Intrapartum antibiotic prophylaxis selects for mutators in group B streptococci among persistently colonized patients.

Through vaginal colonization, GBS causes severe pregnancy outcomes including neonatal sepsis and meningitis. Although intrapartum antibiotic prophylaxis (IAP) has reduced early-onset disease rates, persistent GBS colonization has been observed in patients following prophylaxis. To determine whether IAP selects for genomic signatures that enhance GBS survival and persistence in the vaginal tract, whole-genome sequencing was performed on 97 isolates from 58 patients before (prenatal) and after (postpartum) IAP/childbirth. Core-gene mutation analysis identified 7,025 mutations between the paired isolates. Three postpartum isolates accounted for 98% of mutations and were classified as "mutators" because of point mutations within DNA repair systems. In vitro assays revealed stronger biofilms in two mutators. These findings suggest that antibiotics select for mutations that promote survival in vivo, which increases the likelihood of transmission to neonates. They also demonstrate how mutators can provide a reservoir of beneficial mutations that enhance fitness and genetic diversity in the GBS population.

Review of the clinical diagnosis of sacroiliac dysfunction in horses - Challenges and limitations.

Sacroiliac dysfunction (SID) is a condition seen in horses associated with poor performance that affects hind limb gait and impulsion. The condition comprises pain and dysfunction but there lacks clarity around the aetiopathogenesis and whether SID encompasses abnormal joint pathology, abnormal joint movement, abnormal regional biomechanical function, joint laxity and pain, or various combinations of these that may vary over time. Clinical assessment remains challenging for equine clinicians due to the deep location of the sacroiliac joint (SIJ) and surrounding structures which limits access for palpation, diagnostic imaging and joint-specific injection. There is no recognised single reference standard diagnostic test for SID. Clinical diagnosis has been based on ruling out other causes of hind limb lameness, along with combinations of ultrasonography, scintigraphy and periarticular anaesthesia of the SIJ. Recent studies have highlighted the lack of specificity of injections targeting the SIJ, with significant dispersal of injectate into surrounding structures including around the lumbosacral joint (LSJ). Advanced imaging modalities such as computed tomography offers promise for assessment of the structure and pathology of the SIJ and surrounding bony structures. However, there is a need to improve the understanding of the significance of anatomic variation of the sacroiliac region structures, with recent studies reporting detailed anatomic variation in groups of horses with and without SID. There are also limitations around functional assessment of the joint which is still largely reliant on a thorough clinical examination. This review aims to present an update on clinical approaches to the diagnosis of horses with SID, and to consider the challenges and limitations.

Recording of suspected adverse drug reaction reporting in veterinary free-text clinical narratives.

OBJECTIVES: To use text mining approaches to identify instances of suspected adverse drug reactions recorded in first opinion veterinary free-text clinical narratives, and to evaluate whether these were also reported to either the Veterinary Medicines Directorate or the relevant Marketing Authorisation holder in order to derive an estimate of the suspected adverse drug reaction (sADR) minimum under-reporting rate. To characterise sADR reports and explore whether particular features are associated with report submission. MATERIALS AND METHODS: Two regular expressions were developed to identify mentions of "adverse drug reactions" and "side effects" in the free-text clinical narratives of electronic health records contained within the Small Animal Veterinary Surveillance Network database. Consultations containing a match for the developed regular expressions were manually reviewed for inclusion and further classified to determine the suspected product, seriousness and expectedness of the event, and an indication of whether the event had been reported. The associations between event characteristics and reporting were explored using Fisher's exact tests. RESULTS: A total of 10,565 records were manually reviewed from which 827 sADRs were identified. Approximately 90% of these sADRs were not recorded as reported. Suspected adverse drug reactions that were not considered "expected" were recorded as reported more frequently than "expected" sADRs. However, clinical severity did not appear to impact on whether there was a record of reporting. CLINICAL SIGNIFICANCE: This is the first estimate of under reporting sADRs based on real world evidence from veterinary clinical records. The under-reporting rate implied by this study highlights that further interventions are required to improve reporting rate within the veterinary profession in order to support pharmacovigilance activities and improve drug safety.

