An old foe on peculiar paths: severe falciparum malaria in a Syrian refugee, possibly infected during migrant smuggling from Türkiye to Germany.

Infectious diseases and their imperative awareness gain major relevance through global warming and multi-continent refugee crises. Here, we demonstrate the challenges of malaria diagnosis, disease course, and treatment, including post-artesunate hemolysis in a Syrian refugee with severe falciparum malaria, most probably infected during migrant smuggling from Türkiye to Germany.

An Innovative Telemedical Network to Improve Infectious Disease Management in Critically Ill Patients and Outpatients (TELnet@NRW): Stepped-Wedge Cluster Randomized Controlled Trial.

BACKGROUND: Evidence-based infectious disease and intensive care management is more relevant than ever. Medical expertise in the two disciplines is often geographically limited to university institutions. In addition, the interconnection between inpatient and outpatient care is often insufficient (eg, no shared electronic health record and no digital transfer of patient findings). OBJECTIVE: This study aims to establish and evaluate a telemedical inpatient-outpatient network based on expert teleconsultations to increase treatment quality in intensive care medicine and infectious diseases. METHODS: We performed a multicenter, stepped-wedge cluster randomized trial (February 2017 to January 2020) to establish a telemedicine inpatient-outpatient network among university hospitals, hospitals, and outpatient physicians in North Rhine-Westphalia, Germany. Patients aged ≥18 years in the intensive care unit or consulting with a physician in the outpatient setting were eligible. We provided expert knowledge from intensivists and infectious disease specialists through advanced training courses and expert teleconsultations with 24/7/365 availability on demand respectively once per week to enhance treatment quality. The primary outcome was adherence to the 10 Choosing Wisely recommendations for infectious disease management. Guideline adherence was analyzed using binary logistic regression models. RESULTS: Overall, 159,424 patients (10,585 inpatients and 148,839 outpatients) from 17 hospitals and 103 outpatient physicians were included. There was a significant increase in guideline adherence in the management of Staphylococcus aureus infections (odds ratio [OR] 4.00, 95% CI 1.83-9.20; P<.001) and in sepsis management in critically ill patients (OR 6.82, 95% CI 1.27-56.61; P=.04). There was a statistically nonsignificant decrease in sepsis-related mortality from 29% (19/66) in the control group to 23.8% (50/210) in the intervention group. Furthermore, the extension of treatment with prophylactic antibiotics after surgery was significantly less likely (OR 9.37, 95% CI 1.52-111.47; P=.04). Patients treated by outpatient physicians, who were regularly participating in expert teleconsultations, were also more likely to be treated according to guideline recommendations regarding antibiotic therapy for uncomplicated upper respiratory tract infections (OR 1.34, 95% CI 1.16-1.56; P<.001) and asymptomatic bacteriuria (OR 9.31, 95% CI 3.79-25.94; P<.001). For the other recommendations, we found no significant effects, or we had too few observations to generate models. The key limitations of our study include selection effects due to the applied on-site triage of patients as well as the limited possibilities to control for secular effects. CONCLUSIONS: Telemedicine facilitates a direct round-the-clock interaction over broad distances between intensivists or infectious disease experts and physicians who care for patients in hospitals without ready access to these experts. Expert teleconsultations increase guideline adherence and treatment quality in infectious disease and intensive care management, creating added value for critically ill patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03137589; https://clinicaltrials.gov/ct2/show/NCT03137589.

Gene Expression of Diverse Cryptococcus Isolates during Infection of the Human Central Nervous System.

