Development of a Cell-based Neutralizing Antibody Assay for Zinpentraxin Alfa: Challenges and Mitigation Strategies.

Therapeutic protein drugs can potentially induce immune responses in patients and result in the production of anti-drug antibodies (ADAs), including a subset of ADAs called neutralizing antibodies (NAbs) that might cause loss of efficacy by inhibiting clinical activities of the drug. Herein, we describe the unique challenges encountered during the development of a fit-for-purpose cell-based NAb assay for a new protein modality, zinpentraxin alfa, including our strategies for assay design to overcome various matrix interferences and improve assay drug tolerance. We demonstrated that a typical biotin-drug extraction with acid dissociation (BEAD) approach alone was not sufficient to eliminate matrix interferences in this assay. Instead, the combination of the BEAD and ZebaTM spin size exclusion plate (SEP) was required to achieve the desirable assay performance. We also demonstrated that appropriate acidic buffers were critical in sample pretreatment to improve assay drug tolerance, which not only dissociated the drug/NAb immune complex but also effectively and irreversibly denatured the free drug. The final assay performed well with confirmed assay robustness and suitability for the clinical applications.

FIRST REPORTS OF LIGULA INTESTINALIS AND A SCHISTOCEPHALUS SP. INFECTING SMALL-BODIED FISH IN NEW BRUNSWICK, CANADA.

Morphological characteristics and DNA sequencing were used to identify plerocercoids of a Schistocephalus sp. infecting slimy sculpin (Cottus cognatus) from northern New Brunswick and plerocercoids of Ligula intestinalis infecting blacknose dace (Rhinichthys atratulus) in Fundy National Park (FNP, New Brunswick). To our knowledge, no previous publications documented either cestode from New Brunswick, Canada. Blacknose dace represent a new host record for L. intestinalis. Identifications were made based on the presence or absence of segmentation and sequencing partial nicotinamide adenine dinucleotide dehydrogenase subunit 1 (ND1; mitochondrial DNA) and/or partial cytochrome c oxidase subunit 1 (COI; mitochondrial DNA). Plerocercoids from blacknose dace in FNP were identified as Ligula intestinalis based on >99% nucleotide identity with COI for this species in the NCBI GenBank database. Plerocercoids in slimy sculpin from northern New Brunswick were identified as a Schistocephalus sp. based on high nucleotide identity with congenerics in the NCBI GenBank database. The absence of GenBank entries with sufficient high percent identity to our specimens, and potential species hybrids in this genus, prevents species-level identification of Schistocephalus sp. plerocercoids currently. The absence of previous documentation of these cestodes might reflect recent environmental change promoting the transmission of these parasites that can modulate host fish behavior, induce sterility of host fishes, and contribute to epizootics.

Ethical implications of AI in robotic surgical training: A Delphi consensus statement.

CONTEXT: As the role of AI in healthcare continues to expand there is increasing awareness of the potential pitfalls of AI and the need for guidance to avoid them. OBJECTIVES: To provide ethical guidance on developing narrow AI applications for surgical training curricula. We define standardised approaches to developing AI driven applications in surgical training that address current recognised ethical implications of utilising AI on surgical data. We aim to describe an ethical approach based on the current evidence, understanding of AI and available technologies, by seeking consensus from an expert committee. EVIDENCE ACQUISITION: The project was carried out in 3 phases: (1) A steering group was formed to review the literature and summarize current evidence. (2) A larger expert panel convened and discussed the ethical implications of AI application based on the current evidence. A survey was created, with input from panel members. (3) Thirdly, panel-based consensus findings were determined using an online Delphi process to formulate guidance. 30 experts in AI implementation and/or training including clinicians, academics and industry contributed. The Delphi process underwent 3 rounds. Additions to the second and third-round surveys were formulated based on the answers and comments from previous rounds. Consensus opinion was defined as ≥ 80% agreement. EVIDENCE SYNTHESIS: There was 100% response from all 3 rounds. The resulting formulated guidance showed good internal consistency, with a Cronbach alpha of >0.8. There was 100% consensus that there is currently a lack of guidance on the utilisation of AI in the setting of robotic surgical training. Consensus was reached in multiple areas, including: 1. Data protection and privacy; 2. Reproducibility and transparency; 3. Predictive analytics; 4. Inherent biases; 5. Areas of training most likely to benefit from AI. CONCLUSIONS: Using the Delphi methodology, we achieved international consensus among experts to develop and reach content validation for guidance on ethical implications of AI in surgical training. Providing an ethical foundation for launching narrow AI applications in surgical training. This guidance will require further validation. PATIENT SUMMARY: As the role of AI in healthcare continues to expand there is increasing awareness of the potential pitfalls of AI and the need for guidance to avoid them.In this paper we provide guidance on ethical implications of AI in surgical training.