Association of cerebrospinal fluid parameters with treatment and complications among children with cerebrospinal fluid shunt infections: a multicenter study.

OBJECTIVE: Cerebrospinal fluid (CSF) white blood cell (WBC) count, neutrophil percentage, protein concentration, and glucose level are typically measured at diagnosis and serially during the treatment of CSF shunt infections. The objective of this retrospective cohort study was to describe the longitudinal profile of CSF parameters in children with CSF shunt infections and assess their association with treatment and outcome. METHODS: Participants were children treated at 11 tertiary pediatric hospitals in Canada and the United States for CSF shunt infection, from July 1, 2013, through June 30, 2019, with hardware removal, external ventricular drain placement, intravenous antibiotics, and subsequent permanent shunt reinsertion. The relationship between CSF parameters and a complicated course (a composite outcome representing children with at least one of the following: contiguous soft-tissue infection, worsening hydrocephalus, CSF leak, intracranial bleed, brain abscess, venous thrombosis, reinfection after insertion of the new shunt, other complication, ICU admission, or death) was analyzed. RESULTS: A total of 109 children (median age 2.8 years, 44% female) were included in this study. CSF pleocytosis, elevated protein, and hypoglycorrhachia had sensitivities of 69%, 47%, and 38% for the diagnosis of culture-confirmed CSF shunt infection, respectively. The longitudinal profile of the neutrophil percentage followed a monotonic trend, decreasing by 1.5% (95% CI 1.0%-2.0%, p < 0.0001) per day over the course of treatment. The initial WBC count differed significantly between pathogens (p = 0.011), but the proportion of neutrophils, protein concentration, and glucose level did not, and was lowest with Cutibacterium acnes. The duration of antibiotic treatment and the time to shunt reinsertion were longer in patients with a higher initial neutrophil percentage. Fifty-eight patients (53%) had one or more complications during their admission. A neutrophil percentage > 44% (Youden index) in the initial CSF sample was associated with a 1.8-fold (95% CI 1.2- to 2.8-fold) higher relative risk of a complicated course. In a random-intercept, random-slope linear mixed-effects model, the longitudinal neutrophil trajectory differed significantly between patients with and without complications (p = 0.030). CONCLUSIONS: A higher proportion of neutrophils in the CSF at diagnosis was associated with a complicated clinical course. Other CSF parameters were associated with treatment and outcome; however, wide variability in values may limit their clinical utility.

Comparison of bacterial culture with BioFire® FilmArray® multiplex PCR screening of archived cerebrospinal fluid specimens from children with suspected bacterial meningitis in Nigeria.

BACKGROUND: Diagnosis of bacterial meningitis remains a challenge in most developing countries due to low yield from bacterial culture, widespread use of non-prescription antibiotics, and weak microbiology laboratories. The objective of this study was to compare the yield from standard bacterial culture with the multiplex nested PCR platform, the BioFire® FilmArray® Meningitis/Encephalitis Panel (BioFire ME Panel), for cases with suspected acute bacterial meningitis. METHODS: Following Gram stain and bacterial culture on cerebrospinal fluid (CSF) collected from children aged less than 5 years with a clinical suspicion of acute bacterial meningitis (ABM) as defined by the WHO guidelines, residual CSF specimens were frozen and later tested by BioFire ME Panel. RESULTS: A total of 400 samples were analyzed. Thirty-two [32/400 (8%)] of the specimens were culture positive, consisting of; three Salmonella spp. (2 Typhi and 1 non-typhi), three alpha hemolytic Streptococcus, one Staphylococcus aureus, six Neisseria meningitidis, seven Hemophilus influenzae, 11 Streptococcus pneumoniae and 368 were culture negative. Of the 368 culture-negative specimens, the BioFire ME Panel detected at least one bacterial pathogen in 90 (24.5%) samples, consisting of S. pneumoniae, N. meningitidis and H. influenzae, predominantly. All culture positive specimens for H. influenzae, N. meningitidis and S. pneumoniae also tested positive with the BioFire ME Panel. In addition, 12 specimens had mixed bacterial pathogens identified. For the first time in this setting, we have data on the viral agents associated with meningitis. Single viral agents were detected in 11 (2.8%) samples while co-detections with bacterial agents or other viruses occurred in 23 (5.8%) of the samples. CONCLUSIONS: The BioFire® ME Panel was more sensitive and rapid than culture for detecting bacterial pathogens in CSF. The BioFire® ME Panel also provided for the first time, the diagnosis of viral etiologic agents that are associated with meningoencephalitis in this setting. Institution of PCR diagnostics is recommended as a routine test for suspected cases of ABM to enhance early diagnosis and optimal treatment.

