Cefotaxime/sulbactam plus gentamicin as a potential carbapenem- and amikacin-sparing first-line combination for neonatal sepsis in high ESBL prevalence settings

BACKGROUND: Infection with ESBL-producing Enterobacteriaceae infection is ubiquitous in some neonatal ICUs and increasing levels of antibiotic resistance are a cause for urgent concern. Delineation of bacterial and viral sepsis can be challenging, often leading to patients receiving empirical antibiotics without or whilst waiting for a definitive causal diagnosis. Empirical therapy is often dependent on broad-spectrum ‘Watch’ antibiotics, contributing to further resistance. METHODS: ESBL-producing Enterobacteriaceae clinical isolates found to have caused neonatal sepsis and meningitis underwent a detailed in vitro screening including susceptibility testing, chequerboard combination analysis and hollow-fibre infection model dynamic analyses using combinations of cefotaxime, ampicillin and gentamicin in combination with β-lactamase inhibitors. RESULTS: Additivity or synergy was found for all antibiotic combinations against seven Escherichia coli and three Klebsiella pneumoniae clinical isolates. Cefotaxime or ampicillin plus sulbactam combined with gentamicin was able to consistently inhibit the growth of ESBL-producing isolates at typical neonatal doses, and the combination cleared the hollow-fibre infection model system of organisms resistant to each agent alone. The combination of cefotaxime/sulbactam and gentamicin was consistently bactericidal at clinically achievable concentrations (Cmax of 180, 60 and 20 mg/L for cefotaxime, sulbactam and gentamicin, respectively). CONCLUSIONS: The addition of sulbactam to cefotaxime or ampicillin to the typical first-line empirical therapy could obviate the need for carbapenems and amikacin in settings with high ESBL-infection prevalence

Strong Casimir force reduction through metallic surface nanostructuring

The Casimir force between bodies in vacuum can be understood as arising from their interaction with an infinite number of fluctuating electromagnetic quantum vacuum modes, resulting in a complex dependence on the shape and material of the interacting objects. Becoming dominant at small separations, the force plays a significant role in nanomechanics and object manipulation at the nanoscale, leading to a considerable interest in identifying structures where the Casimir interaction behaves significantly different from the well-known attractive force between parallel plates. Here we experimentally demonstrate that by nanostructuring one of the interacting metal surfaces at scales below the plasma wavelength, an unexpected regime in the Casimir force can be observed. Replacing a flat surface with a deep metallic lamellar grating with sub-100 nm features strongly suppresses the Casimir force and for large inter-surfaces separations reduces it beyond what would be expected by any existing theoretical prediction.Comment: 11 pages, 8 figure

Cefotaxime/sulbactam plus gentamicin as a potential carbapenem- and amikacin-sparing first-line combination for neonatal sepsis in high ESBL prevalence settings.

BACKGROUND: Infection with ESBL-producing Enterobacteriaceae infection is ubiquitous in some neonatal ICUs and increasing levels of antibiotic resistance are a cause for urgent concern. Delineation of bacterial and viral sepsis can be challenging, often leading to patients receiving empirical antibiotics without or whilst waiting for a definitive causal diagnosis. Empirical therapy is often dependent on broad-spectrum 'Watch' antibiotics, contributing to further resistance. METHODS: ESBL-producing Enterobacteriaceae clinical isolates found to have caused neonatal sepsis and meningitis underwent a detailed in vitro screening including susceptibility testing, chequerboard combination analysis and hollow-fibre infection model dynamic analyses using combinations of cefotaxime, ampicillin and gentamicin in combination with β-lactamase inhibitors. RESULTS: Additivity or synergy was found for all antibiotic combinations against seven Escherichia coli and three Klebsiella pneumoniae clinical isolates. Cefotaxime or ampicillin plus sulbactam combined with gentamicin was able to consistently inhibit the growth of ESBL-producing isolates at typical neonatal doses, and the combination cleared the hollow-fibre infection model system of organisms resistant to each agent alone. The combination of cefotaxime/sulbactam and gentamicin was consistently bactericidal at clinically achievable concentrations (Cmax of 180, 60 and 20 mg/L for cefotaxime, sulbactam and gentamicin, respectively). CONCLUSIONS: The addition of sulbactam to cefotaxime or ampicillin to the typical first-line empirical therapy could obviate the need for carbapenems and amikacin in settings with high ESBL-infection prevalence

