Antiseptic mouthwash for gonorrhoea prevention (OMEGA): a randomised, double-blind, parallel-group, multicentre trial.

BACKGROUND: To address the increasing incidence of gonorrhoea and antimicrobial resistance, we compared the efficacy of Listerine and Biotène mouthwashes for preventing gonorrhoea among men who have sex with men (MSM). METHODS: The OMEGA trial was a multicentre, parallel-group, double-blind randomised controlled trial among MSM, done at three urban sexual health clinics and one general practice clinic in Australia. Men were eligible if they were diagnosed with oropharyngeal gonorrhoea by nucleic acid amplification test (NAAT) in the previous 30 days or were aged 16-24 years. They were randomly assigned to receive Listerine (intervention) or Biotène (control) via a computer-generated sequence (1:1 ratio, block size of four). Participants, clinicians, data collectors, data analysts, and outcome adjudicators were masked to the interventions after assignment. Participants were instructed to rinse and gargle with 20 mL of mouthwash for 60 s at least once daily for 12 weeks. Oropharyngeal swabs were collected by research nurses every 6 weeks, and participants provided saliva samples every 3 weeks, to be tested for Neisseria gonorrhoeae with NAAT and quantitative PCR. The primary outcome was proportion of MSM diagnosed with oropharyngeal N gonorrhoeae infection at any point over the 12-week period, defined as a positive result for either oropharyngeal swabs or saliva samples by NAAT, and the cumulative incidence of oropharyngeal gonorrhoea at the week 12 visit. A modified intention-to-treat analysis for the primary outcome was done that included men who provided at least one follow-up specimen over the 12-week study period. The trial was registered on the Australian and New Zealand Clinical Trials Registry (ACTRN12616000247471). FINDINGS: Between March 30, 2016, and Oct 26, 2018, 786 MSM were screened and 256 were excluded. 264 MSM were randomly assigned to the Biotène group and 266 to the Listerine group. The analysis population included 227 (86%) men in the Biotène group and 219 (82%) in the Listerine group. Oropharyngeal gonorrhoea was detected in ten (4%) of 227 of MSM in the Biotène group and in 15 (7%) of 219 in the Listerine group (adjusted risk difference 2·5%, 95% CI -1·8 to 6·8). The cumulative incidence of oropharyngeal gonorrhoea at the week 12 visit did not differ between the two mouthwash groups (adjusted risk difference 3·1%, 95% CI -1·4 to 7·7). INTERPRETATION: Listerine did not reduce the incidence of oropharyngeal gonorrhoea compared with Biotène. However, previous research suggests that mouthwash might reduce the infectivity of oropharyngeal gonorrhoea; therefore, further studies of mouthwash examining its inhibitory effect on N gonorrhoeae are warranted to determine if it has a potential role for the prevention of transmission. FUNDING: Australian National Health and Medical Research Council.

Is gentamicin a viable therapeutic option for treating resistant Neisseria gonorrhoeae in New South Wales?

ABSTRACT: The key issues with Neisseria gonorrhoeae infections, in Australia and elsewhere, are coincident increases in disease rates and in antimicrobial resistance (AMR), although these factors have not been shown to be correlated. Despite advances in diagnosis, control of this disease remains elusive, and incidence in Australia continues to increase. Of the Australian jurisdictions, New South Wales (NSW) has the highest N. gonorrhoeae notifications, and over the five-year period 2015-2019, notifications in NSW have increased above the national average (by 116% versus 85%, respectively). Gonococcal disease control is reliant on effective antibiotic regimens. However, escalating AMR in N. gonorrhoeae is a global health priority, as the collateral injury of untreated infections has substantive impacts on sexual and newborn health. Currently, our first-line therapy for gonorrhoea is also our last line, with no ideal alternative identified. Despite some limitations, gentamicin is licensed and readily available in Australia, and is proposed for treatment of resistant N. gonorrhoeae in national guidelines; however, supportive published microbiological data are lacking. Analysis of gonococcal resistance patterns within Australia for the period 1991-2019, including 35,000 clinical isolates from NSW, illustrates the establishment and spread of population-level resistance to all contemporaneous therapies. An analysis of gentamicin susceptibility on 2,768 N. gonorrhoeae clinical isolates from NSW, for the period 2015-2020, demonstrates that the median minimum inhibitory concentration (MIC) for gentamicin in NSW has remained low, at 4.0 mg/L, and resistance was not detected in any isolate. There has been no demonstration of MIC drift over time (p = 0.91, Kruskal-Wallis test), nor differences in MIC distributions according to patients' sex or site of specimen collection. This is the first large-scale evaluation of gentamicin susceptibility in N. gonorrhoeae in Australia. No gentamicin resistance was detected in clinical isolates, 2015-2020, hence this is likely to be an available treatment option for resistant gonococcal infections in NSW.