Cryptococcus neoformans is a major human central nervous system (CNS) fungal pathogen causing considerable morbidity and mortality. In this study, we provide the widest view to date of the yeast transcriptome directly from the human subarachnoid space and within cerebrospinal fluid (CSF). We captured yeast transcriptomes from C. neoformans of various genotypes in 31 patients with cryptococcal meningoencephalitis as well as several Cryptococcus gattii infections. Using transcriptome sequencing (RNA-seq) analyses, we compared the in vivo yeast transcriptomes to those from other environmental conditions, including in vitro growth on nutritious media or artificial CSF as well as samples collected from rabbit CSF at two time points. We ranked gene expressions and identified genetic patterns and networks across these diverse isolates that reveal an emphasis on carbon metabolism, fatty acid synthesis, transport, cell wall structure, and stress-related gene functions during growth in CSF. The most highly expressed yeast genes in human CSF included those known to be associated with survival or virulence and highlighted several genes encoding hypothetical proteins. From that group, a gene encoding the CMP1 putative glycoprotein (CNAG_06000) was selected for functional studies. This gene was found to impact the virulence of Cryptococcus in both mice and the CNS rabbit model, in agreement with a recent study also showing a role in virulence. This transcriptional analysis strategy provides a view of regulated yeast genes across genetic backgrounds important for human CNS infection and a relevant resource for the study of cryptococcal genes, pathways, and networks linked to human disease. IMPORTANCE Cryptococcus is the most common fungus causing high-morbidity and -mortality human meningitis. This encapsulated yeast has a unique propensity to travel to the central nervous system to produce disease. In this study, we captured transcriptomes of yeasts directly out of the human cerebrospinal fluid, the most concerning site of infection. By comparing the RNA transcript levels with other conditions, we gained insights into how the basic machinery involved in metabolism and environmental responses enable this fungus to cause disease at this body site. This approach was applied to clinical isolates with diverse genotypes to begin to establish a genotype-agnostic understanding of how the yeast responds to stress. Based on these results, future studies can focus on how these genes and their pathways and networks can be targeted with new therapeutics and possibly classify yeasts with bad infection outcomes.

Perception of the 2020 SARS-CoV-2 pandemic among medical professionals in Germany: results from a nationwide online survey.

Background: The COVID-19 pandemic represents an unprecedented global challenge and implicates a wide range of burden on medical professionals. Here, we evaluated the perception of the COVID-19 pandemic among medical professionals in Germany. Methods: A total of n = 2827 medical professionals participated in an online survey between 27 March and 11 April. Results: While most participants stated that Germany was well prepared and rated the measures taken by their employer as positive, subgroup analyses revealed decisive differences. The preventive measures were rated significantly worse by nurses compared to doctors (p < 0.001) and by participants from ambulatory healthcare centres compared to participants from maximum-care hospitals (p < 0.001). Importantly, shortage of protective medical equipment was reported more commonly in the ambulatory sector (p < 0.001) and in East German federal states (p = 0.004). Moreover, the majority of health care professionals (72.4%) reported significant restrictions of daily work routine. Finally, over 60% of medical professionals had concerns regarding their own health, which were more pronounced among female participants (p = 0.024). Conclusion: This survey may indicate starting points on how medical professionals could be supported in carrying out their important activities during the ongoing and future healthcare challenges.

Vancomycin-resistant enterococci (VRE): a reason to isolate?

In recent years, an increase in invasive VRE infections has been reported worldwide, including Germany. The most common gene encoding resistance to glycopeptides is VanA, but predominant VanB clones are emerging. Although neither the incidence rates nor the exact routes of nosocomial transmission of VRE are well established, screening and strict infection control measures, e.g. single room contact isolation, use of personal protective clothing by hospital staff and intensified surface disinfection for colonized individuals, are implemented in many hospitals. At the same time, the impact of VRE infection on mortality remains unclear, with current evidence being weak and contradictory. In this short review, we aim to give an overview on the current basis of evidence on the clinical effectiveness of infection control measures intended to prevent transmission of VRE and to put these findings into a larger perspective that takes further factors, e.g. VRE-associated mortality and impact on patient care, into account.

Phenotypic Variability Correlates with Clinical Outcome in Cryptococcus Isolates Obtained from Botswanan HIV/AIDS Patients.

