Carbapenem-resistant Enterobacteriaceae in patients with bacteraemia at tertiary hospitals in South Africa, 2015 to 2018.

Enhanced surveillance for CREs was established at national sentinel sites in South Africa. We aimed to apply an epidemiological and microbiological approach to characterise CREs and to assess trends in antimicrobial resistance from patients admitted to tertiary academic hospitals. A retrospective analysis was conducted on patients of all ages with CRE bacteraemia admitted at any one of 12 tertiary academic hospitals in four provinces (Gauteng, KwaZulu-Natal, Western Cape and Free State) in South Africa. The study period was from July 2015 to December 2018. A case of CRE bacteraemia was defined as a patient admitted to one of the selected tertiary hospitals where any of the Enterobacteriaceae was isolated from a blood culture, and was resistant to the carbapenems (ertapenem, meropenem, imipenem and/or doripenem) or had a positive result for the Modified Hodge Test (MHT) according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. A positive blood culture result obtained after 21 days of the last blood culture result was regarded as a new case. To distinguish hospital-acquired (HA) from the community-acquired (CA) bacteraemia, the following definitions were applied: the HA CRE bacteraemia was defined as a patient with CRE isolated from blood culture ≥ 72 h of hospital admission or with any prior healthcare contact, within 1 year prior to the current episode or referral from a healthcare facility where the patient was admitted before the current hospital. A case of the CA CRE bacteraemia was defined as a patient with CRE isolated from blood culture < 72 h of hospital admission and with no prior healthcare contact. The majority of carbapenem-resistant Enterobacteriaceae (CRE) (70%) were hospital-acquired (HA) with Klebsiella pneumoniae being the predominant species (78%). In-hospital mortality rate was 38%. The commonest carbapenemase genes were bla-OXA-48 (52%) and bla-NDM (34%). The high mortality rate related to bacteraemia with CRE and the fact that most were hospital-acquired infections highlights the need to control the spread of these drug-resistant bacteria. Replacement with OXA-48 is the striking finding from this surveillance analysis. Infection control and antibiotic stewardship play important roles in decreasing the spread of resistance.

Modafinil and cognitive enhancement in schizophrenia and healthy volunteers: the effects of test battery in a randomised controlled trial.

BACKGROUND: Cognitive deficits in schizophrenia have major functional impacts. Modafinil is a cognitive enhancer whose effect in healthy volunteers is well-described, but whose effects on the cognitive deficits of schizophrenia appear to be inconsistent. Two possible reasons for this are that cognitive test batteries vary in their sensitivity, or that the phase of illness may be important, with patients early in their illness responding better. METHODS: A double-blind, randomised, placebo-controlled single-dose crossover study of modafinil 200 mg examined this with two cognitive batteries [MATRICS Consensus Cognitive Battery (MCCB) and Cambridge Neuropsychological Test Automated Battery (CANTAB)] in 46 participants with under 3 years' duration of DSM-IV schizophrenia, on stable antipsychotic medication. In parallel, the same design was used in 28 age-, sex-, and education-matched healthy volunteers. Uncorrected p values were calculated using mixed effects models. RESULTS: In patients, modafinil significantly improved CANTAB Paired Associate Learning, non-significantly improved efficiency and significantly slowed performance of the CANTAB Stockings of Cambridge spatial planning task. There was no significant effect on any MCCB domain. In healthy volunteers, modafinil significantly increased CANTAB Rapid Visual Processing, Intra-Extra Dimensional Set Shifting and verbal recall accuracy, and MCCB social cognition performance. The only significant differences between groups were in MCCB visual learning. CONCLUSIONS: As in earlier chronic schizophrenia studies, modafinil failed to produce changes in cognition in early psychosis as measured by MCCB. CANTAB proved more sensitive to the effects of modafinil in participants with early schizophrenia and in healthy volunteers. This confirms the importance of selecting the appropriate test battery in treatment studies of cognition in schizophrenia.

Introduction of an assessment toolkit associated with increased rate of DLB diagnosis.