Transfusion of incompatible blood to a patient with alloanti-Sc1.

Sc1 is a high-prevalence blood group antigen that is part of the Scianna blood group system. The clinical significance of Scianna antibodies is not well understood because of their rarity; there are only a handful of cases in the literature. This scarcity of information can make it difficult to decide on the best course of action when transfusing a patient with alloantibodies to Scianna blood group antigens. We describe a case of an 85-year-old woman presenting with melena and a hemoglobin of 66 g/L. Upon request for crossmatched blood, a panreactive antibody was found, later elucidated to be alloanti-Sc1. Because of the urgent nature of the transfusion, the patient was transfused with 2 incompatible, presumed Sc1+, red blood cell units with no evidence of an acute or delayed transfusion reaction. This case has been shared with the International Society of Blood Transfusion Rare Donor Working Party, via their Outcome of Incompatible Transfusion form, and adds to the body of evidence on clinical significance of antibodies to the antigens of the Scianna blood group system.

The relationship between nutrition, gut dysbiosis, and pediatric sickle cell pain outcomes: A pilot study.

BACKGROUND: Nutritional deficiencies are prevalent in sickle cell disease (SCD) and may be associated with worse pain outcomes. Gut dysbiosis has been reported in patients with SCD and may contribute to both nutritional deficiencies and pain. OBJECTIVES: We tested the association of nutrition, fat-soluble vitamin (FSV) deficiency, and gut microbiome composition on clinical outcomes in SCD. Second, we measured the association between diet and exocrine pancreatic function on FSV levels. METHODS: Using case control design, we enrolled children with SCD (n = 24) and matched healthy controls (HC; n = 17, age, sex, race/ethnicity). Descriptive statistics summarized demographic and clinical data. Wilcoxson-rank tests compared FSV levels between cohorts. Regression modeling tested the association between FSV levels and SCD status. Welch's t-test with Satterthwaite adjustment evaluated associations between microbiota profiles, SCD status, and pain outcomes. RESULTS: Vitamin A and D levels were significantly decreased in participants with HbSS as compared to HC (vitamin A, p = < .0001, vitamin D, p = .014) independent of nutritional status. FSV correlated with dietary intake in SCD and HC cohorts. Gut microbial diversity was reduced in hemoglobin SS (HbSS) compared to hemoglobin SC (HbSC) and HC, p = .037 and .059, respectively. The phyla Erysipelotrichaceae and Betaproteobacteria were higher in SCD children reporting the highest quality-of-life (QoL) scores (p = .008 and .049, respectively), while Clostridia were higher in those with lower QoL scores (p = .03). CONCLUSION: FSV deficiencies and gut dysbiosis are prevalent in children with SCA. Gut microbial composition is significantly different in children with SCD with low QoL scores.

Time trade-off study to establish utility decrements in individuals with a spinal cord injury who perform intermittent catheterization.