Pathogenic species of Cryptococcus cause hundreds of thousands of deaths annually. Considerable phenotypic variation is exhibited during infection, including increased capsule size, capsule shedding, giant cells (≥15 µm), and micro cells (≤1 µm). We examined 70 clinical isolates of Cryptococcus neoformans and Cryptococcus tetragattii from HIV/AIDS patients in Botswana to determine whether the capacity to produce morphological variants was associated with clinical parameters. Isolates were cultured under conditions designed to simulate in vivo stresses. Substantial variation was seen across morphological and clinical data. Giant cells were more common in C. tetragattii, while micro cells and shed capsule occurred in C. neoformans only. Phenotypic variables fell into two groups associated with differing symptoms. The production of "large" phenotypes (greater cell and capsule size and giant cells) was associated with higher CD4 count and was negatively correlated with intracranial pressure indicators, suggesting that these are induced in early stage infection. "Small" phenotypes (micro cells and shed capsule) were associated with lower CD4 counts, negatively correlated with meningeal inflammation indicators, and positively correlated with intracranial pressure indicators, suggesting that they are produced later during infection and may contribute to immune suppression and promote proliferation and dissemination. These trends persisted at the species level, indicating that they were not driven by association with particular Cryptococcus species. Isolates possessing giant cells, micro cells, and shed capsule were rare, but strikingly, they were associated with patient death (P = 0.0165). Our data indicate that pleomorphism is an important driver in Cryptococcus infection.IMPORTANCE Cryptococcosis results in hundreds of thousands of deaths annually, predominantly in sub-Saharan Africa. Cryptococcus is an encapsulated yeast, and during infection, cells have the capacity for substantial morphological changes, including capsule enlargement and shedding and variations in cell shape and size. In this study, we examined 70 Cryptococcus isolates causing meningitis in HIV/AIDS patients in Botswana in order to look for associations between phenotypic variation and clinical symptoms. Four variant phenotypes were seen across strains: giant cells of ≥15 µm, micro cells of ≤1 µm, shed extracellular capsule, and irregularly shaped cells. We found that "large" and "small" phenotypes were associated with differing disease symptoms, indicating that their production may be important during the disease process. Overall, our study indicates that Cryptococcus strains that can switch on cell types under different situations may be more able to sustain infection and resist the host response.

Correction to: Strengthening medical training programmes by focusing on professional transitions: a national bridging programme to prepare medical school graduates for their role as medical interns in Botswana.

CORRECTION: Forllowing publication of the original article [1], the first author reported that there was a typographical error in the name of one of his co-authors. The correct spelling is Alemayehu Bedada, not Alemayhu Bedada.

Building Health System Capacity through Medical Education: A Targeted Needs Assessment to Guide Development of a Structured Internal Medicine Curriculum for Medical Interns in Botswana.

BACKGROUND: Medical internship is the final year of training before independent practice for most doctors in Botswana. Internship training in Botswana faces challenges including variability in participants' level of knowledge and skill related to their completion of medical school in a variety of settings (both foreign and domestic), lack of planned curricular content, and limited time for structured educational activities. Data on trainees' opinions regarding the content and delivery of graduate medical education in settings like Botswana are limited, which makes it difficult to revise programs in a learner-centered way. OBJECTIVE: To understand the perceptions and experiences of a group of medical interns in Botswana, in order to inform a large curriculum initiative. METHODS: We conducted a targeted needs assessment using structured interviews at one district hospital. The interview script included demographic, quantitative, and free- response questions. Fourteen interns were asked their opinions about the content and format of structured educational activities, and provided feedback on the preferred characteristics of a new curriculum. Descriptive statistics were calculated. FINDINGS: In the current curriculum, training workshops were the highest-scored teaching format, although most interns preferred lectures overall. Specialists were rated as the most useful teachers, and other interns and medical officers were rated as average. Interns felt they had adequate exposure to content such as HIV and tuberculosis, but inadequate exposure to areas including medical emergencies, non-communicable diseases, pain management, procedural skills, X-ray and EKG interpretation, disclosing medical information, and identifying career goals. For the new curriculum, interns preferred a structured case discussion format, and a focus on clinical reasoning and procedural skills. CONCLUSIONS: This needs assessment identified several foci for development, including a shift toward interactive sessions focused on skill development, the need to empower interns and medical officers to improve teaching skills, and the value of shifting curricular content to mirror the epidemiologic transition occurring in Botswana. Interns' input is being used to initiate a large curriculum intervention that will be piloted and scaled nationally over the next several years. Our results underscore the value of seeking the opinion of trainees, both to aid educators in building programs that serve them and in empowering them to direct their education toward their needs and goals.

Strengthening medical training programmes by focusing on professional transitions: a national bridging programme to prepare medical school graduates for their role as medical interns in Botswana.

