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The World Health Organization developed the Tricycle surveillance programme to obtain a global picture of antimicrobial resistance, especially in countries with limited surveillance capacity. The programme was developed within a One Health perspective. Tricycle provides a framework for applying a standardized technical protocol to determining the prevalence of extended-spectrum [beta]-lactamase (ESBL)-producing Escherichia coli in three sectors: the human, animal and environment sectors. Regular use of the protocol would enable information to be obtained on time trends and on inter- and intraregional variations, thereby generating dynamic data on antibacterial resistance for decision-makers. To date, 19 countries have begun implementing the Tricycle protocol, while other countries will start implementation in the coming years. The Network for Enhancing Tricycle ESBL Surveillance Efficiency (NETESE) was established to support countries implementing the Tricycle protocol. Currently, NETESE includes representatives from 15 institutions in eight low- or middle-income countries at different stages of Tricycle protocol implementation, and from four European countries involved in devising the protocol. This paper describes the Tricycle protocol, reports the initial experiences of NETESE participants with its implementation and discusses future challenges and opportunities.

X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.

Cells build fatty acids with biocatalytic assembly lines in which a subset of enzymes often exhibit overlapping activities (e.g., two enzymes catalyze one or more identical reactions). Although the discrete enzymes that make up fatty acid pathways are well characterized, the importance of catalytic overlap between them is poorly understood. We developed a detailed kinetic model of the fatty acid synthase (FAS) of Escherichia coli and paired that model with a fully reconstituted in vitro system to examine the capabilities afforded by functional redundancy in fatty acid synthesis. The model captures—and helps explain—the effects of experimental perturbations to FAS systems and provides a powerful tool for guiding experimental investigations of fatty acid assembly. Compositional analyses carried out in silico and in vitro indicate that FASs with multiple partially redundant enzymes enable tighter (i.e., more independent and/or broader range) control of distinct biochemical objectives—the total production, unsaturated fraction, and average length of fatty acids—than FASs with only a single multifunctional version of each enzyme (i.e., one enzyme with the catalytic capabilities of two partially redundant enzymes). Maximal production of unsaturated fatty acids, for example, requires a second dehydratase that is not essential for their synthesis. This work provides a kinetic, control-theoretic rationale for the inclusion of partially redundant enzymes in fatty acid pathways and supplies a valuable framework for carrying out detailed studies of FAS kinetics.

DNA double-strand breaks (DSBs) are toxic forms of DNA damage that must be repaired to maintain genome integrity. Telomerase can act upon a DSB to create a de novo telomere, a process that interferes with normal repair and creates terminal deletions. We previously identified sequences in Saccharomyces cerevisiae (SiRTAs; Sites of Repair-associated Telomere Addition) that undergo unusually high frequencies of de novo telomere addition, even when the original chromosome break is several kilobases distal to the eventual site of telomerase action. Association of the single-stranded telomere binding protein Cdc13 with a SiRTA is required to stimulate de novo telomere addition. Because extensive resection must occur prior to Cdc13 binding, we utilized these sites to monitor the effect of proteins involved in homologous recombination. We find that telomere addition is significantly reduced in the absence of the Rad51 recombinase, while loss of Rad52, required for Rad51 nucleoprotein filament formation, has no effect. Deletion of RAD52 suppresses the defect of the rad51Δ strain, suggesting that Rad52 inhibits de novo telomere addition in the absence of Rad51. The ability of Rad51 to counteract this effect of Rad52 does not require DNA binding by Rad51, but does require interaction between the two proteins, while the inhibitory effect of Rad52 depends on its interaction with Replication Protein A (RPA). Intriguingly, the genetic interactions we report between RAD51 and RAD52 are similar to those previously observed in the context of checkpoint adaptation. Forced recruitment of Cdc13 fully restores telomere addition in the absence of Rad51, suggesting that Rad52, through its interaction with RPA-coated single-stranded DNA, inhibits the ability of Cdc13 to bind and stimulate telomere addition. Loss of the Rad51-Rad52 interaction also stimulates a subset of Rad52-dependent microhomology-mediated repair (MHMR) events, consistent with the known ability of Rad51 to prevent single-strand annealing.