AIMS: To generate utility decrements for three attributes associated with catheterization for individuals with a spinal cord injury (SCI): the process of catheterization, the physical impact of urinary tract infections (UTIs) and worry associated with hospitalization. MATERIALS AND METHODS: Health state vignettes comprising various levels of the three attributes were developed. Two cohorts of respondents, corresponding to people with SCIs and a sample broadly representative of the UK population, were presented with nine vignettes (three vignettes for the mild, moderate and severe health states in addition to a random set of six vignettes). It was assumed no or a nominal decrement was associated with the mild health state. Utility decrements were derived from analysing the data obtained from the online time trade-off (TTO). A proportion of the SCI cohort (n = 57) also completed the EQ-5D-5L questionnaire. RESULTS: Utility decrements were generated using statistical models for the general population (n = 358), the SCI population (n = 48) and the two populations combined (merged model, n = 406). Results from the two cohorts showed minimal differences. For the merged model, SCI status was not statistically significant. All interaction terms, excluding SCI and the severe level of the physical attribute, were not statistically significant. Compared to the mild level, the greatest utility decrement calculated was the severe level of the emotional (worry) attribute (0.09, p < .001) for the SCI population. A significant decrement of 0.02 (p < .001) was calculated for the moderate level of the emotional attribute for all models. The mean utility score for those with SCI having completed the EQ-5D-5L was 0.371. LIMITATIONS: Modest sample size of respondents from the SCI population (n = 48). CONCLUSIONS: Worry associated with hospitalization had the greatest impact on patients' health-related quality of life (HRQoL). The catheterization process, such as the lubrication and repositioning of the catheter, also impacted on patients' HRQoL.

Memory recall: New behavioral protocols for examining distinct forms of context specific recall in animals.

This study outlines two novel protocols for examining context specific recall in animals prior to embarking on neurobiological studies. The approach is distinct from and contrasts with studies investigating associative familiarity that depend upon procedural variations of the widely used novel object recognition task. It uses an event arena in which animals are trained across numerous sessions to search for, find and dig up reward from sandwells during sample and choice trials - a prominent spatial event for a rodent. The arena could be laid out as either of two highly distinct contexts with which the animals became fully familiar throughout training. In one protocol, the location of the correct sandwell in each context remained stable across days, whereas in the other, the correct digging location varied in a counterbalanced manner across each successive session. Thus, context-specific recall of the spatial location of successful digging during choice trials was either from a stable long-term memory or could reflect context specific spatial recency of the location where reward had been available that session. Both protocols revealed effective memory recall in choice and probe tests which, at the point of test, were procedurally identical in both cases.

Asset-based Community "Response": A Model Promoting Effective Student- Community Engagement in Disaster Scenarios.

BACKGROUND: In response to the coronavirus disease 2019 (COVID-19) pandemic, medical students organized grass-roots volunteer initiatives to address community-level needs. These required community partnerships and extra-institutional resources to effectively operate. Due to curricular constraints, these efforts often lacked familiarity and working knowledge of existing university infrastructure on how to engage with established community partnerships and resources. OBJECTIVES: The authors call for institutions to capitalize upon the response experience gained by medical students during the pandemic. This includes 1) formally integrating the infrastructure and community relationships established by student COVID-19 volunteer initiatives into existing university community-engagement systems, and 2) incorporating asset-based community development (ABCD) into medical student curricula as a framework for community engagement and disaster response. METHODS: A case study from the University of Nebraska Medical Center presents student COVID-19 response initiatives, their outcomes, and how their approach emulated the ABCD model. The ABCD model asserts that communities should use asset mapping to identify the skills and resources of community members, rather than using deficiency-oriented approaches. Further, the case study demonstrates how the use of an established ABCD model could have contributed to a more effective and efficient COVID-19 student response. CONCLUSIONS: Experiences at University of Nebraska Medical Center support the value of using a modified ABCD model to facilitate community relationships related to rapid health response. Formal integration of the ABCD model within a university's centralized office of community engagement will increase access and foster town-gown reciprocal relationships, empowering students, academic health centers, and surrounding communities in times of crisis and calm.

