Non-Adherence in Adult Male Patients with Community-Acquired Pneumonia: Relative Forgiveness of Amoxicillin versus Respiratory Fluoroquinolones

The consequences of non-adherence to treatment (NAT) on antimicrobial efficacy may depend on drug forgiveness—a property that should account for pharmacokinetics (PK) and pharmacodynamics (PD) as well as interindividual variability. In this simulation study, relative forgiveness (RF) in NAT, defined as the probability of a successful PK/PD target (PTA) attained under perfect adherence compared to imperfect adherence, was evaluated for amoxicillin (AMOX) (oral 1000 mg/8 h) and two respiratory fluoroquinolones—levofloxacin (LFX) (oral 750 mg/24 h) and moxifloxacin (MOX) (oral 400 mg/24 h)—in virtual outpatients with community-acquired pneumonia for S. pneumoniae. Several NAT scenarios (delay in dose intake and a missed dose) were considered. PK characteristics of virtual patients, including variability in creatinine clearance (70–131 mL/min) and S. pneumoniae susceptibility variability associated with geographical location, were simulated in NAT. In this regard, in regions of low MIC delays from 1 h to 7 h or omission of dose ingestion would not have negative consequences on the efficacy of AMOX because of its good RF associated with the AMOX PK and PD properties; RF of LFX 750 mg or MOX 400 mg/24 h regimen vs. AMOX 1000 mg/8 h is one. However, in regions of elevated MIC for S. pneumoniae AMOX loses its RF, LFX and MOX vs. AMOX, showing higher RF (>1) depending on the CLCR of patients. These results illustrate the importance of considering the RF of antimicrobial drugs in NAT and provide a framework for further studying its implications for clinical success rates

Transcription factor Pebbled/RREB1 regulates injury-induced axon degeneration

Genetic studies of Wallerian degeneration have led to the identification of signaling molecules (e.g., dSarm/Sarm1, Axundead, and Highwire) that function locally in axons to drive degeneration. Here we identify a role for the Drosophila C2H2 zinc finger transcription factor Pebbled [Peb, Ras-responsive element binding protein 1 (RREB1) in mammals] in axon death. Loss of Peb in Drosophila glutamatergic sensory neurons results in either complete preservation of severed axons, or an axon death phenotype where axons fragment into large, continuous segments, rather than completely disintegrate. Peb is expressed in developing and mature sensory neurons, suggesting it is required to establish or maintain their competence to undergo axon death. peb mutant phenotypes can be rescued by human RREB1, and they exhibit dominant genetic interactions with dsarm mutants, linking peb/RREB1 to the axon death signaling cascade. Surprisingly, Peb is only able to fully block axon death signaling in glutamatergic, but not cholinergic sensory neurons, arguing for genetic diversity in axon death signaling programs in different neuronal subtypes. Our findings identify a transcription factor that regulates axon death signaling, and peb mutant phenotypes of partial fragmentation reveal a genetically accessible step in axon death signaling

Hyperbolic Space Cosmologies

We present a systematic study of accelerating cosmologies obtained from M/string theory compactifications of hyperbolic spaces with time-varying volume. A set of vacuum solutions where the internal space is a product of hyperbolic manifolds is found to give qualitatively the same accelerating four-dimensional FLRW universe behavior as a single hyperbolic space. We also examine the possibility that our universe is a hyperbolic space and provide exact Milne type solutions, as well as intersecting S-brane solutions. When both the usual 4D spacetime and the m-dimensional internal space are hyperbolic, we find eternally accelerating cosmologies for $m\geq 7$, with and without form field backgrounds. In particular, the effective potential for a magnetic field background in the large 3 dimensions is positive definite with a local minimum and thus enhances the eternally accelerating expansion.Comment: 33 pages, 2 figures; v2 refs added; v3 minor change in text, JHEP versio

