A novel melanocortin fusion protein inhibits fibrinogen oxidation and degradation during trauma-induced coagulopathy.

Immune cell inflammation is implicated in the pathophysiology of acute trauma-induced coagulopathy (TIC). We hypothesized that leukocyte inflammation contributes to TIC through the oxidation and proteolysis of fibrinogen. To test this hypothesis, antioxidants and a novel anti-inflammatory melanocortin fusion protein (AQB-565) were used to study the effects of interleukin-6 (IL-6)-stimulated human leukocytes on fibrinogen using single-cell imaging flow cytometry and multiplex fluorescent western blotting. We also studied the effects of AQB-565 on fibrinogen using an in vivo rat trauma model of native TIC. IL-6 induced cellular inflammation and mitochondrial superoxide production in human monocytes, causing fibrinogen oxidation and degradation in vitro. Antioxidants suppressing mitochondrial superoxide reduced oxidative stress and inflammation and protected fibrinogen. AQB-565 decreased inflammation, inhibited mitochondrial superoxide, and protected fibrinogen in vitro. Trauma with hemorrhagic shock increased IL-6 and other proinflammatory cytokines and chemokines, selectively oxidized and degraded fibrinogen, and induced TIC in rats in vivo. AQB-565, given at the onset of hemorrhage, blocked inflammation, protected fibrinogen from oxidation and degradation, and prevented TIC. Leukocyte activation contributes to TIC through the oxidation and degradation of fibrinogen, which involves mitochondrial superoxide and cellular inflammation. Suppression of inflammation by activation of melanocortin pathways may be a novel approach for the prevention and treatment of TIC.

Low-density lipoprotein promotes microvascular thrombosis by enhancing von Willebrand factor self-association.

von Willebrand factor (VWF) mediates primary hemostasis and thrombosis in response to hydrodynamic forces. We previously showed that high shear promoted self-association of VWF into hyperadhesive strands, which can be attenuated by high-density lipoprotein (HDL) and apolipoprotein A-I. In this study, we show that low-density lipoprotein (LDL) binds VWF under shear and enhances self-association. Vortexing VWF in tubes resulted in its loss from the solution and deposition onto tube surfaces, which was prevented by HDL. At a stabilizing HDL concentration of 1.2 mg/mL, increasing concentrations of LDL progressively increased VWF loss, the effect correlating with the LDL-to-HDL ratio and not the absolute concentration of the lipoproteins. Similarly, HDL diminished deposition of VWF in a post-in-channel microfluidic device, whereas LDL increased both the rate and extent of strand deposition, with both purified VWF and plasma. Hypercholesterolemic human plasma also displayed accelerated VWF accumulation in the microfluidic device. The initial rate of accumulation correlated linearly with the LDL-to-HDL ratio. In Adamts13-/- and Adamts13-/-LDLR-/- mice, high LDL levels enhanced VWF and platelet adhesion to the myocardial microvasculature, reducing cardiac perfusion, impairing systolic function, and producing early signs of cardiomyopathy. In wild-type mice, high plasma LDL concentrations also increased the size and persistence of VWF-platelet thrombi in ionophore-treated mesenteric microvessels, exceeding the accumulation seen in similarly treated ADAMTS13-deficient mice that did not receive LDL infusion. We propose that targeting the interaction of VWF with itself and with LDL may improve the course of thrombotic microangiopathies, atherosclerosis, and other disorders with defective microvascular circulation.

Genome-wide meta-analysis implicates variation affecting mast cell biology in urticaria.

BACKGROUND: Urticaria is characterized by inappropriate mast cell degranulation leading to the development of wheals and/or angioedema. Twin and family studies indicate that there is a substantial heritable component to urticaria risk. OBJECTIVE: Our aim was to identify genomic loci at which common genetic variation influences urticaria susceptibility. METHODS: Genome-wide association studies of urticaria (including all subtypes) from 3 European cohorts (UK Biobank, FinnGen, and the Trøndelag Health Study [HUNT]) were combined through statistical meta-analysis (14,306 urticaria cases and 650,664 controls). Cases were identified via electronic health care records from primary and/or secondary care. To identify putative causal variants and genes, statistical fine-mapping, colocalization, and interrogation of publicly available single-cell transcriptome sequencing resources were performed. RESULTS: Genome-wide significant associations (P < 5 × 10-8) were identified at 6 independent loci. These included 2 previously reported association signals at 1q44 and the human leucocyte antigen region on chromosome 6. Genes with expected or established roles in mast cell biology were associated with the 4 other genome-wide association signals (GCSAML, FCER1A, TPSAB1, and CBLB). Colocalization of association signals consistent with the presence of shared causal variants was observed between urticaria susceptibility and increased expression of GCSAML (posterior probability of colocalization [PPcoloc] = 0.89) and FCER1A (PPcoloc = 0.91) in skin. CONCLUSION: Common genetic variation influencing the risk of developing urticaria was identified at 6 genomic loci. The relationship between genes with roles in mast cell biology and several association signals implicates genetic variability of specific components of mast cell function in the development of urticaria.