BACKGROUND: The improvement of existing medical training programmes in resource-constrained settings is seen as key to addressing the challenge of retaining medical graduates trained at considerable cost both in-country and abroad. In Botswana, the establishment of the national Medical Internship Training Programme (MIT) in 2014 was a first step in efforts to promote retention through the expansion and standardization of internship training, but MIT faces a major challenge related to variability between incoming trainees due to factors such as their completion of undergraduate medical training in different settings. To address this challenge, in August 2016 we piloted a bridging programme for foreign and locally trained medical graduates that aimed to facilitate their transition into internship training. This study aimed to describe the programme and evaluate its impact on the participants' self-rated perceptions of their knowledge, experience, clinical skills, and familiarity with Botswana's healthcare system. METHODS: We conducted a national, intensive, two-week programme designed to facilitate the transition from medical student to intern and to prepare all incoming interns for their work in Botswana's health system. Participants included all interns entering in August 2016. Formats included lectures, workshops, simulations, discussions, and reflection-oriented activities. The Kellogg Foundation Outcomes Logic Model was used to evaluate the programme, and participants self-rated their knowledge, skills, and attitudes across each of the programme objectives on paired questionnaires before and after participation. RESULTS: 48/54 participants (89%) provided paired data. Participants reported a high degree of satisfaction with the programme (mean 4.2/5). Self-rated preparedness improved after participation (mean 3.2 versus 3.7, p < 0.001), as did confidence across 18/19 knowledge/skill domains, suggesting that participants felt that the programme prepared them for their internship training. Exploratory analysis revealed that 20/25 participants (80%) reporting either no effect or a negative effect following participation had rated themselves "extremely" or "quite" prepared beforehand, suggesting the programme grounded expectations for interns who initially were overconfident. In contrast, no interns who had initially rated themselves "moderately" or "somewhat" prepared reported a decline in their self-rated sense of preparedness. Interns commented on the benefits of learning about roles/responsibilities, interacting with clinicians from Botswana's healthcare sectors, and the sense of community the programme engendered. CONCLUSIONS: This programme was feasible to implement and was well-received by participants. Overall, participants perceived an enhancement of their knowledge, skills, and expectations about their role in Botswana's health system after completion of the programme. Our results are likely to be of interest to educators dedicated to training, professional transitions, and career pathways in similar settings in the region and beyond.

Population genomics and the evolution of virulence in the fungal pathogen Cryptococcus neoformans.

Cryptococcus neoformans is an opportunistic fungal pathogen that causes approximately 625,000 deaths per year from nervous system infections. Here, we leveraged a unique, genetically diverse population of C. neoformans from sub-Saharan Africa, commonly isolated from mopane trees, to determine how selective pressures in the environment coincidentally adapted C. neoformans for human virulence. Genome sequencing and phylogenetic analysis of 387 isolates, representing the global VNI and African VNB lineages, highlighted a deep, nonrecombining split in VNB (herein, VNBI and VNBII). VNBII was enriched for clinical samples relative to VNBI, while phenotypic profiling of 183 isolates demonstrated that VNBI isolates were significantly more resistant to oxidative stress and more heavily melanized than VNBII isolates. Lack of melanization in both lineages was associated with loss-of-function mutations in the BZP4 transcription factor. A genome-wide association study across all VNB isolates revealed sequence differences between clinical and environmental isolates in virulence factors and stress response genes. Inositol transporters and catabolism genes, which process sugars present in plants and the human nervous system, were identified as targets of selection in all three lineages. Further phylogenetic and population genomic analyses revealed extensive loss of genetic diversity in VNBI, suggestive of a history of population bottlenecks, along with unique evolutionary trajectories for mating type loci. These data highlight the complex evolutionary interplay between adaptation to natural environments and opportunistic infections, and that selection on specific pathways may predispose isolates to human virulence.

Transcriptomic Profile of Whole Blood Cells from Elderly Subjects Fed Probiotic Bacteria Lactobacillus rhamnosus GG ATCC 53103 (LGG) in a Phase I Open Label Study.