Duration of Antibiotic Therapy and Timing of Shunt Reimplantation in Pediatric CSF Shunt Infections: A Retrospective Multicenter Case Series.

In this retrospective multicenter series of 154 children with cerebrospinal fluid shunt infections, the median (interquartile range) duration of antibiotic therapy was 18 (14-26) days. The time to shunt replacement was 14 (10-19) days. Management appeared to potentially differ according to the targeted pathogen and site.

Cerebrospinal Fluid Shunt Infections: A Multicenter Pediatric Study.

BACKGROUND: Infections complicate 5%-10% of cerebrospinal fluid (CSF) shunts. We aimed to describe the characteristics and contemporary pathogens of shunt infections in children in Canada and the United States. METHODS: Descriptive case series at tertiary care hospitals in Canada (N = 8) and the United States (N = 3) of children up to 18 years of age with CSF shunt infections from July 1, 2013, through June 30, 2019. RESULTS: There were 154 children (43% female, median age 2.7 years, 50% premature) with ≥1 CSF shunt infections. Median time between shunt placement and infection was 54 days (interquartile range, 24 days-2.3 years). Common pathogens were coagulase-negative staphylococci (N = 42; 28%), methicillin-susceptible Staphylococcus aureus (N = 24; 16%), methicillin-resistant S. aureus (N = 9; 5.9%), Pseudomonas aeruginosa (N = 9; 5.9%) and other Gram-negative bacilli (N = 14; 9.0%). Significant differences between pathogens were observed, including timing of infection (P = 0.023) and CSF leukocyte count (P = 0.0019); however, differences were not sufficient to reliably predict the causative organism based on the timing of infection or discriminate P. aeruginosa from other pathogens based on clinical features. Empiric antibiotic regimens, which included vancomycin (71%), cefotaxime or ceftriaxone (29%) and antipseudomonal beta-lactams (33%), were discordant with the pathogen isolated in five cases. There was variability between sites in the distribution of pathogens and choice of empiric antibiotics. Nine children died; 4 (44%) deaths were attributed to shunt infection. CONCLUSIONS: Staphylococci remain the most common cause of CSF shunt infections, although antibiotic resistant Gram-negative bacilli occur and cannot be reliably predicted based on clinical characteristics.

Early detection and intervention for young children with early developmental disabilities in Western Uganda: a mixed-methods evaluation.

BACKGROUND: Early support for children with developmental disabilities is crucial but frequently unavailable in low-resource settings. We conducted a mixed-methods evaluation to assess the feasibility, acceptability, and impact of a programme of early detection and intervention for young children with developmental disabilities in Western Uganda. METHODS: Early child development training for healthcare workers (HCWs) was implemented in three rural districts, and attendance was tracked. HCW knowledge and confidence were assessed pre-/post-intervention, and referral numbers tracked to evaluate impact. Facilitators were trained and mentored to deliver a participatory, group, early intervention programme (EIP) for young children with developmental disabilities and their families. Facilitators were tracked as they were identified, trained, and delivered the intervention, and attendance of families was tracked. Pre-/post-intervention assessments evaluated changes in family quality of life (PedsQL 2.0, Family Impact Module), and child nutritional outcomes. Focus group discussions with stakeholders also assessed feasibility, acceptability and impact. RESULTS: Overall, 93 HCWs from 45 healthcare facilities received training. In the pre-/post-evaluation, median knowledge and confidence scores increased significantly (from 4.0 to 7.0 and from 2.7 to 4.7, respectively (p < 0.001)). HCWs reported feeling empowered to refer and offer care for families with a young child with disability. Referral rates increased significantly from 148 to 251 per annum (70%; p = 0.03). Eleven EIP facilitators were trained, and all delivered the intervention; 84 families were enrolled, of which 78% attended at least 6 out of 10 modules. Amongst those with paired pre-/post-intervention data (n = 48), total family quality of life scores increased significantly (21%, p < 0.001). Improvements were seen across all domains of quality of life, with the largest impacts on emotional functioning and social functioning (p < 0.001). The programme was acceptable to caregivers and facilitators. Caregivers reported improved knowledge, family relationships, hope, emotional wellbeing, and reduced self-stigma. CONCLUSIONS: A programme of early detection and intervention for children with early developmental disabilities and their families was feasible and acceptable in a rural community-based Ugandan setting. HCW training positively impacted knowledge, confidence, attitudes, and referral rates. Families enrolled to the EIP reported significant improvements in quality of life. Important programmatic barriers identified included geographical spread, poverty, gender inequality, and stigma.