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS:We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38­52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63­87), increasing to 89% (80­94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05­3·08) but not after 30 days (1·25, 0·84­2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16­8·84). INTERPRETATION:In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients

Mycobacterium tuberculosis bloodstream infection prevalence, diagnosis, and mortality risk in seriously ill adults with HIV: a systematic review and meta-analysis of individual patient data.

BACKGROUND: The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. METHODS: We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. FINDINGS: We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per µL (the median for the cohort) was 45% (95% CI 38-52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63-87), increasing to 89% (80-94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05-3·08) but not after 30 days (1·25, 0·84-2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16-8·84). INTERPRETATION: In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. FUNDING: This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A.

Impurities in Oligonucleotide Drug Substances and Drug Products.

This white paper, which is the 10th in a series intended to address issues associated with the development of therapeutic oligonucleotides, examines the subject of product-related impurities. The authors consider chemistry and safety aspects and advance arguments in favor of platform approaches to impurity identification and qualification. Reporting, identification, and qualification thresholds suitable for product-related impurities of therapeutic oligonucleotides are proposed.

Derivation and validation of a universal vital assessment (UVA) score: a tool for predicting mortality in adult hospitalised patients in sub-Saharan Africa.

BACKGROUND: Critical illness is a leading cause of morbidity and mortality in sub-Saharan Africa (SSA). Identifying patients with the highest risk of death could help with resource allocation and clinical decision making. Accordingly, we derived and validated a universal vital assessment (UVA) score for use in SSA. METHODS: We pooled data from hospital-based cohort studies conducted in six countries in SSA spanning the years 2009-2015. We derived and internally validated a UVA score using decision trees and linear regression and compared its performance with the modified early warning score (MEWS) and the quick sepsis-related organ failure assessment (qSOFA) score. RESULTS: Of 5573 patients included in the analysis, 2829 (50.8%) were female, the median (IQR) age was 36 (27-49) years, 2122 (38.1%) were HIV-infected and 996 (17.3%) died in-hospital. The UVA score included points for temperature, heart and respiratory rates, systolic blood pressure, oxygen saturation, Glasgow Coma Scale score and HIV serostatus, and had an area under the receiver operating characteristic curve (AUC) of 0.77 (95% CI 0.75 to 0.79), which outperformed MEWS (AUC 0.70 (95% CI 0.67 to 0.71)) and qSOFA (AUC 0.69 (95% CI 0.67 to 0.72)). CONCLUSION: We identified predictors of in-hospital mortality irrespective of the underlying condition(s) in a large population of hospitalised patients in SSA and derived and internally validated a UVA score to assist clinicians in risk-stratifying patients for in-hospital mortality. The UVA score could help improve patient triage in resource-limited environments and serve as a standard for mortality risk in future studies.

Effect of an Early Resuscitation Protocol on In-hospital Mortality Among Adults With Sepsis and Hypotension: A Randomized Clinical Trial.