UNLABELLED: We examined gene expression of whole blood cells (WBC) from 11 healthy elderly volunteers participating on a Phase I open label study before and after oral treatment with Lactobacillus rhamnosus GG-ATCC 53103 (LGG)) using RNA-sequencing (RNA-Seq). Elderly patients (65-80 yrs) completed a clinical assessment for health status and had blood drawn for cellular RNA extraction at study admission (Baseline), after 28 days of daily LGG treatment (Day 28) and at the end of the study (Day 56) after LGG treatment had been suspended for 28 days. Treatment compliance was verified by measuring LGG-DNA copy levels detected in host fecal samples. Normalized gene expression levels in WBC RNA were analyzed using a paired design built within three analysis platforms (edgeR, DESeq2 and TSPM) commonly used for gene count data analysis. From the 25,990 transcripts detected, 95 differentially expressed genes (DEGs) were detected in common by all analysis platforms with a nominal significant difference in gene expression at Day 28 following LGG treatment (FDR<0.1; 77 decreased and 18 increased). With a more stringent significance threshold (FDR<0.05), only two genes (FCER2 and LY86), were down-regulated more than 1.5 fold and met the criteria for differential expression across two analysis platforms. The remaining 93 genes were only detected at this threshold level with DESeq2 platform. Data analysis for biological interpretation of DEGs with an absolute fold change of 1.5 revealed down-regulation of overlapping genes involved with Cellular movement, Cell to cell signaling interactions, Immune cell trafficking and Inflammatory response. These data provide evidence for LGG-induced transcriptional modulation in healthy elderly volunteers because pre-treatment transcription levels were restored at 28 days after LGG treatment was stopped. To gain insight into the signaling pathways affected in response to LGG treatment, DEG were mapped using biological pathways and genomic data mining packages to indicate significant biological relevance. TRIAL REGISTRATION: ClinicalTrials.gov NCT01274598.

Pharmacogenetics of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in resource-limited settings: Influence on antiretroviral therapy response and concomitant anti-tubercular, antimalarial and contraceptive treatments.

The burden of human immunodeficiency virus (HIV) is mainly concentrated to resources-limited countries where the response to available antiretroviral therapy is often limited by the occurrence of toxicity or by the emergence of HIV drug resistance. Efavirenz and nevirapine are the antiretroviral drugs most prescribed in resources-limited countries as part of antiretroviral combination therapy. Their metabolism and conjugation are largely influenced by enzymatic genetic polymorphisms. The genetic variability of their metabolism could be associated to different metabolic phenotypes causing reduced patients' adherence because of toxicity or drug-drug interactions with concomitant therapies. The purpose of this review is to summarize published evidence on pharmacogenetic and pharmacokinetic aspects related to efavirenz and nevirapine, the influence of concomitant anti-tubercular, anti-malarial or contraceptive treatments, and the impact of human genetic variation and drug-drug interaction on the virologic and immunologic response to antiretroviral therapy in resources-limited countries.

AMBITION-cm: intermittent high dose AmBisome on a high dose fluconazole backbone for cryptococcal meningitis induction therapy in sub-Saharan Africa: study protocol for a randomized controlled trial.

BACKGROUND: Cryptococcal meningitis (CM) is a leading cause of mortality among HIV-infected individuals in Africa. Poor outcomes from conventional antifungal therapies, unavailability of flucytosine, and difficulties administering 14 days of amphotericin B are key drivers of this mortality. Novel treatment regimes are needed. This study examines whether short-course high-dose liposomal amphotericin B (AmBisome), given with high dose fluconazole, is non-inferior (in terms of microbiological and clinical endpoints) to standard-dose 14-day courses of AmBisome plus high dose fluconazole for treatment of HIV-associated CM. METHODOLOGY/DESIGN: This is an adaptive open-label phase II/III randomised non-inferiority trial comparing alternative short course AmBisome regimens. Step 1 (phase II) will compare four treatment arms in 160 adult patients (≥ 18 years old) with a first episode of HIV-associated CM, using early fungicidal activity (EFA) as the primary outcome: 1) AmBisome 10 mg/kg day one (single dose); 2) AmBisome 10 mg/kg day one and AmBisome 5 mg/kg day three (two doses); 3) AmBisome 10 mg/kg day one, and AmBisome 5 mg/kg days three and seven (three doses); and 4) AmBisome 3 mg/kg/d for 14 days (control); all given with fluconazole 1200 mg daily for 14 days. STEP 2 (phase III) will enrol 300 participants and compare two treatment arms using all-cause mortality within 70 days as the primary outcome: 1) the shortest course AmBisome regimen found to be non-inferior in terms of EFA to the 14-day control arm in STEP 1, and 2) AmBisome 3 mg/kg/d for 14 days (control), both given with fluconazole 1200 mg daily for 14 days. STEP 2 analysis will include all patients from STEP 1 and STEP 2 taking the STEP 2 regimens. All patients will be followed for ten weeks, and mortality and safety data recorded. All patients will receive consolidation therapy with fluconazole 400-800 mg daily and ART in accordance with local guidelines. The primary analysis (for both STEP 1 and STEP 2) will be intention-to-treat. TRIAL REGISTRATION: ISRCTN10248064. Date of Registration: 22 January 2014.