Laying Waste to Mercury: Inexpensive Sorbents Made from Sulfur and Recycled Cooking Oils.

Mercury pollution threatens the environment and human health across the globe. This neurotoxic substance is encountered in artisanal gold mining, coal combustion, oil and gas refining, waste incineration, chloralkali plant operation, metallurgy, and areas of agriculture in which mercury-rich fungicides are used. Thousands of tonnes of mercury are emitted annually through these activities. With the Minamata Convention on Mercury entering force this year, increasing regulation of mercury pollution is imminent. It is therefore critical to provide inexpensive and scalable mercury sorbents. The research herein addresses this need by introducing low-cost mercury sorbents made solely from sulfur and unsaturated cooking oils. A porous version of the polymer was prepared by simply synthesising the polymer in the presence of a sodium chloride porogen. The resulting material is a rubber that captures liquid mercury metal, mercury vapour, inorganic mercury bound to organic matter, and highly toxic alkylmercury compounds. Mercury removal from air, water and soil was demonstrated. Because sulfur is a by-product of petroleum refining and spent cooking oils from the food industry are suitable starting materials, these mercury-capturing polymers can be synthesised entirely from waste and supplied on multi-kilogram scales. This study is therefore an advance in waste valorisation and environmental chemistry.

Postmortem structural studies of the thalamus in schizophrenia.

In this review, we seek to answer the following question: Do findings in the current literature support the idea that thalamo-cortical dysfunction in schizophrenia is due to structural abnormalities in the thalamus? We base our review on the existing literature of design-unbiased stereological studies of the postmortem thalamus from subjects with schizophrenia. Thus, all reported results are based upon the use of unbiased principles of sampling to determine volume and/or total cell numbers of thalamus or its constituent nuclei. We found 28 such papers covering 26 studies. In a series of tables we list all positive and negative findings from the total thalamus, the mediodorsal, pulvinar and anterior nuclei, as well as less frequently studied thalamic regions. Only four studies examined the entire thalamus and the results were inconsistent. We found largely consistent evidence for structural changes (reduced volume and cell numbers) in the pulvinar located in the posterior thalamus. In contrast, findings in the mediodorsal thalamic nucleus are inconsistent, with the largest and most recent studies generally failing to support earlier reports of a lower number of neurons in schizophrenia. Thus, the current findings of stereological studies of the thalamus in schizophrenia support the idea that thalamo-cortical dysfunction in schizophrenia might be attributable, at least in part, to structural alterations in the pulvinar that could impair thalamic inputs to higher order cortical association areas in the frontal and parietal lobes. However, more studies are needed before robust conclusions can be drawn.

Epidemiology, clinical features, diagnosis and treatment of Haemophilus ducreyi - a disappearing pathogen?

Chancroid, caused by Haemophilus ducreyi, has declined in importance as a sexually transmitted pathogen in most countries where it was previously endemic. The global prevalence of chancroid is unknown as most countries lack the required laboratory diagnostic capacity and surveillance systems to determine this. H. ducreyi has recently emerged as a cause of chronic skin ulceration in some South Pacific islands. Although no antimicrobial susceptibility data for H. ducreyi have been published for two decades, it is still assumed that the infection will respond successfully to treatment with recommended cephalosporin, macrolide or fluoroquinolone-based regimens. HIV-1-infected patients require careful follow-up due to reports of treatment failure with single dose regimens. Buboes may need additional treatment with either aspiration or excision and drainage.

High prevalence of ciprofloxacin-resistant gonorrhea among female sex workers in Kampala, Uganda (2008-2009).