Differentiating Prodromal Dementia with Lewy Bodies from Prodromal Alzheimer’s Disease: A Pragmatic Review for Clinicians

\ua9 The Author(s) 2024.This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer’s disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)—parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners

Risk factors for suicide in Bali: a psychological autopsy study

<p>Abstract</p> <p>Background</p> <p>The suicide rate in Bali has significantly increased in recent years. However, to date, there have been no case-control studies investigating risk factors for suicide.</p> <p>Methods</p> <p>A psychological autopsy study was conducted comparing 60 suicide cases and 120 living controls matched in age, sex, and area of residence.</p> <p>Results</p> <p>Multiple logistic regression analysis identified the following risk factors for suicide: at least one diagnosis of axis-I mental disorder (OR: 14.84 CI: 6.12 - 35.94); low level of religious involvement (OR: 7.24 CI: 2.28 - 22.95); and severe interpersonal problems (OR: 3.86 CI: 1.36 - 11.01). Forty-eight (80.0%) of the suicide cases were diagnosed with mental disorders; however, only 16.7% visited a primary care health professional and none received psychiatric treatment during the 1 month prior to death.</p> <p>Conclusion</p> <p>Clinical, religious, and psychosocial factors were associated with suicide. These results highlight the significance of early recognition and treatment of mental disorders, religious activities, and interpersonal problem-solving strategies for suicide prevention in Bali.</p

A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

Multiparticle azimuthal correlations for extracting event-by-event elliptic and triangular flow in Au + Au collisions at sNN =200 GeV

We present measurements of elliptic and triangular azimuthal anisotropy of charged particles detected at forward rapidity 1&lt;|η|&lt;3 in Au + Au collisions at sNN=200 GeV, as a function of centrality. The multiparticle cumulant technique is used to obtain the elliptic flow coefficients v2{2},v2{4},v2{6}, and v2{8}, and triangular flow coefficients v3{2} and v3{4}. Using the small-variance limit, we estimate the mean and variance of the event-by-event v2 distribution from v2{2} and v2{4}. In a complementary analysis, we also use a folding procedure to study the distributions of v2 and v3 directly, extracting both the mean and variance. Implications for initial geometrical fluctuations and their translation into the final-state momentum distributions are discussed

Beam Energy and Centrality Dependence of Direct-Photon Emission from Ultrarelativistic Heavy-Ion Collisions.

The PHENIX collaboration presents first measurements of low-momentum (0.41  GeV/c) direct-photon yield dN_{γ}^{dir}/dη is a smooth function of dN_{ch}/dη and can be well described as proportional to (dN_{ch}/dη)^{α} with α≈1.25. This scaling behavior holds for a wide range of beam energies at the Relativistic Heavy Ion Collider and the Large Hadron Collider, for centrality selected samples, as well as for different A+A collision systems. At a given beam energy, the scaling also holds for high p_{T} (&gt;5  GeV/c), but when results from different collision energies are compared, an additional sqrt[s_{NN}]-dependent multiplicative factor is needed to describe the integrated-direct-photon yield

Nonperturbative transverse-momentum-dependent effects in dihadron and direct photon-hadron angular correlations in p+p collisions at s =200 GeV

Dihadron and isolated direct photon-hadron angular correlations are measured in p+p collisions at s=200 GeV. The correlations are sensitive to nonperturbative initial-state and final-state transverse momenta kT and jT in the azimuthal nearly back-to-back region Δφ∼π. To have sensitivity to small transverse momentum scales, nonperturbative momentum widths of pout, the out-of-plane transverse-momentum component perpendicular to the trigger particle, are measured. In this region, the evolution of pout can be studied when several different hard scales are measured. These widths are used to investigate possible effects from transverse-momentum-dependent factorization breaking. When accounting for the longitudinal-momentum fraction of the away-side hadron with respect to the near-side trigger particle, the widths are found to increase with the hard scale; this is qualitatively similar to the observed behavior in Drell-Yan and semi-inclusive deep-inelastic scattering interactions, where factorization is predicted to hold. The momentum widths are also studied as a function of center-of-mass energy by comparing to previous measurements at s=510 GeV. The nonperturbative jet widths also appear to increase with s at a similar xT, which is qualitatively consistent to similar measurements in Drell-Yan interactions. Future detailed global comparisons between measurements of processes where transverse-momentum-dependent factorization is predicted to hold and be broken will provide further insight into the role of color in hadronic interactions