Management of severe tetanus in Afghanistan: lessons from the field.

INTRODUCTION: Tetanus is a rather rare disease in the Western countries thanks to widespread vaccination programs and the availability of prophylactics for patients with tetanus-prone injuries. The few cases that do occur are promptly managed in intensive care units (ICUs). However, tetanus is not so rare in developing countries, where access to a suitable level of care is limited. An unstable political situation can be a significant factor influencing patient outcomes. CASE REPORT: A ten-year-old boy presented at the EMERGENCY hospital in Lashkar-Gah (southern Afghanistan) with generalized tetanus after falling off his bicycle. In response to his rapidly deteriorating general conditions - respiratory failure and hemodynamic instability - the patient was urgently transferred by ambulance to the ICU at the EMERGENCY hospital in Kabul (northern Afghanistan). The patient was placed on mechanical ventilation while receiving intravenous sedation and pharmacologic paralysis for almost four weeks. A prolonged infusion of a high dose of magnesium sulphate and labetalol was also given to counteract autonomic dysfunction. Multiple complications related to the long stay in the ICU were observed and promptly addressed. During this period, several mass casualties took place in Kabul, which stretched the hospital's surge capacity. The patient was discharged and accompanied back to Lashkar-Gah three months after his admission to the hospital. CONCLUSION: This case report shows some of the many difficulties that arise when managing a patient with severe tetanus in a war zone where resources are limited.

Impact and Feasibility of Mechanical Ventilation at a Surgical Center in Sierra Leone: Experience From EMERGENCY's Hospital in Goderich.

OBJECTIVES: Despite the large burden of critically ill patients in developing countries, mechanical ventilation (MV) is scarce in these low-resource settings. In the absence of data, issues like costs and lack of training are often felt to outweigh the benefits of potential MV implementation in such places. We aimed to investigate the impact and feasibility of MV in a surgical ICU in West Africa. DESIGN: This is a 7-month retrospective observational study (from October 25, 2022, to May 25, 2023), covering all patients consecutively admitted to ICU. SETTING: The NGO EMERGENCY's hospital in Goderich, Freetown, Sierra Leone. The hospital is a referral center for acute care surgery. PATIENTS: Critical patients admitted to the hospital's ICU. INTERVENTIONS: Following brief, practical training of the nursing staff, one basic mechanical ventilator was installed at the hospital's ICU, under the supervision of two intensivists. Only patients with a body weight of over 15 kg and who met the "extreme criteria" for MV received this life-saving therapy. MEASUREMENTS AND MAIN RESULTS: Of the 195 files of patients admitted to ICU during the study period, 162 were analyzed. The median age was 16 (interquartile range 7-27) and 48.1% of the population were under 14 years. The most common cause of admission was trauma (58.6%), followed by acute abdomen (33.3%), caustic soda ingestion (6.2%), and burns (1.9%). Of the overall population, 26 patients (16%) underwent MV (88.5% trauma cases vs. 11.5% acute abdomen). Median time on MV was 24 hours (12-64). The mortality rate in the MV group was 30.8% (8/26), while in the overall study population, it was 11.7% (19/162). One potentially life-threatening event of tube obstruction was handled appropriately. CONCLUSIONS: This study strongly supports the implementation of MV in low-resource settings. In our experience, the consistent benefit of reduced mortality among critical patients largely outweighs the associated challenges.

Civilian war victims in Afghanistan: five-year report from the Kabul EMERGENCY NGO hospital.