Cognitive deficits among people with schizophrenia and prediabetes or diabetes.

INTRODUCTION: Both type 2 diabetes mellitus (T2DM) and schizophrenia are known to be associated with cognitive deficits. The impact of the comorbidities of T2DM or prediabetes (PD) on cognition among people with schizophrenia has been poorly researched. We evaluated the cognitive functioning of patients with schizophrenia and PD or T2DM and compared them to patients with schizophrenia with normal blood sugar. METHODS: We retrospectively collated data on cognition, fasting blood glucose (FBG), lipids and other selected demographic and clinical variables of 171 patients with schizophrenia and 16 patients with schizoaffective disorder who were admitted to an inpatient rehabilitation facility in Western Australia from 2011 to 2018. The Brief Assessment of Cognition in Schizophrenia (BACS) was used to evaluate cognitive functioning. Parametric and non-parametric analyses were used to examine the study's aims. RESULTS: Sixty-six percent of the patients had normal blood sugar, 25% had PD and 9% had T2DM. The BACS composite score revealed an increasing gradient of cognitive deficits, ranging from mild to severe, between the normal, PD and T2DM groups, respectively. The T2DM group had a significantly lower composite score compared with the PD (p = 0.026) and normal groups (p < 0.001). On the BACS subtests, the scores of T2DM and PD patients were similar except for the token motor task, in which the T2DM group had significantly lower scores (p < 0.001). The T2DM group also had lower scores on the subtests of BACS, except memory tests, compared with those with normal blood sugar. There was no significant difference in the composite and subtest cognitive scores between the PD and normal groups. CONCLUSIONS: Our study revealed more pronounced cognitive deficits among patients with schizophrenia and dysglycaemia, particularly those with T2DM, compared with those with schizophrenia with normal blood sugar.

Periscope Proteins are variable-length regulators of bacterial cell surface interactions.

Changes at the cell surface enable bacteria to survive in dynamic environments, such as diverse niches of the human host. Here, we reveal "Periscope Proteins" as a widespread mechanism of bacterial surface alteration mediated through protein length variation. Tandem arrays of highly similar folded domains can form an elongated rod-like structure; thus, variation in the number of domains determines how far an N-terminal host ligand binding domain projects from the cell surface. Supported by newly available long-read genome sequencing data, we propose that this class could contain over 50 distinct proteins, including those implicated in host colonization and biofilm formation by human pathogens. In large multidomain proteins, sequence divergence between adjacent domains appears to reduce interdomain misfolding. Periscope Proteins break this "rule," suggesting that their length variability plays an important role in regulating bacterial interactions with host surfaces, other bacteria, and the immune system.

Engineering Low Volume Resuscitants for the Prehospital Care of Severe Hemorrhagic Shock.

Globally, traumatic injury is a leading cause of suffering and death. The ability to curtail damage and ensure survival after major injury requires a time-sensitive response balancing organ perfusion, blood loss, and portability, underscoring the need for novel therapies for the prehospital environment. Currently, there are few options available for damage control resuscitation (DCR) of trauma victims. We hypothesize that synthetic polymers, which are tunable, portable, and stable under austere conditions, can be developed as effective injectable therapies for trauma medicine. In this work, we design injectable polymers for use as low volume resuscitants (LVRs). Using RAFT polymerization, we evaluate the effect of polymer size, architecture, and chemical composition upon both blood coagulation and resuscitation in a rat hemorrhagic shock model. Our therapy is evaluated against a clinically used colloid resuscitant, Hextend. We demonstrate that a radiant star poly(glycerol monomethacrylate) polymer did not interfere with coagulation while successfully correcting metabolic deficit and resuscitating animals from hemorrhagic shock to the desired mean arterial pressure range for DCR - correcting a 60 % total blood volume (TBV) loss when given at only 10 % TBV. This highly portable and non-coagulopathic resuscitant has profound potential for application in trauma medicine.