Importance: The effect of an early resuscitation protocol on sepsis outcomes in developing countries remains unknown. Objective: To determine whether an early resuscitation protocol with administration of intravenous fluids, vasopressors, and blood transfusion decreases mortality among Zambian adults with sepsis and hypotension compared with usual care. Design, Setting, and Participants: Randomized clinical trial of 212 adults with sepsis (suspected infection plus ≥2 systemic inflammatory response syndrome criteria) and hypotension (systolic blood pressure ≤90 mm Hg or mean arterial pressure ≤65 mm Hg) presenting to the emergency department at a 1500-bed referral hospital in Zambia between October 22, 2012, and November 11, 2013. Data collection concluded December 9, 2013. Interventions: Patients were randomized 1:1 to either (1) an early resuscitation protocol for sepsis (n = 107) that included intravenous fluid bolus administration with monitoring of jugular venous pressure, respiratory rate, and arterial oxygen saturation and treatment with vasopressors targeting mean arterial pressure (≥65 mm Hg) and blood transfusion (for patients with a hemoglobin level <7 g/dL) or (2) usual care (n = 105) in which treating clinicians determined hemodynamic management. Main Outcomes and Measures: The primary outcome was in-hospital mortality and the secondary outcomes included the volume of intravenous fluid received and receipt of vasopressors. Results: Among 212 patients randomized to receive either the sepsis protocol or usual care, 3 were ineligible and the remaining 209 completed the study and were included in the analysis (mean [SD] age, 36.7 [12.4] years; 117 men [56.0%]; 187 [89.5%] positive for the human immunodeficiency virus). The primary outcome of in-hospital mortality occurred in 51 of 106 patients (48.1%) in the sepsis protocol group compared with 34 of 103 patients (33.0%) in the usual care group (between-group difference, 15.1% [95% CI, 2.0%-28.3%]; relative risk, 1.46 [95% CI, 1.04-2.05]; P = .03). In the 6 hours after presentation to the emergency department, patients in the sepsis protocol group received a median of 3.5 L (interquartile range, 2.7-4.0 L) of intravenous fluid compared with 2.0 L (interquartile range, 1.0-2.5 L) in the usual care group (mean difference, 1.2 L [95% CI, 1.0-1.5 L]; P < .001). Fifteen patients (14.2%) in the sepsis protocol group and 2 patients (1.9%) in the usual care group received vasopressors (between-group difference, 12.3% [95% CI, 5.1%-19.4%]; P < .001). Conclusions and Relevance: Among adults with sepsis and hypotension, most of whom were positive for HIV, in a resource-limited setting, a protocol for early resuscitation with administration of intravenous fluids and vasopressors increased in-hospital mortality compared with usual care. Further studies are needed to understand the effects of administration of intravenous fluid boluses and vasopressors in patients with sepsis across different low- and middle-income clinical settings and patient populations. Trial Registration: clinicaltrials.gov Identifier: NCT01663701.

Nonacademic Attributes Predict Medical and Nursing Student Intentions to Emigrate or to Work Rurally: An Eight-Country Survey in Asia and Africa.

AbstractWe sought to identify independent, nonacademic predictors of medical and nursing student intent to migrate abroad or from rural to urban areas after graduation in low- and middle-income countries (LMIC). This was a cross-sectional survey of 3,199 first- and final-year medical and nursing students at 16 training institutions in eight LMIC. Questionnaires assessed demographics, career intentions, and preferences regarding selected career, location, and work-related attributes. Using principal component analysis, student preferences were reduced into four discrete categories of priorities: 1) work environment resources, 2) location livability, 3) altruistic job values, and 4) individualistic job values. Students' preferences were scored in each category. Using students' characteristics and priority scores, multivariable proportional odds models were used to derive independent predictors of intentions to emigrate for work outside the country, or to work in a rural area in their native country. Students prioritizing individualistic values more often planned international careers (adjusted odds ratio [aOR] = 1.44, 95% confidence interval [CI] = 1.16-1.78), whereas those prioritizing altruistic values preferred rural careers (aOR = 1.82, 95% CI = 1.50-2.21). Trainees prioritizing high-resource environments preferentially planned careers abroad (aOR = 1.38, 95% CI = 1.12-1.69) and were unlikely to seek rural work (aOR = 0.60, 95% CI = 0.49-0.73). Independent of their priorities, students with prolonged prior rural residence were unlikely to plan emigration (aOR = 0.67, 95% CI = 0.50-0.90) and were more likely to plan a rural career (aOR = 1.53, 95% CI = 1.16-2.03). We conclude that use of nonacademic attributes in medical and nursing admissions processes would likely increase retention in high-need rural areas and reduce emigration "brain drain" in LMIC.