BACKGROUND: Dementia with Lewy bodies (DLB) and dementia in Parkinson's disease (PDD) are recognised to be under-recognised in clinical practice in the UK, with only one third to a half of expected cases diagnosed. We aimed to assess whether clinical diagnostic rates could be increased by the introduction of a structured assessment toolkit for clinicians. METHODS: We established baseline diagnostic rates for DLB and PDD in four memory clinics and three movement disorder/Parkinson's disease (PD) clinics in two separate geographical regions in the UK. An assessment toolkit specifically developed to assist with the recognition and diagnosis of DLB and PDD was then introduced to the same clinical teams and diagnostic rates for DLB and PDD were reassessed. For assessing DLB diagnosis, a total of 3820 case notes were reviewed before the introduction of the toolkit, and 2061 case notes reviewed after its introduction. For PDD diagnosis, a total of 1797 case notes were reviewed before the introduction of the toolkit and 3405 case notes after it. Mean values and proportions were analysed using Student's t test for independent samples and χ2 test, respectively. RESULTS: DLB was diagnosed in 4.6% of dementia cases prior to the introduction of the toolkit, and 6.2% of dementia cases afterwards, an absolute rise of 1.6%, equal to a 35% increase in the number of DLB cases diagnosed when using the toolkit (χ2 = 4.2, P = 0.041). The number of PD patients diagnosed with PDD was not found overall to be significantly different when using the toolkit: 9.6% of PD cases before and 8.2% of cases after its introduction (χ2 = 1.8, P = 0.18), though the ages of PD patients assessed after the toolkit's introduction were lower (73.9 years vs 80.0 years, t = 19.2, p < 0.001). CONCLUSION: Introduction of the assessment toolkit was associated with a significant increase in the rate of DLB diagnosis, suggesting that a structured means of assessing symptoms and clinical features associated with DLB can assist clinicians in recognising cases. The assessment toolkit did not alter the overall rate of PDD diagnosis, suggesting that alternate means may be required to improve the rate of diagnosis of dementia in Parkinson's disease.

COVID-19 pandemic-a focused review for clinicians.

BACKGROUND: The COVID-19 pandemic caused by SARS-CoV-2 remains a significant issue for global health, economics and society. A wealth of data has been generated since its emergence in December 2019, and it is vital for clinicians to keep up with this data from across the world at a time of uncertainty and constantly evolving guidelines and clinical practice. OBJECTIVES: Here we provide an update for clinicians on the recent developments in the virology, diagnostics, clinical presentation, viral shedding, and treatment options for COVID-19 based on current literature. SOURCES: We considered published peer-reviewed papers and non-peer-reviewed pre-print manuscripts on COVID19 and related aspects with an emphasis on clinical management aspects. CONTENT: We describe the virological characteristics of SARS-CoV-2 and the clinical course of COVID-19 with an emphasis on diagnostic challenges, duration of viral shedding, severity markers and current treatment options. IMPLICATIONS: The key challenge in managing COVID-19 remains patient density. However, accurate diagnosis as well as early identification and management of high-risk severe cases are important for many clinicians. For improved management of cases, there is a need to understand test probability of serology, qRT-PCR and radiological testing, and the efficacy of available treatment options that could be used in severe cases with a high risk of mortality.

A comparison of baleen whale density estimates derived from overlapping satellite imagery and a shipborne survey.

As whales recover from commercial exploitation, they are increasing in abundance in habitats that they have been absent from for decades. However, studying the recovery and habitat use patterns of whales, particularly in remote and inaccessible regions, frequently poses logistical and economic challenges. Here we trial a new approach for measuring whale density in a remote area, using Very-High-Resolution WorldView-3 satellite imagery. This approach has capacity to provide sightings data to complement and assist traditional sightings surveys. We compare at-sea whale density estimates to estimates derived from satellite imagery collected at a similar time, and use suction-cup archival logger data to make an adjustment for surface availability. We demonstrate that satellite imagery can provide useful data on whale occurrence and density. Densities, when unadjusted for surface availability are shown to be considerably lower than those estimated by the ship survey. However, adjusted for surface availability and weather conditions (0.13 whales per km2, CV = 0.38), they fall within an order of magnitude of those derived by traditional line-transect estimates (0.33 whales per km2, CV = 0.09). Satellite surveys represent an exciting development for high-resolution image-based cetacean observation at sea, particularly in inaccessible regions, presenting opportunities for ongoing and future research.

