Implementation and impact of pediatric antimicrobial stewardship programs: a systematic scoping review.

Background: Antibiotics are the most common medicines prescribed to children in hospitals and the community, with a high proportion of potentially inappropriate use. Antibiotic misuse increases the risk of toxicity, raises healthcare costs, and selection of resistance. The primary aim of this systematic review is to summarize the current state of evidence of the implementation and outcomes of pediatric antimicrobial stewardship programs (ASPs) globally. Methods: MEDLINE, Embase and Cochrane Library databases were systematically searched to identify studies reporting on ASP in children aged 0-18 years and conducted in outpatient or in-hospital settings. Three investigators independently reviewed identified articles for inclusion and extracted relevant data. Results: Of the 41,916 studies screened, 113 were eligible for inclusion in this study. Most of the studies originated in the USA (52.2%), while a minority were conducted in Europe (24.7%) or Asia (17.7%). Seventy-four (65.5%) studies used a before-and-after design, and sixteen (14.1%) were randomized trials. The majority (81.4%) described in-hospital ASPs with half of interventions in mixed pediatric wards and ten (8.8%) in emergency departments. Only sixteen (14.1%) studies focused on the costs of ASPs. Almost all the studies (79.6%) showed a significant reduction in inappropriate prescriptions. Compliance after ASP implementation increased. Sixteen of the included studies quantified cost savings related to the intervention with most of the decreases due to lower rates of drug administration. Seven studies showed an increased susceptibility of the bacteria analysed with a decrease in extended spectrum beta-lactamase producers E. coli and K. pneumoniae; a reduction in the rate of P. aeruginosa carbapenem resistance subsequent to an observed reduction in the rate of antimicrobial days of therapy; and, in two studies set in outpatient setting, an increase in erythromycin-sensitive S. pyogenes following a reduction in the use of macrolides. Conclusions: Pediatric ASPs have a significant impact on the reduction of targeted and empiric antibiotic use, healthcare costs, and antimicrobial resistance in both inpatient and outpatient settings. Pediatric ASPs are now widely implemented in the USA, but considerable further adaptation is required to facilitate their uptake in Europe, Asia, Latin America and Africa

Experimental evidence of antiproton reflection by a solid surface

We report here experimental evidence of the reflection of a large fraction of a beam of low energy antiprotons by an aluminum wall. This derives from the analysis of a set of annihilations of antiprotons that come to rest in rarefied helium gas after hitting the end wall of the apparatus. A Monte Carlo simulation of the antiproton path in aluminum indicates that the observed reflection occurs primarily via a multiple Rutherford-style scattering on Al nuclei, at least in the energy range 1-10 keV where the phenomenon is most visible in the analyzed data. These results contradict the common belief according to which the interactions between matter and antimatter are dominated by the reciprocally destructive phenomenon of annihilation.Comment: 5 pages with 5 figure

COVID-19 and MIS-C treatment in children—results from an international survey

Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. In addition, access to COVID-19 therapeutics remains limited. Collecting physicians’ experiences with off-label use of therapeutics is important to inform global prioritization processes and better target pediatric research and development. A standardized questionnaire was designed to explore the use of therapeutics used to treat COVID-19 and multisystem inflammatory syndrome in children (MIS-C) in pediatric patients globally. Seventy-three physicians from 29 countries participated. For COVID-19, steroids were used by 75.6% of respondents; remdesivir and monoclonal antibodies were prescribed by 48.6% and 27.1% of respondents, respectively. For MIS-C, steroids were prescribed by 79.1% of respondents and intravenous immunoglobulins by 69.6%. The use of these products depended on their pediatric approval and the limited availability of antivirals and most monoclonal antibodies in Africa, South America, Southeast Asia, and Eastern Europe. Off-label prescription resulted widespread due to the paucity of clinical trials in young children at the time of the survey; though, based on our survey results, it was generally safe and led to clinical benefits. Conclusion: This survey provides a snapshot of current practice for treating pediatric COVID-19 worldwide, informing global prioritization efforts to better target pediatric research and development for COVID-19 therapeutics. Off-label use of such medicines is widespread for the paucity of clinical trials under 12 years and 40 kg, though appears to be safe and generally results in clinical benefits, even in young children. However, access to care, including medicine availability, differs widely globally. Clinical development of COVID-19 antivirals and monoclonal antibodies requires acceleration to ensure pediatric indication and allow worldwide availability of therapeutics that will enable more equitable access to COVID-19 treatment. What is Known: • Children have been mostly excluded from COVID-19 clinical trials, and, as a result, most medicines approved for COVID-19 have no pediatric indication. • Access to care differs widely globally, so because of the diversity of national healthcare systems; the unequal availability of medicines for COVID-19 treatment represents an obstacle to the pediatric population's universal right to health care. What is New: • Off-label COVID-19 drug prescription is widespread due to the lack of clinical trials in children younger than 12 years and weighing less than 40 kg, but relatively safe and generally leading to clinical benefit. • The application of the GAP-f framework to COVID-19 medicines is crucial, ensuring widespread access to all safe and effective drugs, enabling the rapid development of age-appropriate formulations, and developing specific access plans (including stability, storage, packaging, and labeling) for distribution in low- and middle-income countries (LMICs). Antivirals and monoclonal antibodies may benefit from the acceleration to reach widespread and equal diffusion

FoxO3a as a positive prognostic marker and a therapeutic target in Tamoxifen-resistant breast cancer