BACKGROUND: Afghanistan has been plagued by war for more than 30 years, but little is known about the civilian cost of such a long-lasting conflict. In particular, the incidence of war injuries among civilians has largely been under-reported. EMERGENCY NGO's Surgical Centre for War Victims has been operating in Kabul since 2001, providing care free of charge to anyone injured in war. The primary aim of our study is to describe the population of patients admitted to our hospital in Kabul. METHODS: This is a 5-year retrospective analysis of all recorded hospital admissions at EMERGENCY NGO's hospital in Kabul, Afghanistan, from 1 January 2017 to 31 December 2021. RESULTS: During the study period, 16,053 patients were admitted. Of these, 85.7% were male and 17.5% were under 14 years old. The proportion of male patients increased progressively with the age ranges (from 63.4 to 89.0%). Bullet wounds were the most frequent kind of injury (55.6%), followed by shell, stab and mine wounds (32.2%, 8.3% and 3.9% respectively). Only 5.8% of patients arrived at our hospital within the "golden hour" following injury. No significant reduction in the hospitalization trend was observed over the study period. The overall in-hospital mortality rate was 4.41%, which bore no correlation to the number of admissions. CONCLUSIONS: This study provides for the first time epidemiology of war-related injuries in a hospital located in a place of long-standing conflict.

Rates and Determinants of Hospital-Acquired Infection among ICU Patients Undergoing Cardiac Surgery in Developing Countries: Results from EMERGENCY'NGO's Hospital in Sudan.

Introduction. Knowledge of local and regional antimicrobial resistance (AMR) is crucial in clinical decision-making, especially with critically ill patients. The aim of this study was to investigate the rate and pattern of infections in valvular heart disease patients admitted to the intensive care unit (ICU) at the Salam Centre for Cardiac Surgery in Khartoum, Sudan (run by EMERGENCY NGO). Methods. This is a retrospective, observational study from a single, large international referral centre (part of a Regional Programme), which enrolled patients admitted to the ICU between 1 January and 31 December 2019. Data collected for each patient included demographic data, operating theatre/ICU data and microbiological cultures. Results. Over the study period, 611 patients were enrolled (elective surgery n = 491, urgent surgery n = 34 and urgent medical care n = 86). The infection rate was 14.2% and turned out to be higher in medical than in surgical patients (25.6% vs. 12.4%; p = 0.002; OR = 2.43) and higher in those undergoing urgent surgery than those undergoing elective (29.4% vs. 11.2%; p = 0.004; OR = 3.3). Infection was related to (a) SOFA score (p < 0.001), (b) ICU length of stay (p < 0.001) and (c) days from ICU admission to OT (p = 0.003). A significant relationship between the type of admission (elective, urgent surgery or medical) and the presence of infections was found (p < 0.001). The mortality rate was higher among infected patients (infected vs. infection-free: 10.3% vs. 2.1%; p < 0.001; OR = 5.38; 95% CI: 2.16−13.4; p < 0.001). Conclusions. Hospital-acquired infections remain a relevant preventable cause of mortality in our particular population.

Simple open-heart surgery protocol for sickle-cell disease patients: a retrospective cohort study comparing patients undergoing mitral valve surgery.

OBJECTIVES: Sickle-cell disease (SCD) patients are considered to be at high risk from open-heart surgery. This study assessed the role of a simple sickling-prevention protocol. METHODS: Perioperative non-specific and SCD-specific morbidity and 30-day mortality are investigated in a retrospective cohort study on patients undergoing isolated mitral valve surgery. Patients with and without SCD were compared. In the SCD cohort, a bundle of interventions was applied to limit the risk of sickling: 'on-demand' transfusions to keep haemoglobin levels of around 7-8 g/dl, cardiopulmonary bypass (CPB) with higher blood flow and perfusion temperature, close monitoring of acid-base balance and oxygenation. RESULTS: Twenty patients with and 40 patients without SCD were included. At baseline, only preoperative haemoglobin levels differed between cohorts (8.1 vs 11.8 g/dl, P < 0.001). Solely SCD patients received preoperative transfusions (45.0%). Intraoperative transfusions were significantly larger in SCD patients during CPB (priming: 300 vs 200 ml; entire length: 600 vs 300 ml and 20 vs 10 ml/kg). SCD patients had higher perfusion temperatures during CPB (34.7 vs 33.0°C, P = 0.01) with consequently higher pharyngeal temperature, both during cooling (34.1 vs 32.3°C, P = 0.02) and rewarming (36.5 vs 36.2°C, P = 0.02). No mortality occurred, and non-SCD-specific complications were comparable between groups, but one SCD patient suffered from perioperative cerebrovascular accident with seizures, and another had evident haemolysis. CONCLUSIONS: SCD patients may undergo open-heart surgery for mitral valve procedures with an acceptable risk profile. Simple but thoughtful perioperative management, embracing 'on-demand' transfusions and less-aggressive CPB cooling is feasible and probably efficacious.