High prevalence of Mycobacterium tuberculosis bacteraemia among a cohort of HIV-infected patients with severe sepsis in Lusaka, Zambia.

Tuberculosis is recognised as one of the leading causes of severe sepsis among HIV-infected patients. Most patients with Mycobacterium tuberculosis bacteraemia have advanced HIV disease with CD4 counts less than 100 cells/µl and its presentation is non-specific in most instances. This was a cross-sectional study which was done by analyzing data from 201 adult HIV-infected patients who met the inclusion criteria for severe sepsis. The prevalence of Mycobacterium tuberculosis bactraemia in the study population was 34.8%. Severe sepsis caused by other etiologies was observed in 33 (16.4%) of the participants. Concomitant infection of Mycobacterium tuberculosis bactraemia with other organisms is not uncommon in patients with severe sepsis. This cohort of HIV-infected patients had severe immunosuppression with a median CD4 count of 51 (20-136) cells/µl with moderate anaemia, mean haemoglobin 8.0 (3.0) g/dl, and were generally underweight with a mean mid upper arm circumference (MUAC) of 21.0 (3.4) cm. Mycobacterium tuberculosis bacteraemia is very common in HIV-infected patients with advanced HIV disease who present with severe sepsis. Mycobacterium tuberculosis bacteraemia co-infection with aerobic organisms is not uncommon. Factors that were independently associated with Mycobacterium tuberculosis bacteraemia in our study population were MUAC and sodium level.

How we implemented an analytical support clinic to strengthen student research capacity in Zambia.

BACKGROUND: Research outputs in sub-Saharan Africa may be limited by a scarcity of clinical research expertise. In Zambia, clinical and biomedical postgraduate students are often delayed in graduation due to challenges in completing their research dissertations. We sought to strengthen institutional research capacity by supporting student and faculty researchers through weekly epidemiology and biostatistics clinics. METHODS: We instituted a weekly Analytical Support Clinic at the University of Zambia, School of Medicine. A combination of biostatisticians, clinical researchers and epidemiologists meet weekly with clients to address questions of proposal development, data management and analysis. Clinic sign-in sheets were reviewed. RESULTS: 109 students and faculty members accounted for 197 visits to the Clinic. Nearly all clients (107/109, 98.2%) were undergraduate or postgraduate students. Reasons for attending the Clinic were primarily for proposal development (46.7%) and data management/analysis (42.1%). The most common specific reasons for seeking help were data analysis and interpretation (36.5%), development of study design and research questions (26.9%) and sample size calculation (21.8%). CONCLUSIONS: The Analytical Support Clinic is an important vehicle for strengthening postgraduate research through one-on-one and small group demand-driven interactions. The clinic approach supplements mentorship from departmental supervisors, providing specific expertise and contextual teaching.

Medical and nursing students' intentions to work abroad or in rural areas: a cross-sectional survey in Asia and Africa.

OBJECTIVE: To assess medical and nursing students' intentions to migrate abroad or practice in rural areas. METHODS: We surveyed 3199 first- and final-year medical and nursing students at 16 premier government institutions in Bangladesh, Ethiopia, India, Kenya, Malawi, Nepal, the United Republic of Tanzania and Zambia. The survey contained questions to identify factors that could predict students' intentions to migrate. Primary outcomes were the likelihoods of migrating to work abroad or working in rural areas in the country of training within five years post-training. We assessed predictors of migration intentions using multivariable proportional odds models. FINDINGS: Among respondents, 28% (870/3156) expected to migrate abroad, while only 18% (575/3158) anticipated a rural career. More nursing than medical students desired professions abroad (odds ratio, OR: 1.76; 95% confidence interval, CI: 1.25-2.48). Career desires before matriculation correlated with current intentions for international (OR: 4.49; 95% CI: 3.21-6.29) and rural (OR: 4.84; 95% CI: 3.52-6.66) careers. Time spent in rural areas before matriculation predicted the preference for a rural career (20 versus 0 years: OR: 1.53, 95% CI: 1.19-1.98) and against work abroad (20 versus 0 years: OR: 0.69, 95% CI: 0.50-0.96). CONCLUSION: A significant proportion of students surveyed still intend to work abroad or in cities after training. These intentions could be identified even before matriculation. Admissions standards that account for years spent in rural areas could promote greater graduate retention in the country of training and in rural areas.

