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

Epidemiology, diagnostics and factors associated with mortality during a cholera epidemic in Nigeria, October 2020-October 2021: a retrospective analysis of national surveillance data.

OBJECTIVES: Nigeria reported an upsurge in cholera cases in October 2020, which then transitioned into a large, disseminated epidemic for most of 2021. This study aimed to describe the epidemiology, diagnostic performance of rapid diagnostic test (RDT) kits and the factors associated with mortality during the epidemic. DESIGN: A retrospective analysis of national surveillance data. SETTING: 33 of 37 states (including the Federal Capital Territory) in Nigeria. PARTICIPANTS: Persons who met cholera case definition (a person of any age with acute watery diarrhoea, with or without vomiting) between October 2020 and October 2021 within the Nigeria Centre for Disease Control surveillance data. OUTCOME MEASURES: Attack rate (AR; per 100 000 persons), case fatality rate (CFR; %) and accuracy of RDT performance compared with culture using area under the receiver operating characteristic curve (AUROC). Additionally, individual factors associated with cholera deaths and hospitalisation were presented as adjusted OR with 95% CIs. RESULTS: Overall, 93 598 cholera cases and 3298 deaths (CFR: 3.5%) were reported across 33 of 37 states in Nigeria within the study period. The proportions of cholera cases were higher in men aged 5-14 years and women aged 25-44 years. The overall AR was 46.5 per 100 000 persons. The North-West region recorded the highest AR with 102 per 100 000. Older age, male gender, residency in the North-Central region and severe dehydration significantly increased the odds of cholera deaths. The cholera RDT had excellent diagnostic accuracy (AUROC=0.91; 95% CI 0.87 to 0.96). CONCLUSIONS: Cholera remains a serious public health threat in Nigeria with a high mortality rate. Thus, we recommend making RDT kits more widely accessible for improved surveillance and prompt case management across the country

Порівняння гістограм об’єму доз та сечового міхура та прямої кишки у хворих на рак шийки матки, яких лікували за допомогою внутрішньопорожнинної брахітерапії у відділенні променевої терапії

International commission of radiation units and measurement point doses to the bladder and rectum in carcinoma cervix patients treated with intracavitary brachytherapy in the department of radiotherapy. The aim: to evaluate two-dimensional point-based dose planning and three-dimensional computed tomography-based dose-volume parameters for high-dose-rate intracavitary brachytherapy of cervical cancer. Materials and methods: prospective study done between the years June 2018 to April 2020, a total of 50 prospectively registered women of non-metastatic carcinoma cervix treated with definitive concurrent chemo-radiotherapy followed by HDR intracavitary brachytherapy who met inclusion criteria were accrued in the study. All women in the study were treated with 50 Gy EBRT then assessment was done for response and adequacy for comfortable insertion of application. Brachytherapy procedure was performed under sedation in the lithotomy position. Results: Median age of the entire group was 54.5 years, majority of them were in their 5th (34 %) or 4th (28 %) decade. Pathologically, all were squamous cell carcinoma. Most common subtype was large cell non keratinizing type (64 %). Major bulk of the study is contributed by stage IIA, IIB, IIIB. All patients were treated with external beam radiotherapy of 50Gy in 25 fractions with 2Gy per fraction followed by high dose rate brachytherapy of 7 Gy per fraction for 3 fractions, one week apart to a total intracavitary brachytherapy dose of 21Gy. Conclusion: Results from the study suggests that rectum ICRU reference points can be surrogate markers for D2cc, but not for bladder and hence reporting should preferably be done in volumetric method rather than reference point dosesМета: оцінка двовимірного точкового планування дози та тривимірної комп’ютерної томографії на основі параметрів доза-об’єм для внутрішньопорожнинної брахітерапії раку шийки матки з використанням високої дози. Матеріали та методи: проспективне дослідження, проведено в період з червня 2018 року по квітень 2020 року, загалом за участю 50 проспективно зареєстрованих жінок з неметастатичною карциномою шийки матки, які отримували остаточну одночасну хіміо-променеву терапію з подальшою внутрішньопорожнинною брахітерапією з ВПД, які відповідали критеріям, були включені в дослідження. Всі жінки отримували 50 Гр EBRT, потім було проведено оцінку відповідей та адекватності для зручного введення аплікації. Процедуру брахітерапії проводили під седацією в літотомічному положенні. Результати: Середній вік усієї групи за медіаною становив 54,5 року, більшість із них були на 5-му (34 %) або 4-му (28 %) десятку років. Патоморфологічно всі мали плоскоклітинний рак. Найбільш поширеним підтипом був великоклітинний незроговілий тип (64 %). Основну частину дослідження становлять стадії IIA, IIB, IIIB. Усіх пацієнтів лікували зовнішньою променевою терапією 50 Гр у 25 фракціях з 2 Гр на фракцію з наступною брахітерапією високою потужністю 7 Гр на фракцію протягом 3 фракцій з інтервалом в один тиждень до загальної внутрішньопорожнинної дози брахітерапії 21 Гр. Висновки: Результати дослідження свідчать про те, що референтні точки ICRU прямої кишки можуть бути сурогатними маркерами для D2cc, але не для сечового міхура, і, отже, звітування бажано робити за допомогою об’ємного методу, а не контрольних точок для різних до

