2, 4, and 8 h after the end of the infusion. The middle line shows the median value, the box shows the interquartile range, and the whiskers spread from the lower to the upper adjacent values. Outside values, that is, observations that are larger/smaller than the upper/lower adjacent values, are shown as circles.</p

Baseline demographic and clinical characteristics of trial population.

<p>Baseline demographic and clinical characteristics of trial population.</p