Comparative analyses of clinical and environmental populations of Cryptococcus neoformans in Botswana.

Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis, and its prevalence is highest in sub-Saharan Africa. Patients become infected by inhaling airborne spores or desiccated yeast cells from the environment, where the fungus thrives in avian droppings, trees and soil. To investigate the prevalence and population structure of Cng in southern Africa, we analysed isolates from 77 environmental samples and 64 patients. We detected significant genetic diversity among isolates and strong evidence of geographic structure at the local level. High proportions of isolates with the rare MATa allele were observed in both clinical and environmental isolates; however, the mating-type alleles were unevenly distributed among different subpopulations. Nearly equal proportions of the MATa and MATα mating types were observed among all clinical isolates and in one environmental subpopulation from the eastern part of Botswana. As previously reported, there was evidence of both clonality and recombination in different geographic areas. These results provide a foundation for subsequent genomewide association studies to identify genes and genotypes linked to pathogenicity in humans.

Functional dynamics of the gut microbiome in elderly people during probiotic consumption.

UNLABELLED: A mechanistic understanding of the purported health benefits conferred by consumption of probiotic bacteria has been limited by our knowledge of the resident gut microbiota and its interaction with the host. Here, we detail the impact of a single-organism probiotic, Lactobacillus rhamnosus GG ATCC 53103 (LGG), on the structure and functional dynamics (gene expression) of the gut microbiota in a study of 12 healthy individuals, 65 to 80 years old. The analysis revealed that while the overall community composition was stable as assessed by 16S rRNA profiling, the transcriptional response of the gut microbiota was modulated by probiotic treatment. Comparison of transcriptional profiles based on taxonomic composition yielded three distinct transcriptome groups that displayed considerable differences in functional dynamics. The transcriptional profile of LGG in vivo was remarkably concordant across study subjects despite the considerable interindividual nature of the gut microbiota. However, we identified genes involved in flagellar motility, chemotaxis, and adhesion from Bifidobacterium and the dominant butyrate producers Roseburia and Eubacterium whose expression was increased during probiotic consumption, suggesting that LGG may promote interactions between key constituents of the microbiota and the host epithelium. These results provide evidence for the discrete functional effects imparted by a specific single-organism probiotic and challenge the prevailing notion that probiotics substantially modify the resident microbiota within nondiseased individuals in an appreciable fashion. IMPORTANCE: Probiotic bacteria have been used for over a century to promote digestive health. Many individuals report that probiotics alleviate a number of digestive issues, yet little evidence links how probiotic microbes influence human health. Here, we show how the resident microbes that inhabit the healthy human gut respond to a probiotic. The well-studied probiotic Lactobacillus rhamnosus GG ATCC 53103 (LGG) was administered in a clinical trial, and a suite of measurements of the resident microbes were taken to evaluate potential changes over the course of probiotic consumption. We found that LGG transiently enriches for functions to potentially promote anti-inflammatory pathways in the resident microbes.

No evidence of harms of probiotic Lactobacillus rhamnosus GG ATCC 53103 in healthy elderly-a phase I open label study to assess safety, tolerability and cytokine responses.

BACKGROUND: Although Lactobacillus rhamnosus GG ATCC 53103 (LGG) has been consumed by 2 to 5 million people daily since the mid 1990s, there are few clinical trials describing potential harms of LGG, particularly in the elderly. OBJECTIVES: The primary objective of this open label clinical trial is to assess the safety and tolerability of 1×1010 colony forming units (CFU) of LGG administered orally twice daily to elderly volunteers for 28 days. The secondary objectives were to evaluate the effects of LGG on the gastrointestinal microbiome, host immune response and plasma cytokines. METHODS: Fifteen elderly volunteers, aged 66-80 years received LGG capsules containing 1×1010 CFU, twice daily for 28 days and were followed through day 56. Volunteers completed a daily diary, a telephone call on study days 3, 7 and 14 and study visits in the Clinical Research Center at baseline, day 28 and day 56 to determine whether adverse events had occurred. Assessments included prompted and open-ended questions. RESULTS: There were no serious adverse events. The 15 volunteers had a total of 47 events (range 1-7 per volunteer), 39 (83%) of which were rated as mild and 40% of which were considered related to consuming LGG. Thirty-one (70%) of the events were expected, prompted symptoms while 16 were unexpected events. The most common adverse events were gastrointestinal (bloating, gas, and nausea), 27 rated as mild and 3 rated as moderate. In the exploratory analysis, the pro-inflammatory cytokine interleukin 8 decreased during LGG consumption, returning towards baseline one month after discontinuing LGG (p = 0.038) while there was no difference in other pro- or anti-inflammatory plasma cytokines. CONCLUSIONS: Lactobacillus rhamnosus GG ATCC 53103 is safe and well tolerated in healthy adults aged 65 years and older. TRIAL REGISTRATION: ClinicalTrials.gov NCT 01274598.