Pregnancy Outcomes in Women With Mechanical Valve Prostheses Using Vitamin K Antagonist Therapy: The Experience of the Salam Centre for Cardiac Surgery in Sudan.

Pregnancy and childbirth on anticoagulants after mechanical heart valve replacement present a high risk of complications for both mother and baby. On top of pregnancy worsening the mother's cardiac function, anticoagulant therapy itself is a crucial problem. A safe and effective anticoagulation regimen for both mother and fetus is not possible. The most effective drugs for preventing valve thrombosis are VKAs, whose dosage needs to be adjusted with frequent INR checks. Moreover, VKAs can have embryopathic and teratogenic action. Patients in follow-up and anticoagulant treatment at the Salam Centre for Cardiac Surgery in Sudan live spread out over a large area where transport to the Center is generally difficult; pregnancy treatment has, therefore, been adapted to the limitations of reality. Pregnancy is discouraged and contraception and therapeutic abortion are recommended, but this guidance frequently goes unheeded. Here we describe maternal and fetal outcomes in 307 consecutive pregnancies recorded by staff at the oral anticoagulant clinic (OAC) from April 2017 to November 2021. Out of 307 pregnancies, there were 15 maternal deaths (4.9%), 24 thrombotic events (7.8%) and 22 major bleedings (7.2%). Fifty pregnancies (16.3%) were terminated by therapeutic abortion. Only 47.6% of pregnancies had good maternal and neonatal outcomes. Data clearly show that, due to the complexity of pregnancy in women with mechanical heart valves and the scarcity of tertiary healthcare services in the area where patients live, maternal mortality is at an unacceptable level and requires a structured, multi-disciplinary intervention.

Kabul airport suicide bombing attack: Mass casualty management at the EMERGENCY NGO Hospital.

BACKGROUND: Terrorist attacks with large numbers of civilian victims are not uncommon in war-torn countries, and present a unique challenge for health care facilities with limited resources. However, these events are largely underreported and little is known about how the mass casualty events (MCEs) are handled outside of a military setting. METHODS: This study is a retrospective analysis of the MCE which ensued the Kabul Airport suicide attack (August 26, 2021) at the Kabul EMERGENCY NGO Hospital (Afghanistan). RESULTS: Within 6 hours, 93 causalities presented at our hospital. Of them, 36 severe injured were admitted. Mean age was 30.8 years (SD, 10.1 years). The most common injury mechanism was shell fragments. The most common injury site was head (63%; 23/36), followed by limbs (55.5%; 20/36) and thoracoabdominal region (30.5%; 11/36). Combined injuries occurred in 38.9% of cases. Patients receiving surgery presented more combined injuries in comparison with patients receiving only medical treatment (47.1% vs. 31.6%). Thoracoabdomen (25.0% vs. 15.4%) and/or extremity injury (42.9% vs. 28.6%) were more prevalent in the surgical group. Thirty major surgical procedures were carried out on 17 patients in the 9 hours following the first arrival. The rate of intensive care unit/high dependency unit admission was 36.1% and the 30-day in-hospital mortality was 16.6% (6/36). All deaths were recorded in the first 24 hours, and none of them received surgery. CONCLUSION: A large number of wounded patients must be anticipated after suicide bombing attacks. The authors report the challenges faced and key aspects of their management of MCEs. LEVEL OF EVIDENCE: Prognostic/Epidemiological; Level IV.

Bergamo Field Hospital Confronting COVID-19: Operating Instructions.