Rates and Reasons for Clozapine Treatment Interruptions: Impact of the Frequency of Hematologic Monitoring and Cardiac Adverse Events.

BACKGROUND: Differing rates and reasons for interruptions of clozapine treatment have been reported globally. This article evaluated the rates and reasons for clozapine therapy interruptions in Australia and explored the impact of the frequency of hematological monitoring on these parameters. METHODS: Data of the patients who were newly commenced on clozapine at three metropolitan public mental health services in Western Australia over 11 years were retrospectively collated. The rate and reasons for clozapine therapy interruptions and their association with the frequency of hematological monitoring, age, sex, and treatment site were analyzed using parametric, nonparametric, and correlational analyses. RESULTS: Of the 457 patients whose data were collected, 69.6% had an interruption of treatment with 41.2% of those occurring during the period of mandatory weekly hematological monitoring in the first 18 weeks. Nonadherence (57.4%) and adverse effects (28.8%) were the 2 main reasons for the treatment interruptions. Cardiac issues accounted for the majority of the interruptions (61.8%) due to specified adverse effects, and these occurred significantly more commonly within the first 18 weeks. Location, age, and sex did not predict the possibility of treatment interruptions. CONCLUSIONS: The high rates of clozapine treatment interruption observed during the period of weekly monitoring point toward the need to address the burden of frequent hematological monitoring for patients. Disproportionately higher rates of interruption due to cardiac adverse effects observed in this study compared with research from non-Australian settings raise the possibility of geographical differences in the adverse effects leading to treatment discontinuation.

Empirical treatment and mortality in bacteremia due to extended spectrum ß-lactamase producing Enterobacterales (ESßL-E), a retrospective cross-sectional study in a tertiary referral hospital from Colombia.

BACKGROUND: Infections caused by extended spectrum ß-lactamase (ESßL) producing bacteria are common and problematic. When they cause bloodstream infections, they are associated with significant morbidity and mortality. METHODS: A retrospective cross-sectional observational study was conducted in a single center in Pereira, Colombia. It included people hospitalized with bacteremia due to gram-negative bacilli with the extended-spectrum ß-lactamase producing phenotype. A logistic regression analysis was constructed. Clinical characteristics and risk factors for death from sepsis were established. RESULTS: The prevalence of bacteremia due to Enterobacterales with extended-spectrum ß-lactamase producing phenotype was 17%. 110 patients were analyzed. Most patients were men (62%) with a median age of 58 years, hospital mortality was 38%. Admission to intensive care was 45%. The following risk factors for mortality were established: shock requiring vasoactive support, Pitt score > 3 points, and not having an infectious disease consultation (IDC). CONCLUSIONS: bacteremia due to Enterobacterales with extended-spectrum ß-lactamase producing phenotype have a high mortality. Early recognition of sepsis, identification of risk factors for antimicrobial resistance, and prompt initiation of appropriate empiric antibiotic treatment are important. An infectious disease consultation may help improve outcomes.

Efficacy of topical versus oral analgesic medication compared to a placebo in injured athletes: A systematic review with meta-analysis.

BACKGROUND: Athletes are injured frequently and often take analgesic medication. Moreover, athletes commonly use non-prescription topical and oral medications with little guidance. Despite wide use, relatively few studies exist on the efficacy of pain medication in injured athletes compared to a placebo. OBJECTIVE: To determine efficacy of topical or oral medications in pain reduction compared to a placebo in injured athletes. STUDY DESIGN: A systematic review and meta-analysis. METHODS: We conducted an electronic search using Medline/Pubmed, Web of Science, Ovid, and SportDiscus for all literature relating to topical or oral medications in athletes for pain management post-injury. Two reviewers screened the studies and measured their quality. To determine efficacy, we calculated the Hedges' g value. We created forest plots with 95% CI to graphically summarize the meta-analyses. RESULTS: There was a significant pooled effect size reflecting a reduction in pain outcomes for the topical treatment versus placebo (g = -0.64; 95% CI [-0.89, -0.39]; p < 0.001). There was not a significant reduction in pain outcomes for the oral treatment versus placebo (g = -0.26; 95% CI [-0.60, 0.17]; p = 0.272). CONCLUSION: Topical medications were significantly better at reducing pain compared to oral medications versus a placebo in injured athletes. These results are different when compared to other studies that used experimentally induced pain versus musculoskeletal injuries. The results from our study suggest that athletes should use topical medications for pain reduction, as it is more effective, and there are less reported adverse effects compared to oral medication.