Strengthening faculty recruitment for health professions training in basic sciences in Zambia.

Zambia is facing a crisis in its human resources for health, with deficits in the number and skill mix of health workers. The University of Zambia School of Medicine (UNZA SOM) was the only medical school in the country for decades, but recently it was joined by three new medical schools--two private and one public. In addition to expanding medical education, the government has also approved several allied health programs, including pharmacy, physiotherapy, biomedical sciences, and environmental health. This expansion has been constrained by insufficient numbers of faculty. Through a grant from the Medical Education Partnership Initiative (MEPI), UNZA SOM has been investing in ways to address faculty recruitment, training, and retention. The MEPI-funded strategy involves directly sponsoring a cohort of faculty at UNZA SOM during the five-year grant, as well as establishing more than a dozen new master's programs, with the goal that all sponsored faculty are locally trained and retained. Because the issue of limited basic science faculty plagues medical schools throughout Sub-Saharan Africa, this strategy of using seed funding to build sustainable local capacity to recruit, train, and retain faculty could be a model for the region.

Simplified severe sepsis protocol: a randomized controlled trial of modified early goal-directed therapy in Zambia.

OBJECTIVE: To assess the efficacy of a simple, goal-directed sepsis treatment protocol for reducing mortality in patients with severe sepsis in Zambia. DESIGN: Single-center nonblinded randomized controlled trial. SETTING: Emergency department, ICU, and medical wards of the national referral hospital in Lusaka, Zambia. PATIENTS: One hundred twelve patients enrolled within 24 hours of admission with severe sepsis, defined as systemic inflammatory response syndrome with suspected infection and organ dysfunction INTERVENTIONS: : Simplified Severe Sepsis Protocol consisting of up to 4 L of IV fluids within 6 hours, guided by jugular venous pressure assessment, and dopamine and/or blood transfusion in selected patients. Control group was managed as usual care. Blood cultures were collected and early antibiotics administered for both arms. MEASUREMENTS AND MAIN RESULTS: Primary outcome was in-hospital all-cause mortality. One hundred nine patients were included in the final analysis and 88 patients (80.7%) were HIV positive. Pulmonary infections were the most common source of sepsis. In-hospital mortality rate was 64.2% in the intervention group and 60.7% in the control group (relative risk, 1.05; 95% CI, 0.79-1.41). Mycobacterium tuberculosis complex was isolated from 31 of 82 HIV-positive patients (37.8%) with available mycobacterial blood culture results. Patients in Simplified Severe Sepsis Protocol received significantly more IV fluids in the first 6 hours (2.7 L vs 1.7 L, p = 0.002). The study was stopped early because of high mortality rate among patients with hypoxemic respiratory failure in the intervention arm (8/8, 100%) compared with the control arm (7/10, 70%; relative risk, 1.43; 95% CI, 0.95-2.14). CONCLUSION: Factors other than tissue hypoperfusion probably account for much of the end-organ dysfunction in African patients with severe sepsis. Studies of fluid-based interventions should utilize inclusion criteria to accurately capture patients with hypovolemia and tissue hypoperfusion who are most likely to benefit from fluids. Exclusion of patients with severe respiratory distress should be considered when ventilatory support is not readily available.

Some hazards are more attractive than others: drivers of varying experience respond differently to different types of hazard.

The ability to detect hazards in video clips of driving has been inconsistently linked to driving experience and skill. One potential reason for the lack of consistency is the failure to understand the structural differences between those hazards that discriminate between safe and unsafe drivers, and those that do not. The current study used a car simulator to test drivers of differing levels of experience on approach to a series of hazards that were categorized a priori according to their underlying structure. The results showed that learner drivers took longer to fixate hazards, although they were particularly likely to miss hazards that were obscured by the environment (such as a pedestrian emerging from behind a parked truck). While drivers with a moderate amount of experience were as fast as driving instructors to look at hazards, they spent the greatest amount of time looking at them. Only instructors' ability to detect hazards early in the approach translated into differences in driving speed for certain types of hazard. The results demonstrate that drivers of varying experience respond differently to different hazards, and lay the foundations for a hazard typology.