Cognition and reproductive success in cowbirds.

Understanding the relationships between cognitive abilities and fitness is integral to an evolutionary study of brain and behavior. However, these relationships are often difficult to measure and detect. Here we draw upon an opportunistic sample of brown-headed cowbird (Molothrus ater) subjects that had two separate research experiences: First, they engaged in a large series of cognitive tests in David Sherry's Lab in the Advanced Facility for Avian Research (AFAR) at Western University, then subsequently moved to the Field Avian Research Megalab (FARM) at Wilfrid Laurier University where they lived in large breeding flocks in aviaries with other wild-caught cowbirds. Thus, we had extensive measures of cognitive abilities, breeding behavior, and reproductive success for these birds. We report here, for the fist time, the surprisingly strong connections we found among these different measures. Female cowbirds' spatial cognitive abilities correlated positively with how intensely they were courted by males, and with their overall egg production. Males' spatial cognition correlated positively with their ability to engage in singing contests ("countersinging") with other males. In addition, a separate non-spatial cognitive ability correlated positively with the attractiveness of the songs they sung. In sum, these results suggest the cognitive skills assessed in the lab were strongly connected to breeding behavior and reproductive success. Moreover, since certain cognitive abilities related to different aspects of breeding success, it suggests that cognitive modules may have specialized adaptive value, but also that these specialized skills may interact and influence fitness in surprising ways.

Metal vs fibre posts - which is clinically superior for the restoration of endodontically treated teeth?

Data sources Medline/PubMed, Web of Science, Scopus and Cochrane Library databases. Grey literature searches (OpenGrey, ProQuest databases), hand searches in the reference list of eligible studies and relevant journals.Study selection Randomised controlled trials (RCTs) and prospective clinical trials (PCTs) with direct comparisons between metal posts (MPs) and fibre posts (FPs). Trials contained a minimum of ten patients and endodontically treated permanent teeth that had received either single crowns or fixed partial dentures (bridges) and followed up for a minimum of one year. The primary outcome compared the difference in failure rates between FPs and MPs, with subgroup analysis comparing location (anterior/posterior), type of MP (cast post core/preformed MP) and most frequent modes of failure (debond/root fracture).Data extraction and synthesis Study selection, data collection and risk of bias assessments were completed independently by two reviewers. Disagreements were discussed with a third reviewer to reach a consensus. The risk of bias was evaluated using the Cochrane risk of bias tool (RCTs) or the ROBINS-I tool (PCTs). The quality of responses was assessed using the Grading of Recommendations Assessment, Development And Evaluation (GRADE) approach. The meta-analysis (MA) was performed using the Mantel-Haenszel method. Trial heterogeneity was assessed using random- and fixed-effects models. Inter-examiner agreement during the database search and study selection process was checked using the kappa statistic.Results After duplicates were removed, 1,026 articles were assessed and screened by title and abstract. Of these, 21 articles underwent full-text evaluation, with ten articles meeting the eligibility criteria. Eligible studies included six RCTs and four PCTs. A total of 844 endodontically treated teeth (ETT) were restored with intra-radicular posts in 704 participants. Four hundred and fifty-three ETT were restored with FPs and 391 with MPs. The mean age of participants was 42.7 (33.95-55.45) years, with a mean follow-up period of 50.95 (12-154) months. Most studies reported failures during the follow-up period, but the MA revealed no significant difference between FPs and MPs in terms of failure rates (P = 0.39; RR: 0.82 mm; CI: 0.52-1.29). Sub-analysis showed no difference in failure rates between anterior and posterior regions and no difference when comparing FPs to cast post and core vs prefabricated MPs. Root fractures and post debondings were the most common modes of failure, but within these failures, no difference was observed between FPs and MPs.Conclusions No evidence was identified for a difference in failure rates between FPs and MPs. This was independent of the type of MP and position within the arch. Reporting of RCTs and PCTs was variable and further high-quality studies are needed.