Extraocular Muscle Enlargement in Acromegaly.

BACKGROUND: To determine whether acromegaly is associated with increased extraocular muscle (EOM) size at time of presentation. METHODS: Patients with a new diagnosis of acromegaly in a single tertiary care clinic with a CT scan that adequately delineated the EOMs were included. Control subjects were age- and sex-matched patients with a new diagnosis of nonfunctioning pituitary adenoma. Retrospective chart review was performed to extract baseline clinical and laboratory parameters including growth hormone, insulin-like growth factor 1, thyroid stimulating hormone, free T3, and free T4. A single neuroradiologist analyzed all CT scans and measured the maximum diameter and cross-sectional area of the superior rectus, inferior rectus, medial rectus, and lateral rectus in both eyes of all patients. RESULTS: We evaluated 17 patients with acromegaly and 18 control subjects. Mean maximum diameter of the superior, inferior, medial, and lateral recti were 4.80 mm (SD = 0.81), 4.67 mm (SD = 0.54), 4.86 mm (SD = 0.77), and 4.53 mm (SD = 0.70) respectively, in the acromegaly group. In the control group, they were 3.62 mm (SD = 0.58),3.71 mm (SD = 0.46), 3.66 mm (SD = 0.32), and 3.21 mm (SD = 0.44), respectively. The maximum diameter and cross-sectional area of all 4 EOMs measured in the acromegaly group were significantly larger ( P < 0.001) compared with the control group. CONCLUSIONS: Patients with acromegaly present with significantly enlarged EOMs compared with control subjects with nonfunctioning pituitary adenomas.

Phenotypic analysis of erythrocytes in sickle cell disease using imaging flow cytometry.

The morphology and other phenotypic characteristics of erythrocytes in sickle cell disease (SCD) have been analyzed for decades in patient evaluation. This involves a variety of techniques, including microscopic analysis of stained blood films, flow cytometry, and cell counting. Here, we analyzed SCD blood using imaging flow cytometry (IFC), a technology that combines flow cytometry and microscopy to enable simultaneous rapid-throughput analysis of cellular morphology and cell-surface markers. With IFC, we were able to automate quantification of poikilocytes from SCD blood. An important subpopulation of poikilocytes represented dense cells, although these could not be distinguished from other poikilocytes without first centrifuging the blood through density gradients. In addition, CD71-positive RBCs from SCD patients had two subpopulations: one with high CD71 expression and a puckered morphology and another with lower CD71 expression and biconcave morphology and presumably representing a later stage of differentiation. Some RBCs with puckered morphologies that were strongly positive for DAPI and CD49d were in fact nucleated RBCs. IFC identified more phosphatidylserine-expressing red cells in SCD than did conventional flow cytometry and these could also be divided into two subpopulations. One population had diffuse PS expression and appeared to be composed primarily of RBC ghosts; the other had lower overall PS expression present in intense, punctate dots overlying Howell-Jolly bodies. This study demonstrates that IFC can rapidly reveal and quantify RBC features in SCD that require numerous tedious methods to identify conventionally. Thus, IFC is likely to be a useful technique for evaluating and monitoring SCD.

Pathogenesis of solar urticaria: Classic perspectives and emerging concepts.

Solar urticaria is a rare, immunologically mediated photodermatosis in which activation of cutaneous mast cells is triggered by specific wavelengths of solar electromagnetic radiation. This manifests clinically as the rapid development of cutaneous itch, erythema and wheal formation after several minutes of sun exposure. Disease mechanisms in solar urticaria remain incompletely elucidated and there have been few recent investigations of its pathobiology. Historic passive transfer experiments performed during the twentieth century provide support for a 'photoallergy' model of disease pathogenesis, wherein molecular alteration of a putative chromophore by solar electromagnetic radiation produces mast cell activation via an IgE-dependent mechanism. However, this model does not account for several observations made during passive transfer experiments nor does it explain a range of subsequent clinical and photobiological observations made in solar urticaria patients. Furthermore, increased understanding of the molecular dynamics underpinning cutaneous mast cell responses highlights the need to reformulate our understanding of solar urticaria pathogenesis in the context of this contemporary scientific landscape. In this review, we discuss the current understanding of solar urticaria pathogenesis and, by incorporating recent scientific and clinical observations, develop new hypotheses to drive future investigation into this intriguing disorder.