Surveillance and comparison of antimicrobial susceptibility patterns of ESKAPE organisms isolated from patients with bacteraemia in South Africa, 2016 - 2017.

BACKGROUND: In South Africa (SA), the National Department of Health has developed an Antimicrobial Resistance National Strategy Framework document to manage antimicrobial resistance (AMR). One of the strategic objectives is to optimise surveillance and early detection of AMR. At the National Institute for Communicable Diseases (NICD), an analysis of selected organisms and antimicrobial agents from both the public and the private sectors was conducted. OBJECTIVES: The relevance of surveillance for AMR is increasingly recognised in the light of global action plans to combat resistance. In this report, we present an overview of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) organisms and Escherichia coli reported from public and private sector laboratories in SA for the period 2016 - 2017. METHODS: Antimicrobial susceptibility testing (AST) profiles on selected ESKAPE organisms and E. coli isolated from blood cultures from the public and private sectors in 2016 and 2017 were analysed. AST data were extracted from a web-based electronic platform created by the NICD. Drug-bug combinations following the World Health Organization's Global Antimicrobial Surveillance System guidelines were included in the analysis. RESULTS: A total of 28 920 ESKAPE organisms and E. coli were reported in 2016 and 32 293 in 2017 across the two health sectors. Proportions of some organisms differed between the two health sectors, such as E. coli (19% in the public sector and 36% in the private sector), A. baumannii (14% public and 4% private), P. aeruginosa (7% public and 11% private) and S. aureus (27% public and 17% private). Susceptibility data indicated changing patterns in both sectors towards an increase in non-susceptibility to carbapenems in K. pneumoniae (p<0.01). However, we demonstrated an increase in susceptibility to cloxacillin in S. aureus (p<0.01) in both sectors. CONCLUSIONS: The key clinically important finding is the rapidly decreasing carbapenem susceptibility among Enterobacteriaceae reported in SA, irrespective of sector. In addition, the analysis provides information that could be used to monitor the effectiveness of interventions implemented at a national level under the guidance and direction of the national AMR framework.

Co-infection with Streptococcus pneumoniae and Listeria monocytogenes in an immunocompromised patient.

A 34-year-old HIV-positive man with a history of chronic substance abuse was admitted with dual infection of Streptococcus pneumoniae and Listeria monocytogenes. Combined bacteraemia with S. pneumoniae and L. monocytogenes is very rare. To the best of our knowledge, this is the first such case documented at our institution and in South Africa. Ampicillin should be added to antibiotic regimens to improve patient outcome if L. monocytogenes infection is suspected. Co-infections that occur with L. monocytogenes may have conflicting antibiotic treatment options. This case report emphasises the need for a good relationship between the local microbiology pathologist and physician to select appropriate antibiotic treatment before definitive results are available.

Interaction of a polymeric biguanide biocide with phospholipid membranes.

Differential scanning calorimetry (DSC) and fluorescence polarization methods have been used to study the interactions between phospholipid membranes and a polymeric biocide, poly(hexamethylene biguanide hydrochloride) (PHMB). It was found that PHMB had very little effect on neutral lipids such as phosphatidylcholine (PC) and phosphatidylethanolamine (PE), whereas it greatly reduced the phase transition temperature of phosphatidylglycerol (PG), an acidic lipid found in bacteria. Although the corresponding monomeric biocide had a similar effect on the PG bilayer, the behaviour towards mixed lipid bilayers of PC and PG has been shown to be completely different for the polymeric and monomeric biocides: viz. the former can induce isothermal phase separation into a PHMB-PG complex domain and a PC-enriched domain, whilst the latter cannot. This may account for the great difference in bactericidal activity between them. It is suggested that PHMB interacts primarily with negatively charged species in the membranes, inducing aggregation of acidic lipids in the vicinity of the adsorption site, where higher fluidity and higher permeability are expected. The results have shown that two factors might be crucial in the cidal activity of such types of cationic disinfectants as biguanides: phase separation and interaction with the hydrocarbon interior of the membranes. Polymeric biocides could be particularly effective by virtue of their ability to combine hydrophobic character and multiple charges within a single molecule.