Healthcare workers knowledge of cholera multi-stranded interventions and its determining factors in North-East Nigeria: planning and policy implications

Abstract Background Healthcare workers’ (HCWs) knowledge of multi-stranded cholera interventions (including case management, water, sanitation, and hygiene (WASH), surveillance/laboratory methods, coordination, and vaccination) is crucial to the implementation of these interventions in healthcare facilities, especially in conflict-affected settings where cholera burden is particularly high. We aimed to assess Nigerian HCWs’ knowledge of cholera interventions and identify the associated factors. Methods We conducted a cross-sectional study using a structured interviewer-administered questionnaire with HCWs from 120 healthcare facilities in Adamawa and Bauchi States, North-East Nigeria. A knowledge score was created by assigning a point for each correct response. HCWs’ knowledge of cholera interventions, calculated as a score, was recoded for ease of interpretation as follows: 0–50 (low); 51–70 (moderate); ≥ 71 (high). Additionally, we defined the inadequacy of HCWs’ knowledge of cholera interventions based on a policy-relevant threshold of equal or lesser than 75 scores for an intervention. Multivariable logistic regression was used to identify the factors associated with the adequacy of knowledge score. Results Overall, 490 HCWs participated in the study (254 in Adamawa and 236 in Bauchi), with a mean age of 35.5 years. HCWs’ knowledge score was high for surveillance/laboratory methods, moderate for case management, WASH, and vaccination, and low for coordination. HCWs’ knowledge of coordination improved with higher cadre, working in urban- or peri-urban-based healthcare facilities, and secondary education; cholera case management and vaccination knowledge improved with post-secondary education, working in Bauchi State and urban areas, previous training in cholera case management and response to a cholera outbreak—working in peri-urban areas had a negative effect. HCWs’ knowledge of surveillance/laboratory methods improved with a higher cadre, 1-year duration in current position, secondary or post-secondary education, previous training in cholera case management and response to a cholera outbreak. However, HCWs’ current position had both positive and negative impacts on their WASH knowledge. Conclusions HCWs in both study locations recorded a considerable knowledge of multi-stranded cholera interventions. While HCWs’ demographic characteristics appeared irrelevant in determining their knowledge of cholera interventions, geographic location and experiences from the current position, training and involvement in cholera outbreak response played a significant role

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

Patient screening and enrolment.

<p>*One patient did not give consent. One patient was not competent to give consent, and a suitable proxy to provide consent could not be identified within inclusion time limits. **Two patients who died within 48 h of admission were excluded from the primary outcome analysis, as specified in the protocol.</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

Ebola virus RT-PCR cycle threshold values and RNA copies/ml over time.

<p>Top row: TKM-130803 recipients. Bottom row: Observational patients. RT-PCR Ct upper limit of quantitation (LOQ) = 40. RT-qPCR lower limit of quantitation = 1,000 genome copies. The Ebola virus RT-qPCR quantification is expressed as the number of genome copies/millilitre of plasma. Black diamonds denote results for survivors. Grey circles denote results for non-survivors.</p