Demographic and clinical characteristics of patients who recommence clozapine following therapy interruptions.

OBJECTIVE: The proportion of patients who recommence clozapine after cessation, the time taken to resume clozapine post-cessation, and distinguishing demographic and clinical characteristics of this group have been poorly researched. We evaluated these in the current study. METHOD: We retrospectively extracted selected demographic and clinical variables and clozapine treatment interruption and recommencement data up to December 2018 of a cohort of 458 patients who first commenced clozapine between 2006 and 2016. The study was conducted at three Australian health services. RESULTS: Of the 310 (69%) patients who had at least one interruption of clozapine treatment, 170 (54.8%) did not resume clozapine, and 140 (45.2%) recommenced it after the first interruption. More than half of those who recommenced did so within a month and 80% by 12 months. Cox regression analysis revealed that age was significantly associated with recommencement, with a 2% decrease in the likelihood of restarting after an interruption for each year later that clozapine was initially commenced (HR = 0.98 95%CI: 0.97, 0.997, p = 0.02). Those who ceased clozapine due to adverse effects were less likely to restart than those who ceased due to noncompliance (HR = 0.63 95%CI: 0.41, 0.97, p = 0.03). More time on clozapine prior to interruption increased the likelihood of restarting it, with each additional month on clozapine increasing this likelihood by 1% (HR = 1.01 95%CI: 1.01, 1.02, p < 0.001). CONCLUSION: If the distinguishing demographic and clinical characteristics of the group identified in this study are corroborated through further research, this could further validate the need to identify treatment resistance and commence clozapine early in people with schizophrenia and provide appropriate interventions to those more at risk of permanent discontinuation of clozapine.

Glycaemic potency reduction by coarse grain structure in breads is largely eliminated during normal ingestion.

The hypothesis that coarse grain particles in breads reduce glycaemic response only if the particles remain intact during ingestion was tested. Three breads were formulated: (1) White bread (WB - reference), (2) 75 % of kibbled purple wheat in 25 % white bread matrix (PB) and (3) a 1:1 mixture of 37·5 % kibbled soya beans and 37·5 % of kibble purple wheat in 25 % white bread matrix (SPB). Each bread was ingested in three forms: unchewed (U), as customarily consumed (C) and homogenised (H). Twelve participants ingested 40 g available carbohydrate portions of each bread in each form, with post-prandial blood glucose measured over 120 min. Glycaemic responses to WB were the same regardless of its form when ingested. Unchewed PB had significantly less glycaemic effect than WB, whereas the C and H forms were similar to WB. Based on a glycaemic index (GI) of 70 for WB, the GI values for the C, U and H breads, respectively, were WB: 70·0, 70 and 70, PB: 75, 42 and 61, SPB: 57, 48 and 55 (%) (Least significant difference = 17·43, P < 0·05, bold numbers significantly different from WB). The similar glycaemic response to the H and C forms of the breads, and their difference from the U form, showed that the glycaemia-moderating effect of grain structure on starch digestion was lost during customary ingestion of bread. We conclude that the kibbled-grain structure may not effectively retard starch digestion in breads as normally consumed because it is largely eliminated by ingestive processes including chewing.

Defining the remarkable structural malleability of a bacterial surface protein Rib domain implicated in infection.

Streptococcus groups A and B cause serious infections, including early onset sepsis and meningitis in newborns. Rib domain-containing surface proteins are found associated with invasive strains and elicit protective immunity in animal models. Yet, despite their apparent importance in infection, the structure of the Rib domain was previously unknown. Structures of single Rib domains of differing length reveal a rare case of domain atrophy through deletion of 2 core antiparallel strands, resulting in the loss of an entire sheet of the ß-sandwich from an immunoglobulin-like fold. Previously, observed variation in the number of Rib domains within these bacterial cell wall-attached proteins has been suggested as a mechanism of immune evasion. Here, the structure of tandem domains, combined with molecular dynamics simulations and small angle X-ray scattering, suggests that variability in Rib domain number would result in differential projection of an N-terminal host-colonization domain from the bacterial surface. The identification of 2 further structures where the typical B-D-E immunoglobulin ß-sheet is replaced with an α-helix further confirms the extensive structural malleability of the Rib domain.