Nanoscale-confined Terahertz Polaritons in a van der Waals Crystal

Electromagnetic field confinement is crucial for nanophotonic technologies, since it allows for enhancing light-matter interactions, thus enabling light manipulation in deep sub-wavelength scales. In the terahertz (THz) spectral range, radiation confinement is conventionally achieved with specially designed metallic structures - such as antennas or nanoslits - with large footprints due to the rather long wavelengths of THz radiation. In this context, phonon polaritons - light coupled to lattice vibrations - in van der Waals (vdW) crystals have emerged as a promising solution for controlling light beyond the diffraction limit, as they feature extreme field confinements and low optical losses. However, experimental demonstration of nanoscale-confined phonon polaritons at THz frequencies has so far remained elusive. Here, we provide it by employing scattering-type scanning near-field optical microscopy (s-SNOM) combined with a free-electron laser (FEL) to reveal a range of low-loss polaritonic excitations at frequencies from 8 to 12 THz in the vdW semiconductor ${\alpha}-MoO_3$. We visualize THz polaritons with i) in-plane hyperbolic dispersion, ii) extreme nanoscale field confinement (below ${\lambda}_o/75$) and iii) long polariton lifetimes, with a lower limit of > 2 ps

Trends analysis of specialized palliative care services in 51 countries of the WHO European region in the last 14 years

Background: Service provision is a key domain to assess national-level palliative care development. Three editions of the European Association for Palliative Care (EAPC) Atlas of Palliative Care monitored the changes in service provision across Europe since 2005. Aim: To study European trends of specialized service provision at home care teams, hospital support teams, and inpatient palliative care services between 2005 and 2019. Design: Secondary analysis was conducted drawing from databases on the number of specialized services in 2005, 2012, and 2019. Ratios of services per 100,000 inhabitants and increase rates on number of services for three periods were calculated. Analysis of variance (ANOVA) analyses were conducted to determine significant changes and chi-square to identify countries accounting for the variance. Income-level and sub-regional ANOVA analysis were undertaken. Setting: 51 countries. Results: Forty-two countries (82%) increased the number of specialized services between 2005 and 2019 with changes for home care teams (104% increase-rate), inpatient services (82%), and hospital support teams (48%). High-income countries showed significant increase in all types of services (p < 0.001), while low-to-middle-income countries showed significant increase only for inpatient services. Central–Eastern European countries showed significant improvement in home care teams and inpatient services, while Western countries showed significant improvement in hospital support and home care teams. Home care was the most prominent service in Western Europe. Conclusion: Specialized service provision increased throughout Europe, yet ratios per 100,000 inhabitants fell below the EAPC recommendations. Western Europe ratios’ achieved half of the suggested services, while Central–Eastern countries achieved only a fourth. High-income countries and Western European countries account for the major increase. Central–Eastern Europe and low-to-middle-income countries reported little increase on specialized service provision

Developing and implementing an integrated delirium prevention system of care:a theory driven, participatory research study

Background: Delirium is a common complication for older people in hospital. Evidence suggests that delirium incidence in hospital may be reduced by about a third through a multi-component intervention targeted at known modifiable risk factors. We describe the research design and conceptual framework underpinning it that informed the development of a novel delirium prevention system of care for acute hospital wards. Particular focus of the study was on developing an implementation process aimed at embedding practice change within routine care delivery. Methods: We adopted a participatory action research approach involving staff, volunteers, and patient and carer representatives in three northern NHS Trusts in England. We employed Normalization Process Theory to explore knowledge and ward practices on delirium and delirium prevention. We established a Development Team in each Trust comprising senior and frontline staff from selected wards, and others with a potential role or interest in delirium prevention. Data collection included facilitated workshops, relevant documents/records, qualitative one-to-one interviews and focus groups with multiple stakeholders and observation of ward practices. We used grounded theory strategies in analysing and synthesising data. Results: Awareness of delirium was variable among staff with no attention on delirium prevention at any level; delirium prevention was typically neither understood nor perceived as meaningful. The busy, chaotic and challenging ward life rhythm focused primarily on diagnostics, clinical observations and treatment. Ward practices pertinent to delirium prevention were undertaken inconsistently. Staff welcomed the possibility of volunteers being engaged in delirium prevention work, but existing systems for volunteer support were viewed as a barrier. Our evolving conception of an integrated model of delirium prevention presented major implementation challenges flowing from minimal understanding of delirium prevention and securing engagement of volunteers alongside practice change. The resulting Prevention of Delirium (POD) Programme combines a multi-component delirium prevention and implementation process, incorporating systems and mechanisms to introduce and embed delirium prevention into routine ward practices. Conclusions: Although our substantive interest was in delirium prevention, the conceptual and methodological strategies pursued have implications for implementing and sustaining practice and service improvements more broadly