A root-cause analysis of maternal deaths in Botswana: towards developing a culture of patient safety and quality improvement.

BACKGROUND: In 2007, 95% of women in Botswana delivered in health facilities with 73% attending at least 4 antenatal care visits. HIV-prevalence in pregnant women was 28.7%. The maternal mortality ratio in 2010 was 163 deaths per 100,000 live births versus the government target of 130 for that year, indicating that the Millennium Development Goal 5 was unlikely to be met. A root-cause analysis was carried out with the aim of determining the underlying causes of maternal deaths reported in 2010, to categorise contributory factors and to prioritise appropriate interventions based on the identified causes, to prevent further deaths. METHODS: Case-notes for maternal deaths were reviewed by a panel of five clinicians, initially independently then discussed together to achieve consensus on assigning contributory factors, cause of death and whether each death was avoidable or not at presentation to hospital. Factors contributing to maternal deaths were categorised into organisational/management, personnel, technology/equipment/supplies, environment and barriers to accessing healthcare. RESULTS: Fifty-six case notes were available for review from 82 deaths notified in 2010, with 0-4 contributory factors in 19 deaths, 5-9 in 27 deaths and 9-14 in nine. The cause of death in one case was not ascertainable since the notes were incomplete. The high number of contributory factors demonstrates poor quality of care even where deaths were not avoidable: 14/23 (61%) of direct deaths were considered avoidable compared to 12/32 (38%) indirect deaths. Highest ranking categories were: failure to recognise seriousness of patients' condition (71% of cases); lack of knowledge (67%); failure to follow recommended practice (53%); lack of or failure to implement policies, protocols and guidelines (44%); and poor organisational arrangements (35%). Half the deaths had some barrier to accessing health services. CONCLUSIONS: Root-cause analysis demonstrates the interactions between patients, health professionals and health system in generating adverse outcomes for patients. The lessons provided indicate where training of undergraduate and postgraduate medical, midwifery and nursing students need to be intensified, with emphasis on evidence-based practice and adherence to protocols. Action plans and interventions aimed at changing the circumstances that led to maternal deaths can be implemented and re-evaluated.

Airborne outreach: building HIV capacity and strengthening health care systems in rural Botswana.

There is a paucity of research demonstrating how HIV-funded services in Africa have improved equity and access to non-HIV services for both HIV-infected and uninfected patients. In this short communication, we describe the impact of an airborne outreach program to provide HIV services to high-HIV burden health facilities in rural Botswana. The analysis demonstrates how this HIV-funded program enhanced access to essential subspecialist services at several rural health facilities across Botswana.

The development of an emergency sepsis care algorithm in Botswana

Introduction :Sepsis is a common cause of morbidity and mortality in populations with a high prevalence of HIV; but the full package of early goal directed therapy (EGDT) for sepsis is not feasible in most low and middle-income countries. The objective was to develop emergency adult sepsis care guidelines for Botswana appropriate to available resources and local epidemiology in referral hospitals and in lower levels of care. Methods : The individual components of guidelines from the Surviving Sepsis Campaign were compared with available resources for their applicability in a tertiary referral hospital in Botswana. Antibiotics were chosen based on the hospital antibiogram; national antibiotic guidelines; and the cost and availability of antibiotics. The preliminary algorithm was presented to emergency centre medical officers in a referral hospital for feasibility and acceptability of implementation. The referral hospital guideline was further modified as part of a National Guidelines Project for suitability to all levels of care: Results :An acceptable and feasible sepsis algorithm was developed and implemented in a referral hospital in Botswana in accordance with the established hospital process. In turn; it served as the basis for the development of a national guideline. Discussion The principles of EGDT are adaptable to Botswana; and are likely to be adaptable to a variety of low- and middle-income countries on the basis of local resources and epidemiology. Further research is needed to study adherence and outcome related to the modified guidelines