The coronavirus disease (COVID-19) pandemic represented an unprecedented challenge for health care facilities, and innovative solutions were urgently required to overcome the high volume of critically ill infectious patients, limit in-hospital outbreaks, and limit the risk of occupational infection for health care workers (HCWs). Bergamo was the hardest-hit Italian province by COVID-19, and the local health care system had to undergo a profound and prompt reorganization. A COVID-19-only field hospital was rapidly set up meeting the standards for severe acute respiratory infection (SARI) treatment centers (https://apps.who.int/iris/handle/10665/331603). A zones partition, dedicated in-hospital pathways for HCWs, strict infection prevention and control (IPC) measures, and constant staff supervision were key components of our strategy to limit the risk of occupational infection for HCWs. Herein, we present the Bergamo field hospital layout enlightening fundamental IPC measures adopted as a valuable example of a SARI treatment center confronting COVID-19.

Treating Children With Advanced Rheumatic Heart Disease in Sub-Saharan Africa: The NGO EMERGENCY's Project at the Salam Centre for Cardiac Surgery in Sudan.

Rheumatic heart disease is endemic in Sub-Saharan Africa and while efforts are under way to boost prophylaxis and early diagnosis, access to cardiac surgery is rarely affordable. In this article, we report on a humanitarian project by the NGO EMERGENCY, to build and run the Salam Centre for Cardiac Surgery in Sudan. This hospital is a center of excellence offering free-of-charge, high-quality treatment to patients needing open-heart surgery for advanced rheumatic and congenital heart disease. Since it opened in 2007, more than 8,000 patients have undergone surgery there; most of them Sudanese, but ~20% were admitted from other countries, an example of inter-African cooperation. The program is not limited to surgical procedures. It guarantees long-term follow-up and anticoagulant treatment, where necessary. By way of example, we report clinical features and outcome data for the pediatric cohort: 1,318 children under the age of 15, operated on for advanced rheumatic heart disease between 2007 and 2019. The overall 5-year survival rate was 85.0% (95% CI 82.7-87.3). The outcomes for patients with mitral valves repaired and with mitral valves replaced are not statistically different. Nevertheless, observing the trend of patients undergoing valve repair, a better outcome for this category might be assumed. RHD in children is an indicator of poor socio-economic conditions and an inadequate health system, which clearly will not be cured by cardiac surgery alone. Nevertheless, the results achieved by EMERGENCY, with the crucial involvement and participation of the Sudanese government over the years, show that building a hospital, introducing free cardiac surgery, and offering long-term post-operative care may help spread belief in positive change in the future.

Non-inferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance: the case for post-marketing, adaptive randomised controlled trials.

Antimicrobial resistance is one of the most important threats to global health security. A range of Gram-negative bacteria associated with high morbidity and mortality are now resistant to almost all available antibiotics. In this context of urgency to develop novel drugs, new antibiotics for multidrug-resistant Gram-negative bacteria (namely, ceftazidime-avibactam, plazomicin, and meropenem-vaborbactam) have been approved by regulatory authorities based on non-inferiority trials that provided no direct evidence of their efficacy against multidrug-resistant bacteria such as Enterobacteriaceae spp, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, and Acinetobacter baumannii. The use of non-inferiority and superiority trials, and selection of appropriate and optimal study designs, remains a major challenge in the development, registration, and post-marketing implementation of new antibiotics. Using an example of the development process of ceftazidime-avibactam, we propose a strategy for a new research framework based on adaptive randomised clinical trials. The operational research strategy has the aim of assessing the efficacy of new antibiotics in special groups of patients, such as those infected with multidrug-resistant bacteria, who were not included in earlier phase studies, and for whom it is important to establish an appropriate standard of care.

Inflammatory and Humoral Immune Response during Ebola Virus Infection in Survivor and Fatal Cases Occurred in Sierra Leone during the 2014⁻2016 Outbreak in West Africa.

Ebola virus (EBOV) infection is characterized by an excessive inflammatory response, a loss of lymphocytes and a general paralysis of the immune system, however pathophysiological mechanisms are not fully understood. In a cohort of 23 fatal and 21 survivors of ebola virus disease (EVD) cases admitted to the Emergency Ebola-Treatment-Center in Goderich (Freetown, Sierra Leone) during the 2014 to 2016 EBOV epidemic in Western Africa, we analyzed the pathway-focused gene expression profile of secreted proteins involved in the immune response and the levels of specific anti-EBOV IgM and IgG from the time of admission till discharge or death. We observed a dysregulated inflammatory response in fatal patients as compared to survivors, mainly consisting of the upregulation of inflammatory mediators, whose extent directly correlated with viremia levels. The upregulation persisted and intensified during the late phase of infection. Relevant differences were also found in humoral immunity, as an earlier and more robust EBOV antibody response was observed in survivor patients.