The Etiology And Outcome Of Adult Patients Presenting With Sepsis To The University Teaching Hospital, Lusaka, Zambia.

BACKGROUND: Sepsis accounts for a significant burden of morbidity and mortality.In developed world, it is implicated as the second leading cause of non-cardiac death. Mortality from sepsis is on the increase with a mortality rate of 33-61%. In spite of the high burden of sepsis in sub Saharan Africa, data regarding the etiology and outcome of septic patients is limited. We conducted a prospective cohort study to describe the etiology, characteristic and outcome of patients presenting with sepsis to the University Teaching Hospital in Lusaka, Zambia. METHODS: Patients who met the inclusion criteria were enrolled into the study and after a thorough examination, bloods were drawn for full blood count, urea and electrolytes, liver function tests and for culture. Samples for culture were collected under aseptic techniques and cultured for aerobic organisms. Biochemical and bacteriological methods were used to identify the isolates and antibiotic sensitivity patterns were determined using agar diffusion methods. Patients were then followed up until they either demised or were discharge. RESULTS: A total of 161 patients were enrolled of which 110(68%) were HIV positive and 23(14%) had unknown HIV status. Bacteremia was found in 39 (24%) with the most isolated organism being staphylococcus aureus. Mortality in our cohort of septic patients was determinedat 40%. Identified predictors for in patient mortality were low admission Glasgow coma scale[OR 11.2(CI 3.5-36.4)], positive blood culture[OR 2.38(CI 1.14-4.95)] and HIV status, those with unknown HIV status were more likely to die than those who were HIV negative[OR 8.38(CI2.36-29.7)]. CONCLUSION: Most of the septic patients presenting to UTH had advanced immunosuppression (WHO stage 3 and 4) and had a high mortality rate. Staphylococcus aureus and streptococcus pneumoniae were the highest isolates. Identified predictors for in patient mortality could be used to try and improve outcome in septic patients at UTH.

Running over unknown rough terrain with a one-legged planar robot.

The ability to traverse unknown, rough terrain is an advantage that legged locomoters have over their wheeled counterparts. However, due to the complexity of multi-legged systems, research in legged robotics has not yet been able to reproduce the agility found in the animal kingdom. In an effort to reduce the complexity of the problem, researchers have developed single-legged models to gain insight into the fundamental dynamics of legged running. Inspired by studies of animal locomotion, researchers have proposed numerous control strategies to achieve stable, one-legged running over unknown, rough terrain. One such control strategy incorporates energy variations into the system during the stance phase by changing the force-free leg length as a sinusoidal function of time. In this research, a one-legged planar robot capable of implementing this and other state-of-the-art control strategies was designed and built. Both simulated and experimental results were used to determine and compare the stability of the proposed controllers as the robot was subjected to unknown drop and raised step perturbations equal to 25% of the nominal leg length. This study illustrates the relative advantages of utilizing a minimal-sensing, active energy removal control scheme to stabilize running over rough terrain.

Commentary training improves responsiveness to hazards in a driving simulator.

Can commentary driving produce safer drivers? Producing a verbal commentary of potential hazards during driving has long been considered by the police to improve hazard perception skills. In this study we investigated whether learner drivers would benefit from being trained to produce a commentary drive. All learners were initially assessed on a virtual route in a driving simulator that contained 9 hazards. One group of drivers was then trained in commentary driving, and their subsequent simulated driving behaviour was compared to a control group. The results showed that the trained group had fewer crashes, reduced their speed sooner on approach to hazards, and applied pressure to the brakes sooner than untrained drivers. Conversely the untrained drivers' behaviour on approach to hazards was symptomatic of being surprised at the appearance of the hazards. The benefit of training was found to be greater for certain types of hazard than others.