BACKGROUND: Recent antimicrobial resistance data for Neisseria gonorrhoeae are lacking in Uganda, where, until 2010, ciprofloxacin was the nationally recommended first-line treatment of presumptive gonorrhea. This study assessed the antimicrobial susceptibility patterns of N. gonorrhoeae isolates cultured from female sex workers (FSWs) in Kampala. METHODS: Gonococci were isolated from endocervical specimens collected from women enrolled in a FSW cohort for 18 months (2008-2009). Minimum inhibitory concentrations for 7 antibiotics (ciprofloxacin, cefixime, ceftriaxone, azithromycin, spectinomycin, penicillin, and tetracycline) were determined for 148 isolates using Etest strips. The European Committee on Antimicrobial Susceptibility Testing version 1.3 clinical breakpoints were used to assign susceptibility categories. The 2008 World Health Organization N. gonorrhoeae panel was used for quality assurance purposes. RESULTS: For ciprofloxacin, 123 (83.1%) gonococcal isolates were resistant, 2 (1.4%) had intermediate susceptibility, and 23 (15.6%) were fully susceptible. All isolates were susceptible to ceftriaxone and spectinomycin, whereas 1 isolate (0.7%) was resistant to cefixime. For azithromycin, 124 isolates (83.8%) were susceptible, 20 (13.5%) had decreased susceptibility, and 4 (2.7%) were resistant. Most isolates were resistant to penicillin (101; 68.2%) and tetracycline (144; 97.3%). The minimum inhibitory concentration ranges for each antibiotic were as follows: ciprofloxacin (0.002-32 mg/L), ceftriaxone (≤0.002-0.064 mg/L), cefixime (≤0.016-0.38 mg/L), spectinomycin (2-24 mg/L), azithromycin (0.023-1 mg/L), penicillin (0.094-32 mg/L), and tetracycline (0.019-256 mg/L). CONCLUSIONS: The high prevalence of ciprofloxacin-resistant gonorrhea observed in Kampala-based FSW emphasizes the need for sustainable gonococcal antimicrobial resistance surveillance programs in Uganda and, in general, Africa.

Intracortical excitatory and thalamocortical boutons are intact in primary auditory cortex in schizophrenia.

Schizophrenia is associated with auditory processing impairments that could arise as a result of primary auditory cortex excitatory circuit pathology. We have previously reported a deficit in dendritic spine density in deep layer 3 of primary auditory cortex in subjects with schizophrenia. As boutons and spines can be structurally and functionally co-regulated, we asked whether the densities of intracortical excitatory or thalamocortical presynaptic boutons are also reduced. We studied 2 cohorts of subjects with schizophrenia and matched controls, comprising 27 subject pairs, and assessed the density, number, and within-bouton vesicular glutamate transporter (VGluT) protein level of intracortical excitatory (VGluT1-immunoreactive) and thalamocortical (VGluT2-immunoreactive) boutons in deep layer 3 of primary auditory cortex using quantitative confocal microscopy and stereologic sampling methods. We found that VGluT1- and VGluT2-immunoreactive puncta densities and numbers were not altered in deep layer 3 of primary auditory cortex of subjects with schizophrenia. Our results indicate that reduced dendritic spine density in primary auditory cortex of subjects with schizophrenia is not matched by a corresponding reduction in excitatory bouton density. This suggests excitatory boutons in primary auditory cortex in schizophrenia may synapse with structures other than spines, such as dendritic shafts, with greater frequency. The discrepancy between dendritic spine reduction and excitatory bouton preservation may contribute to functional impairments of the primary auditory cortex in subjects with schizophrenia.

Antimicrobial susceptibility of organisms causing community-acquired urinary tract infections in Gauteng Province, South Africa.

BACKGROUND: Patients with community-acquired urinary tract infections (UTIs) frequently present to healthcare facilities in South Africa (SA). AIM: To provide information on UTI aetiology and antimicrobial susceptibility of pathogens. METHODS: We recruited women with UTI-related symptoms, who tested positive for ≥2 urine dipstick criteria (proteinuria, blood, leucocytes or nitrites) at 1 public and 5 private primary healthcare facilities in 2011. Demographic and clinical data were recorded and mid-stream urine (MSU) specimens were cultured. UTI pathogens were Gram-stained and identified to species level. Etest-based antimicrobial susceptibility testing was performed for amoxicillin/clavulanic acid, cefixime, cefuroxime, ciprofloxacin, fosfomycin, levofloxacin, nitrofurantoin, norfloxacin and trimethoprim/sulphamethoxazole. RESULTS: Of the 460 women recruited, 425 MSU samples were processed and 204 UTI pathogens were identified in 201 samples. Most pathogens were Gram-negative bacilli (GNB) (182; 89.2%) and 22 (10.8%) were Gram-positive cocci (GPC). Escherichia coli was the most frequent GNB (160; 79.6%), while Enterococcus faecalis was the predominant GPC (8; 4.0%). The UTI pathogens had similar susceptibility profiles for fosfomycin (95.5%; 95% confidence interval (CI) 92.6 - 98.4), the 3 fluoroquinolones (94.1%; 95% CI 90.8 - 97.4), nitrofurantoin (91.7%; 95% CI 87.8 - 95.6), cefuroxime (90.1%; 95% CI 86.0 - 94.3) and cefixime (88.2%; 95% CI 83.7 - 92.6). UTI pathogens were less susceptible to amoxicillin/clavulanic acid (82.8%; 95% CI 77.5 - 88.0) when compared with fluoroquinolones and fosfomycin. Trimethoprim/ sulphamethoxazole was the least efficacious antimicrobial agent (44.3% susceptible; 95% CI 37.4 - 51.2). CONCLUSION: This study provides relevant data for the empirical treatment of community-acquired UTIs in SA.

Phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant Neisseria gonorrhoeae infection in South Africa and association with cefixime treatment failure.

OBJECTIVES: To describe the phenotypic and genetic characteristics of the first two cases of extended-spectrum cephalosporin (ESC)-resistant Neisseria gonorrhoeae in South Africa, one of which was associated with verified cefixime treatment failure. PATIENTS AND METHODS: Two ESC-resistant N. gonorrhoeae isolates were cultured from the urethral discharge of two men who have sex with men (MSM). One man reported a persistent urethral discharge that had failed to respond to previous therapy with oral cefixime. Agar dilution MICs were determined for eight antibiotics. ß-Lactam-associated resistance mutations were identified through PCR-based amplification and sequencing for several key genes: penA, mtrR and its promoter, porB1b (penB), ponA and pilQ. For molecular epidemiological characterization, full-length porB gene sequencing, N. gonorrhoeae multiantigen sequence typing (NG-MAST) and multilocus sequence typing (MLST) were performed. RESULTS: Both isolates were resistant to cefixime, ciprofloxacin, penicillin and tetracycline and intermediate/resistant to azithromycin, but susceptible to ceftriaxone, gentamicin and spectinomycin. Both isolates had the type XXXIV penA mosaic allele in addition to previously described resistance mutations in the mtrR promoter (A deletion), porB1b (penB) (G101K and A102N) and ponA1 (L421P). Both isolates had an identical NG-MAST sequence type (ST4822) and MLST sequence type (ST1901). CONCLUSIONS: Both isolates were resistant to cefixime and possessed a number of identical mutations in key genes contributing to ESC resistance in N. gonorrhoeae. The two isolates contained the type XXXIV penA mosaic allele and belonged to a successful international MSM-linked multidrug-resistant gonococcal clone (MLST ST1901) associated with several cefixime treatment failures in Europe and North America.

Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia.

OBJECTIVE: Individuals with schizophrenia exhibit disturbances in a number of cognitive, affective, sensory, and motor functions that depend on the circuitry of different cortical areas. The cognitive deficits associated with dysfunction of the dorsolateral prefrontal cortex result, at least in part, from abnormalities in GABA neurotransmission, as reflected in a specific pattern of altered expression of GABA-related genes. Consequently, the authors sought to determine whether this pattern of altered gene expression is restricted to the dorsolateral prefrontal cortex or could also contribute to the dysfunction of other cortical areas in subjects with schizophrenia. METHOD: Real-time quantitative polymerase chain reaction was used to assess the levels of eight GABA-related transcripts in four cortical areas (dorsolateral prefrontal cortex, anterior cingulate cortex, and primary motor and primary visual cortices) of subjects (N=12) with schizophrenia and matched normal comparison subjects. RESULTS: Expression levels of seven transcripts were lower in subjects with schizophrenia, with the magnitude of reduction for each transcript comparable across the four areas. The largest reductions were detected for mRNA encoding somatostatin and parvalbumin, followed by moderate decreases in mRNA expression for the 67-kilodalton isoform of glutamic acid decarboxylase, the GABA membrane transporter GAT-1, and the alpha 1 and delta subunits of GABA(A) receptors. In contrast, the expression of calretinin mRNA did not differ between the subject groups in any of the four areas. CONCLUSIONS: Because the areas examined represent the major functional domains (e.g., association, limbic, motor, and sensory) of the cerebral cortex, our findings suggest that a conserved set of molecular alterations affecting GABA neurotransmission contribute to the pathophysiology of different clinical features of schizophrenia.

Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction.