Intensive care support and clinical outcomes of patients with Ebola virus disease (EVD) in West Africa.

PURPOSE: We investigate the impact on outcome of different levels of supportive treatment in Ebola virus disease (EVD). The NGO EMERGENCY delivered care sequentially at two Ebola Treatment Centres (ETC) in Sierra Leone: first at Lakka (fluids, symptomatic, antibiotic, antimalaria treatment, and hospital level medical care), and thereafter in Goderich, adding organ support in the only African ETC with an equipped and staffed intensive care unit (ETC-ICU). METHODS: The primary outcome in this retrospective cohort study was in-ETC mortality. Secondarily, we used multivariable logistic regression to investigate the independent impact of the IC on mortality by comparing patients in two ETCs, adjusting for potential confounders, including the viral load (base-10 logarithm in copies/ml) (LVL), modelled as a piecewise linear function. Mortality was plotted versus LVL. Confidence bands were constructed by a bootstrap technique. The number of hospital-free days within 28 was computed to assess the burden of EVD. RESULTS: Data from 229 EVD patients were analysed (123 in Lakka, 106 in Goderich). Crude analysis showed a non-statistically significant difference in mortality (57.7% in Lakka vs 50.0% in Goderich; p = 0.19). Age and LVL were associated with mortality. Adjusted mortality was lower at the Goderich ICU-ETC (p = 0.055). This difference was observed with 80% confidence for patients with LVL between 7.5 and 8.5 copies/ml. Hospital-free days (of 28 days) were greater (7.7 vs 5.5; p = 0.03) for patients treated in the ICU-ETC. CONCLUSIONS: Provision of critical care to patients with EVD is feasible in resource-limited settings and was associated with improved survival and less time in hospital.

Relationship Between Viremia and Specific Organ Damage in Ebola Patients: A Cohort Study.

Background: Pathogenesis of Ebola virus disease remains poorly understood. We used concomitant determination of routine laboratory biomarkers and Ebola viremia to explore the potential role of viral replication in specific organ damage. Methods: We recruited patients with detectable Ebola viremia admitted to the EMERGENCY Organizzazione Non Governativa Organizzazione Non Lucrativa di Utilità Sociale (ONG ONLUS) Ebola Treatment Center in Sierra Leone. Repeated measure of Ebola viremia, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), activated prothrombin time (aPTT), international normalized ratio (INR), creatinine, and blood urea nitrogen (BUN) were recorded. Patients were followed up from admission until death or discharge. Results: One hundred patients (49 survivors and 51 nonsurvivors) were included in the analysis. Unadjusted analysis to compare survivors and nonsurvivors provided evidence that all biomarkers were significantly above the normal range and that the extent of these abnormalities was generally higher in nonsurvivors than in survivors. Multivariable mixed-effects models provided strong evidence for a biological gradient (suggestive of a direct role in organ damage) between the viremia levels and either ALT, AST, CPK LDH, aPTT, and INR. In contrast, no direct linear association was found between viremia and either creatinine, BUN, or bilirubin. Conclusions: This study provides evidence to support that Ebola virus may have a direct role in muscular damage and imbalance of the coagulation system. We did not find strong evidence suggestive of a direct role of Ebola virus in kidney damage. The role of the virus in liver damage remains unclear, but our evidence suggests that acute severe liver injury is not a typical feature of Ebola virus disease.

Ebola virus disease and critical illness.