Expansion of simulation and extended reality for undergraduate health professions education: A call to action.

In the spring of 2020, the COVID-19 pandemic limited access for many health professions students to clinical settings amid concerns about availability of appropriate personal protective equipment as well as the desire to limit exposure in these high-risk settings. Furthermore, the pandemic led to a need to cancel clinics and inpatient rotations, with a major impact on training for health professions and interprofessional health delivery, the long-term effects of which are currently unknown. While problematic, this also presents an opportunity to reflect on challenges facing the traditional clinical training paradigm in a rapidly changing and complex health care system and develop sustainable, high-quality competency-based educational models that incorporate rapidly progressing technologies. We call for pilot studies to explore specific simulation-based inpatient and outpatient clinical rotations for professional and interprofessional training.

Reproducibility of 'COST reference microplasma jets'.

Atmospheric pressure plasmas have been ground-breaking for plasma science and technologies, due to their significant application potential in many fields, including medicinal, biological, and environmental applications. This is predominantly due to their efficient production and delivery of chemically reactive species under ambient conditions. One of the challenges in progressing the field is comparing plasma sources and results across the community and the literature. To address this a reference plasma source was established during the 'biomedical applications of atmospheric pressure plasmas' EU COST Action MP1101. It is crucial that reference sources are reproducible. Here, we present the reproducibility and variance across multiple sources through examining various characteristics, including: absolute atomic oxygen densities, absolute ozone densities, electrical characteristics, optical emission spectroscopy, temperature measurements, and bactericidal activity. The measurements demonstrate that the tested COST jets are mainly reproducible within the intrinsic uncertainty of each measurement technique.

Fulminant Neisseria meningitidis septicaemia with purpura fulminans requiring limb amputation.

Despite the isolation of Neisseria meningitidis over 200 years ago, meningococcal disease remains a feared cause of bacterial sepsis, with significant morbidity and mortality, despite prompt antibiotic use and modern critical care support. Neisseria meningitides is a Gram-negative encapsulated diplococcus, which exists only in the human host (Kvalsvig and Unsworth, 2003). The bacterium can cause life-threatening septic shock and coagulopathy, which may rapidly manifest within a matter of hours from preceding mild symptoms (Kvalsvig and Unsworth, 2003). Whilst N. meningitidis is recognised as a common commensal organism in the nasopharynx, associated with asymptomatic carriage in up to 10 %, manifestation of life-threatening disease is rare (Rappuoli and Pizza, 2015). We report the case of 31-year-old male presenting with devastating meningococcal septicaemia with disseminated intravascular coagulopathy (DIC) and purpura fulminans, requiring surgical debridement and a right above-knee amputation for sepsis-driven skin necrosis. The patient suffered extensive tissue loss secondary to a type 3 immune hypersensitivity reaction involving immune-complex mediated inflammation and tissue necrosis. Due to a strong immune component driving the patient's failure to convalesce pulsed intravenous methylprednisolone was used alongside antimicrobial therapy. The use of steroids was associated with fever subsidence and significant clinical improvement, highlighting the benefit of corticosteroid use in immune-complex mediated pathology.