RATIONALE: Disturbances in critical cognitive processes, such as working memory, are now regarded as core features of schizophrenia, but available pharmacological treatments produce little or no improvement in these cognitive deficits. Although other explanations are possible, these cognitive deficits appear to reflect a disturbance in executive control, the processes that facilitate complex information processing and behavior and that include context representation and maintenance, functions dependent on the dorsolateral prefrontal cortex (DLPFC). Studies in non-human primates indicate that normal working memory function depends upon appropriate GABA neurotransmission in the DLPFC, and alterations in markers of GABA neurotransmission are well documented in the DLPFC of subjects with schizophrenia. OBJECTIVES: Thus, the purpose of this paper is to review the nature of the altered GABA neurotransmission in the DLPFC in schizophrenia, and to consider how these findings might inform the search for new treatments for cognitive dysfunction in this illness. RESULTS AND CONCLUSIONS: Postmortem studies suggest that markers of reduced GABA neurotransmission in schizophrenia may be selective for, or at least particularly prominent in, the subclass of GABA neurons, chandelier cells, that provide inhibitory input to the axon initial segment of populations of pyramidal neurons. Given the critical role that chandelier cells play in synchronizing the activity of pyramidal neurons, the pharmacological amelioration of this deficit may be particularly effective in normalizing the neural network activity required for working memory function. Because GABA(A) receptors containing the a(2) subunit are selectively localized to the axon initial segment of pyramidal cells, and appear to be markedly up-regulated in schizophrenia, treatment with novel benzodiazepine-like agents with selective activity at GABA(A) receptors containing the a(2) subunit may be effective adjuvant agents for improving working memory function in schizophrenia.

Cortical connections of the lateral mediodorsal thalamus in cynomolgus monkeys.

The prefrontal cortex has been defined as that cortical territory that has "essential or sustaining" connections with the mediodorsal (MD) nucleus of the thalamus. However, recent studies in the monkey have documented projections from MD to the more caudal, agranular regions of the frontal cortex, suggesting that the connections of MD may be characterized by a breadth of distribution and diversity of functional roles too great to be useful as a unifying and defining feature for a specific cortical territory. In this study, we placed tracer injections in the lateral divisions of MD in cynomolgus monkeys (Macaca fascicularis) to assess the relative proportions of connections devoted to diverse regions of the frontal cortex (FC). Three different patterns of label were observed in the cortex, associated with different locations within lateral MD. We have designated these as the ventrolateral MD-arcuate FC circuit, having most label in areas 8 and 6; the caudoventral MD-dorsomedial FC circuit, having most label in areas 24 and presupplementary motor area (SMA); and the anterodorsal MD-anterior FC circuit, with the most label in areas 9, 46, 12, and 10. Only two of the nine cases injected in lateral MD were predominantly connected with the anterior FC. Thus, particular locales within lateral MD are connected with multiple, functionally diverse cortical regions, including several not classically recognized as "prefrontal" areas. This divergence may distinguish MD-frontocortical and reciprocal corticothalamic pathways from the largely segregated pathways arising from the other thalamic nuclei that are interconnected with the frontal cortex, such as those from the ventrolateral nuclear group.

Effects of a mediodorsal thalamus lesion on prefrontal inhibitory circuitry: implications for schizophrenia.

BACKGROUND: Schizophrenia is associated with both reductions in prefrontal cortical (PFC) inhibitory markers and in neuron number in the mediodorsal thalamus (MDTN), which provides excitatory input to the PFC. To investigate the potential pathophysiologic relationship between these observations, we sought to provide experimental evidence that a reduction in MDTN neurons can produce decreased PFC glutamate decarboxylase (GAD(67)) mRNA expression. METHODS: Ibotenic acid was injected bilaterally into MDTN in rats. Four weeks later, thalamic lesion volumes were assessed stereologically, and PFC GAD(67) mRNA expression was measured using in situ hybridization. RESULTS: Selective MDTN lesions produced no changes in PFC GAD(67) mRNA expression, either overall or by cortical layer, and lesion volumes and GAD(67) mRNA expression were not correlated. CONCLUSIONS: In rats, a substantial lesion of MDTN neurons does not decrease PFC GAD(67) mRNA expression. These results do not support the hypothesis that decreased PFC GAD(67) mRNA expression in schizophrenia is attributable to a reduction in MDTN neuron number.

Specificity in the functional architecture of primate prefrontal cortex.

Multiple lines of evidence indicate that the performance of complex cognitive processes, such as those involving working memory, depend upon the functional properties of the circuitry of the prefrontal cortex (PFC). In primates, working memory has been proposed to be dependent upon the sustained activity of specific populations of PFC pyramidal cells, with this activity regulated by certain types of GABAergic interneurons. Thus, knowledge of the connectivity between PFC pyramidal cells and interneurons is crucial to the understanding the neural mechanisms that subserve working memory. This paper reviews recent findings that reveal specificity in the spatial organization, synaptic targets and postnatal development of pyramidal cells and interneurons in the primate prefrontal cortex, and considers the relevance of these findings for the neural circuitry that subserves working memory.