Left Ventricular Function in the Initial Period After Severe Traumatic Brain Injury in Swine.

BACKGROUND: Cardiac dysfunction is common in the days after severe traumatic brain injury (TBI) and may contribute to hypotension episodes, leading to worse outcomes. Little is known about cardiac function in the minutes and hours immediately following TBI. By using fluid percussion TBI in a swine model, we aimed to characterize the immediate post injury cardiac function. METHODS: Intubated, anesthetized immature (25.8 ± 1.5 kg) female swine were subjected to severe fluid percussion TBI (4.2 ± 0.2 atm). Beginning at 45 min, simulating hospital arrival, all animals were resuscitated with normal saline (NS), mannitol, and phenylephrine as needed to maintain a cerebral perfusion pressure more than 60 mm Hg and intracranial pressure (ICP) less than 20 mm Hg. Primary outcomes of cardiac function were cardiac output measured by thermodilution and transesophageal echo measurements of cardiac function recorded at prespecified time points and tested for trends over time using linear regression with spline at the time of resuscitation onset. Secondary outcomes included hemodynamic measurements, ICP, and cerebral perfusion pressure. RESULTS: Eighteen animals were included. Post-TBI hemodynamic changes demonstrated an early decrease in mean arterial pressure and cerebral perfusion pressure with a corresponding increase in heart rate and ICP. Immediately after injury, there was a significant decrease in both left atrial area and tissue Doppler imaging e' of the LV lateral wall. In addition, there was a simultaneous increase in LV end diastolic diameter and increase in E/e' ratio of the lateral mitral annulus. All other transesophageal echo measurements demonstrated no significant changes throughout the duration of the experiment. CONCLUSIONS: Traumatic brain injury is associated with cardiac dysfunction and increased mortality, however there is still a limited understanding of the hemodynamic and echocardiographic response associated with TBI. In this study we demonstrate the hemodynamic and echocardiographic changes in the early stages of TBI in swine. The authors hope that these results may help better understanding on the management of patients with severe head injury.

Miniaturized free-flow electrophoresis: production, optimization, and application using 3D printing technology.

The increasing resolution of three-dimensional (3D) printing offers simplified access to, and development of, microfluidic devices with complex 3D structures. Therefore, this technology is increasingly used for rapid prototyping in laboratories and industry. Microfluidic free flow electrophoresis (µFFE) is a versatile tool to separate and concentrate different samples (such as DNA, proteins, and cells) to different outlets in a time range measured in mere tens of seconds and offers great potential for use in downstream processing, for example. However, the production of µFFE devices is usually rather elaborate. Many designs are based on chemical pretreatment or manual alignment for the setup. Especially for the separation chamber of a µFFE device, this is a crucial step which should be automatized. We have developed a smart 3D design of a µFFE to pave the way for a simpler production. This study presents (1) a robust and reproducible way to build up critical parts of a µFFE device based on high-resolution MultiJet 3D printing; (2) a simplified insertion of commercial polycarbonate membranes to segregate separation and electrode chambers; and (3) integrated, 3D-printed wells that enable a defined sample fractionation (chip-to-world interface). In proof of concept experiments both a mixture of fluorescence dyes and a mixture of amino acids were successfully separated in our 3D-printed µFFE device.

The Relationship Between Disorders of Bone Metabolism and Benign Paroxysmal Positional Vertigo: A Systematic Review.

OBJECTIVES: Several studies have reported an association between benign paroxysmal positional vertigo (BPPV) and bone mineral density or serum vitamin D levels. The aim of this review is to provide further clarification regarding the relationship between BPPV and calcium metabolism. DESIGN: PubMed and MEDLINE databases were systematically reviewed to identify all English language papers regarding the relationship between BPPV and the following terms: osteoporosis, osteopenia, bone mineral density, serum vitamin D levels, and bone metabolism. RESULTS: Of the 456 identified records, 28 studies were eligible for this review. Most were retrospective studies with inherent limitations and often conflicting results. While the literature is not conclusive, osteoporosis in patients of at least 50 years old appears to have an association with BPPV. Similarly, an association was observed between recurrent BPPV and vitamin D deficiency. CONCLUSION: There is only weak evidence to support the relationship between BPPV and osteoporosis or low serum 25-hydroxyvitamin D levels. Further prospective studies with more robust methodologies are needed to clarify the association between BPPV and disorders of bone metabolism.