Polymeric inhibitors of platelet aggregation. II. Copolymers of dipyridamole and related drugs with N-vinylpyrrolidone.

A study has been made of the behaviour of the drugs dipyridamole and mopidamol (RA 233) attached to poly(N-vinylpyrrolidone). The inhibitory activities towards platelet aggregation induced by ADP or platelet activation factor (PAF) in sheep plasma have been examined and found to exceed the activities of the parent drugs, by factors up to 20. At the same time the abilities of the polymer-bound drugs in potentiating prostaglandin-type anti-aggregatory activities are much lower than those of the unattached drugs. The observations are explained in terms of polymer adsorption on to the platelet membranes, producing a high surface concentration of the drugs with consequent high inhibitory action. Intracellular action, such as the inhibition of phosphodiesterase, is reduced by the difficulty experienced by the polymeric drug in passing through the membrane, so that potentiation of prostaglandin activity, particularly against PAF, becomes small. A terpolymer containing units of dipyridamole and the prostaglandin analogue 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin (245C) shows a degree of 'self-potentiation'.

Polymeric inhibitors of platelet aggregation. Synergistic effects and proposals for a new mechanism.

We have studied the inhibition of ADP-induced platelet aggregation in sheep platelet-rich plasma by water-soluble polymers bound to the prostaglandin analogue 5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin ('BW 245' C, (I). The use of unambiguous modes of binding this antiplatelet drug to polymers has enabled us to study some structural features which influence inhibitory activity. Evidence is adduced which indicates that the chemical mechanisms responsible for inhibition by free and coupled BW 245 are similar. The most important observation is a remarkable synergism demonstrated by the greatly enhanced activity of a mixture of a polymer coupled to BW 245 with the uncoupled parent polymer. In some cases (e.g., with high-molecular-weight dextran) the effect may reach (and possibly exceed) two orders of magnitude. The influence of polymer molecular weights and 'cross-polymer' effects have both been examined. A mechanism has been proposed to account for these phenomena, involving adsorption of the added (inactive) polymer on to the platelet membranes, facilitating interaction of the polymer-bound drug with receptors, made more accessible by alteration to the surface geometry. This mechanism is based on physical processes, unlike other explanations of synergistic behaviour, e.g., that of prostaglandins used in conjunction with non-polymeric drugs. The observed dependences of synergistic effects upon polymer molecular weight and type and distribution of drug molecules along chains are typical 'polymer' phenomena which are all consistent with the proposed mechanism.

Identification and removal of a promiscuous CD4+ T cell epitope from the C1 domain of factor VIII.

BACKGROUND: The development of inhibitors in hemophiliacs is a severe complication of factor VIII (FVIII) replacement therapy and is a process driven by FVIII specific T helper cells. OBJECTIVES: To finely map T cell epitopes within the whole FVIII protein in order to investigate the possibility of engineering FVIII variants with reduced propensity for inhibitor development. PATIENTS AND METHODS: T cell lines were generated from five patients with severe hemophilia who had developed inhibitors, and were screened for T cell proliferation against pools of overlapping peptides spanning the entire B domain deleted (BDD) FVIII sequence. Positive peptide pools were decoded by screening individual peptides against the T cell lines. Positive peptides, and mutants thereof, were tested for their ability to bind major histocompatibility complex (MHC) Class II and stimulate T cell proliferation in a panel of healthy donors. The activities of the corresponding mutant proteins were assessed via chromogenic assay. RESULTS: One peptide, spanning FVIII amino acids 2098-2112, elicited a vigorous response from one hemophiliac donor, induced strong T cell responses in the panel of healthy donors and bound to a number of HLA-DR alleles. Mutations were made in this peptide that removed its ability to stimulate T cells of healthy donors and to bind to MHC Class II while retaining full activity when incorporated into a mutant BDD-FVIII protein. CONCLUSIONS: Fine T cell epitope mapping of the entire FVIII protein is feasible, although challenging, and this knowledge may be used to create FVIII variants which potentially have reduced immunogenicity.