Background: Resistance to endocrine treatments is a major clinical challenge in the management of estrogen receptor positive breast cancers. Although multiple mechanisms leading to endocrine resistance have been proposed, the poor outcome of this subgroup of patients demands additional studies. Methods: FoxO3a involvement in the acquisition and reversion of tamoxifen resistance was assessed in vitro in three parental ER+ breast cancer cells, MCF-7, T47D and ZR-75-1, in the deriving Tamoxifen resistant models (TamR) and in Tet-inducible TamR/FoxO3a stable cell lines, by growth curves, PLA, siRNA, RT-PCR, Western blot, Immunofluorescence, Transmission Electron Microscopy, TUNEL, cell cycle, proteomics analyses and animal models. FoxO3a clinical relevance was validated in silico by Kaplan−Meier survival curves. Results: Here, we show that tamoxifen resistant breast cancer cells (TamR) express low FoxO3a levels. The hyperactive growth factors signaling, characterizing these cells, leads to FoxO3a hyper-phosphorylation and subsequent proteasomal degradation. FoxO3a re-expression by using TamR tetracycline inducible cells or by treating TamR with the anticonvulsant lamotrigine (LTG), restored the sensitivity to the antiestrogen and strongly reduced tumor mass in TamR-derived mouse xenografts. Proteomics data unveiled novel potential mediators of FoxO3a anti-proliferative and pro-apoptotic activity, while the Kaplan−Meier analysis showed that FoxO3a is predictive of a positive response to tamoxifen therapy in Luminal A breast cancer patients. Conclusions: Altogether, our data indicate that FoxO3a is a key target to be exploited in endocrine-resistant tumors. In this context, LTG, being able to induce FoxO3a, might represent a valid candidate in combination therapy to prevent resistance to tamoxifen in patients at risk

Multi-drug-resistant infections in the COVID-19 era: a framework for considering the potential impact

none3sinoneDona' D.; Di Chiara C.; Sharland M.Dona', D.; Di Chiara, C.; Sharland, M

Analysis of lower limb internal kinetics and electromyography in elite race walking.

The aim of this study was to analyse lower limb joint moments, powers and electromyography patterns in elite race walking. Twenty international male and female race walkers performed at their competitive pace in a laboratory setting. The collection of ground reaction forces (1000 Hz) was synchronised with two-dimensional high-speed videography (100 Hz) and electromyography of seven lower limb muscles (1000 Hz). As well as measuring key performance variables such as speed and stride length, normalised joint moments and powers were calculated. The rule in race walking which requires the knee to be extended from initial contact to midstance effectively made the knee redundant during stance with regard to energy generation. Instead, the leg functioned as a rigid lever which affected the role of the hip and ankle joints. The main contributors to energy generation were the hip extensors during late swing and early stance, and the ankle plantarflexors during late stance. The restricted functioning of the knee during stance meant that the importance of the swing leg in contributing to forward momentum was increased. The knee flexors underwent a phase of great energy absorption during the swing phase and this could increase the risk of injury to the hamstring muscles

SARS-CoV-2 testing and infection control strategies in European paediatric emergency departments during the first wave of the pandemic.

Between February and May 2020, during the first wave of the COVID-19 pandemic, paediatric emergency departments in 12 European countries were prospectively surveyed on their implementation of SARS-CoV-2 disease (COVID-19) testing and infection control strategies. All participating departments (23) implemented standardised case definitions, testing guidelines, early triage and infection control strategies early in the outbreak. Patient testing criteria initially focused on suspect cases and later began to include screening, mainly for hospital admissions. Long turnaround times for test results likely put additional strain on healthcare resources.Conclusion: Shortening turnaround times for SARS-CoV-2 tests should be a priority. Specific paediatric testing criteria are needed. What is Known: • WHO and public health authorities issued case definitions, testing and infection control recommendations for COVID-19 in January. • SARS-CoV-2 testing was made available across Europe in February. What is New: • Paediatric emergency departments implemented COVID-19-specific procedures rapidly, including case definitions, testing guidelines and early triage. • A third of surveyed departments waited more than 24 h for SARS-CoV-2 test to be reported, resulting in additional strain on resources

A new look at loop quantum gravity

I describe a possible perspective on the current state of loop quantum gravity, at the light of the developments of the last years. I point out that a theory is now available, having a well-defined background-independent kinematics and a dynamics allowing transition amplitudes to be computed explicitly in different regimes. I underline the fact that the dynamics can be given in terms of a simple vertex function, largely determined by locality, diffeomorphism invariance and local Lorentz invariance. I emphasize the importance of approximations. I list open problems.Comment: 15 pages, 5 figure

Flow angle from intermediate mass fragment measurements

Directed sideward flow of light charged particles and intermediate mass fragments was measured in different symmetric reactions at bombarding energies from 90 to 800 AMeV. The flow parameter is found to increase with the charge of the detected fragment up to Z = 3-4 and then turns into saturation for heavier fragments. Guided by simple simulations of an anisotropic expanding thermal source, we show that the value at saturation can provide a good estimate of the flow angle, $\Theta_{flow}$, in the participant region. It is found that $\Theta_{flow}$ depends strongly on the impact parameter. The excitation function of $\Theta_{flow}$ reveals striking deviations from the ideal hydrodynamical scaling. The data exhibit a steep rise of \Theta_{\flow} to a maximum at around 250-400 AMeV, followed by a moderate decrease as the bombarding energy increases further.Comment: 28 pages Revtex, 6 figures (ps files), to appear in Nucl.Phys.