As of 20 May 2016 there have been 28,646 cases and 11,323 deaths resulting from the West African Ebola virus disease (EVD) outbreak reported to the World Health Organization. There continue to be sporadic flare-ups of EVD cases in West Africa.EVD presentation is nonspecific and characterized initially by onset of fatigue, myalgias, arthralgias, headache, and fever; this is followed several days later by anorexia, nausea, vomiting, diarrhea, and abdominal pain. Anorexia and gastrointestinal losses lead to dehydration, electrolyte abnormalities, and metabolic acidosis, and, in some patients, acute kidney injury. Hypoxia and ventilation failure occurs most often with severe illness and may be exacerbated by substantial fluid requirements for intravascular volume repletion and some degree of systemic capillary leak. Although minor bleeding manifestations are common, hypovolemic and septic shock complicated by multisystem organ dysfunction appear the most frequent causes of death.Males and females have been equally affected, with children (0-14 years of age) accounting for 19 %, young adults (15-44 years) 58 %, and older adults (≥45 years) 23 % of reported cases. While the current case fatality proportion in West Africa is approximately 40 %, it has varied substantially over time (highest near the outbreak onset) according to available resources (40-90 % mortality in West Africa compared to under 20 % in Western Europe and the USA), by age (near universal among neonates and high among older adults), and by Ebola viral load at admission.While there is no Ebola virus-specific therapy proven to be effective in clinical trials, mortality has been dramatically lower among EVD patients managed with supportive intensive care in highly resourced settings, allowing for the avoidance of hypovolemia, correction of electrolyte and metabolic abnormalities, and the provision of oxygen, ventilation, vasopressors, and dialysis when indicated. This experience emphasizes that, in addition to evaluating specific medical treatments, improving the global capacity to provide supportive critical care to patients with EVD may be the greatest opportunity to improve patient outcomes.

Blood kinetics of Ebola virus in survivors and nonsurvivors.

BACKGROUND: Infection with Ebola virus (EBOV) results in a life-threatening disease, with reported mortality rates between 50%-70%. The factors that determine patient survival are poorly understood; however, clinical observations indicate that EBOV viremia may be associated with fatal outcome. We conducted a study of the kinetics of Zaire EBOV viremia in patients with EBOV disease (EVD) who were managed at an Ebola Treatment Centre in Sierra Leone during the recent West African outbreak. METHODS: Data from 84 EVD patients (38 survivors, 46 nonsurvivors) were analyzed, and EBOV viremia was quantified between 2 and 13 days after symptom onset. Time since symptom onset and clinical outcome were used as independent variables to compare EBOV viral kinetics in survivors and nonsurvivors. RESULTS: In all patients, EBOV viremia kinetics was a quadratic function of time; however, EBOV viremia was 0.94 logarithm (log) copies per ml (cp/ml) (P = 0.011) higher in nonsurvivors than in survivors from day 2 after the onset of symptoms. Survivors reached peak viremia levels at an earlier time after symptom onset than nonsurvivors (day 5 versus day 7) and had lower mean peak viremia levels compared with nonsurvivors (7.46 log cp/ml; 95% CI, 7.17-7.76 vs. 8.60 log cp/ml; 95% CI, 8.27-8.93). Before reaching peak values, EBOV viremia similarly increased both in survivors and nonsurvivors; however, the decay of viremia after the peak was much stronger in survivors than in nonsurvivors. CONCLUSION: Our results demonstrate that plasma concentrations of EBOV are markedly different between survivors and nonsurvivors at very early time points after symptom onset and may be predicative of outcome. Further studies focused on the early phase of the disease will be required to identify the causal and prognostic factors that determine patient outcome. FUNDING: Italian Ministry of Health; Italian Ministry of Foreign Affairs; EMERGENCY's private donations; and Royal Engineers for DFID-UK.

Molecular Signature of the Ebola Virus Associated with the Fishermen Community Outbreak in Aberdeen, Sierra Leone, in February 2015.

We report the complete genome sequence of Ebola virus from a health worker linked to a cluster of cases occurring in the fishing community of Aberdeen, Sierra Leone (February 2015), which were characterized by unusually severe presentation. The sequence, clustering in the SL subclade 3.2.4, harbors mutations potentially relevant for pathogenesis.

Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24,900 cases and about 10,300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group.