A case of neck abscess caused by rare hypervirulent Klebsiella pneumoniae, capsular type K20 and sequence type 420.

BACKGROUND: This case report describes a neck abscess caused by a strain of Hypervirulent Klebsiella pneumoniae in a middle aged man with diabetes without a history of travel to East and South East Asia. This case report is of notable significance as Hypervirulent Klebsiella pneumoniae neck abscesses are rarely seen in the UK and are very infrequently documented in individuals who have not first travelled to the high prevalence areas of East and South East Asia. CASE PRESENTATION: This case report describes a 53 year old diabetic man who contracted a Hypervirulent Klebsiella pneumoniae neck abscess which led to the development of sepsis. Klebsiella pneumoniae was cultured from blood cultures and fluid aspirated from the abscess grew the pathogen with same antimicrobial susceptibility. Hypervirulence was demonstrated after the samples were analysed, at the Antimicrobial Resistance and Healthcare Associated Infections Reference Unit Public Health England Colindale, and found to contain the K20 (rmp)A and rmpA2 virulence genes. DISCUSSION: Hypervirulent Klebsiella pneumoniae is a Gram-negative, encapsulated, non-motile bacillus notable for its ability to metastatically spread and cause potentially life threatening infections in otherwise healthy adults, but especially in those with diabetes. Genes responsible for the production of hyperviscous mucoid polysaccharide capsules and siderophores, such as those isolated in this case, enable the bacteria to more efficiently evade the hosts immune system and disseminate and invade surrounding and distant tissues. Data from Public Health England shows Hypervirulent Klebsiella pneumoniae are rare in the UK. A review of current literature also showed Hypervirulent Klebsiella pneumoniae almost exclusively occur in those who have traveled to East and South East Asia. CONCLUSIONS: This case reported a rare Hypervirulent Klebsiella pneumoniae neck abscess outside of, and without travel to, East and South East Asia. This raises concerns about future, potentially life threatening, Hypervirulent Klebsiella pneumoniae infections becoming more widespread without the need for endemic travel. This concern is further exacerbated by the growing global challenge of antimicrobial resistance.

Closing gaps in histoplasmosis: clinical characteristics and factors associated with probable/histoplasmosis in HIV/AIDS hospitalized patients, a retrospective cross-sectional study in two tertiary centers in Pereira, Colombia.

BACKGROUND: The HIV pandemic continues to cause a high burden of morbidity and mortality due to delayed diagnosis. Histoplasmosis is prevalent in Latin America and Colombia, is difficult to diagnose and has a high mortality. Here we determined the clinical characteristics and risk factors of histoplasmosis in people living with HIV (PLWH) in Pereira, Colombia. MATERIALS AND METHODS: This was a retrospective cross-sectional study (2014-2019) involving two tertiary medical centers in Pereira, Colombia. People hospitalized with HIV were included. Histoplasma antigen detection was performed in urine samples. Probable histoplasmosis was defined according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group/National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria. RESULTS: 172 HIV-infected patients were analyzed. Histoplasmosis was confirmed in 29% (n = 50/172) of patients. The logistic regression analysis showed that the risk factors for histoplasmosis were pancytopenia (OR 4.1, 95% CI 1.6-10.3, P = 0.002), < 50 CD4 + cells/µL (OR 3.1, 95% CI 1.3-7.3, P = 0.006) and Aspartate transaminase (AST) levels > 46 IU/L (OR 3.2, 95% CI 1.3-8, P = 0.010). CONCLUSIONS: Histoplasmosis is highly prevalent in hospitalized patients with HIV in Pereira, Colombia. The clinical findings are nonspecific, but there are some clinical abnormalities that can lead to suspicion of the disease, early diagnosis and prompt treatment. Urine antigen detection is useful for diagnosis, but is not widely available. An algorithmic approach is proposed for low-resource clinical settings.