Swine influenza vaccination in patients with multiple sclerosis.

Swine influenza vaccination was tolerated well by 61 multiple sclerosis patients. A new neurologic symptom developed in one patient, one noticed the recurrence of previous symptoms, and two patients experienced systemic signs of toxicity.

Neurologic complications of the tryptophan-associated eosinophilia-myalgia syndrome.

A case of tryptophan-associated eosinophilia, central nervous system complications, and multiple white matter lesions by magnetic resonance imaging is presented. Eosinophilia regardless of its cause should be included within the differential of patients exhibiting periventricular white matter lesions.

Toxoplasmosis mimicking a brain abscess in an adult with treated scleroderma.

Toxoplasmosis was found in a 41-year-old man whose presenting symptoms suggested the presence of a presenting symptoms suggested the presence of a space-occupying cerebral lesion and meningitis. The diagnosis was confirmed histologically and serologically. Sulfisoxazole and pyrimethamine therapy resulted in resolution of the meningitis within 2 weeks, but no significant clinical change was otherwise observed. The pathology and epidemiology of similar cases are reviewed.

Migrainous ischemic optic neuropathy.

Anterior ischemic optic neuropathy (AION) is a stroke syndrome of the eye seen in isolation or as a manifestation of underlying disease. A case of migrainous AION is reported, and the implications of anterior visual pathway migraine discussed.

Seasonal variation of multiple sclerosis exacerbations in Arizona.

We studied 178 MS patients and 82 controls for 5 years. A monthly pattern in in the frequency of exacerbations in Arizona differed from the patterns seen in other regions of the world. Exacerbations were most common in warmer months. No explanation for this was found. In this prospective study, the frequency of viral infections in the MS patients was lower than in the controls.

Anamnestic studies in multiple sclerosis: a relationship between familial multiple sclerosis and neoplasia.

A survey of family histories of malignant neoplasia in multiple sclerosis (MS) patients indicates that a positive history of cancer in near relatives is present in 44 percent of patients and 46 percent of controls. However, those MS patients having such a positive history were much more likely than others to also have a family history of MS. Contrariwise, MS patients with a positive family history of MS had a significantly higher rate of cancer in first degree relatives (71 percent) than others. There was a trend indicating less cancer in families of MS patients possessing the HLA-B7 and DW2 histocompatibility antigens.

Abnormal lumbar isotope cisternography in an unusual case of spontaneous hypoliquorrheic headache.

The unusual case of spontaneous hypoliquorrheic headache reported here was clinically identical to that originally described by Schaltenbrand. This is the first case to be studied by radioisotope cisternography, which showed that the cerebrospinal fluid flow was essentially normal. However, the radioactivity counts percent decreased rapidly, with simultaneous appearance of high isotope concentration in the urinary bladder. Scan images did not show cerebrospinal fluid (CSF) leakage at the puncture sites. Our data suggest that this postural headache syndrome is not caused by decreased CSF production, but by a very rapid absorption or unusual CSF leakage.

Trauma as an etiologic and aggravating factor in multiple sclerosis.

We carried out a retrospective and prospective epidemiologic study designed to detect an association between trauma and multiple sclerosis in 130 patients and 82 age- and sex-matched controls. Electrical injury was followed by an increased frequency of exacerbation, which did not achieve statistical significance. There was no statistically significant association between other types of trauma and onset or deterioration of the disease. These findings do not prove that such an association cannot exist for any one individual patient; however, they do not provide evidence to support this idea.