Purpose To describe the current standards of care and major recent advances with regard to antimicrobial resistance (AMR) and to give a prospective overview for the next 30 years in this field. Methods Review of medical literature and expert opinion were used in the development of this review. Results There is undoubtedly a large clinical and public health burden associated with AMR in ICU, but it is challenging to quantify the associated excess morbidity and mortality. In the last decade, antibiotic stewardship and infection prevention and control have been unable to prevent the rapid spread of resistant Gram-negative bacteria (GNB), in particular carbapenem-resistant Pseudomonas aeruginosa (and other non-fermenting GNB), extended-spectrum β-lactamase (ESBL)-producing and carbapenem-resistant Enterobacteriaceae (CRE). The situation appears more optimistic currently for Gram-positive, where Staphylococcus aureus , and particularly methicillin-resistant S. aureus (MRSA), remains a cardinal cause of healthcare-associated infections worldwide. Recent advancements in laboratory techniques allow for a rapid identification of the infecting pathogen and antibiotic susceptibility testing. Their impact can be particularly relevant in settings with prevalence of MDR, since they may guide fine-tuning of empirically selected regimen, facilitate de-escalation of unnecessary antimicrobials, and support infection control decisions. Currently, antibiotics are the primary anti-infective solution for patients with known or suspected MDR bacteria in intensive care. Numerous incentives have been provided to encourage researchers to work on alternative strategies to reverse this trend and to provide a means to treat these pathogens. Although some promising antibiotics currently in phase 2 and 3 of development will soon be licensed and utilized in ICU, the continuous development of an alternative generation of compounds is extremely important. There are currently several promising avenues available to fight antibiotic resistance, such as faecal microbiota, and phage therapy.

Bloodstream infection (BSI) is defined by positive blood cultures in a patient with systemic signs of infection and may be either secondary to a documented source or primary—that is, without identified origin. Community-acquired BSIs in immunocompetent adults usually involve drug-susceptible bacteria, while healthcare-associated BSIs are frequently due to multidrug-resistant (MDR) strains. Early adequate antimicrobial therapy is a key to improve patient outcomes, especially in those with criteria for sepsis or septic shock, and should be based on guidelines and direct examination of available samples. Local epidemiology, suspected source, immune status, previous antimicrobial exposure, and documented colonization with MDR bacteria must be considered for the choice of first-line antimicrobials in healthcare-associated and hospital-acquired BSIs. Early genotypic or phenotypic tests are now available for bacterial identification and early detection of resistance mechanisms and may help, though their clinical impact warrants further investigations. Initial antimicrobial dosing should take into account the pharmacokinetic alterations commonly observed in ICU patients, with a loading dose in case of sepsis or septic shock. Initial antimicrobial combination attempting to increase the antimicrobial spectrum should be discussed when MDR bacteria are suspected and/or in the most severely ill patients. Source identification and control should be performed as soon as the hemodynamic status is stabilized. De-escalation from a broad-spectrum to a narrow-spectrum antimicrobial may reduce antibiotic selection pressure without negative impact on mortality. The duration of therapy is usually 5–8 days though longer durations may be discussed depending on the underlying illness and the source of infection. This narrative review covers the epidemiology, diagnostic workflow and therapeutic aspects of BSI in ICU patients and proposed up-to-date expert statements.

The underwater environment is more and more being depicted as particularly noisy, and the inventory of calling fishes is continuously increasing. However, it currently remains unknown how species share the soundscape and are able to communicate without misinterpreting the messages. Different mechanisms of interference avoidance have been documented in birds, mammals, and frogs, but little is known about interference avoidance in fishes. How fish thus partition the soundscape underwater remains unknown, as acoustic communication and its organization have never been studied at the level of fish communities. In this study, passive acoustic recordings were used to inventory sounds produced in a fish community (120 m depth) in an attempt to understand how different species partition the acoustic environment. We uncovered an important diversity of fish sounds, and 16 of the 37 different sounds recorded were sufficiently abundant to use in a quantitative analysis. We show that sonic activity allows a clear distinction between a diurnal and a nocturnal group of fishes. Moreover, frequencies of signals made during the day overlap, whereas there is a clear distinction between the different representatives of the nocturnal callers because of a lack of overlap in sound frequency. This first demonstration, to our knowledge, of interference avoidance in a fish community can be understood by the way sounds are used. In diurnal species, sounds are mostly used to support visual display, whereas nocturnal species are generally deprived of visual cues, resulting in acoustic constraints being more important. Significance More and more studies stress the potential deleterious effect of anthropogenic sounds on fish acoustic communication. Paradoxically, how the communication between fishes in a community is organized remains extremely poorly known, as studies using passive acoustic recordings are typically restricted to one or two species. At a single site, we were able to follow 16 different vertebrate sounds for 15 days. We demonstrate that the fish population can be distributed into two groups: one diurnal and one nocturnal. Most interestingly, fish calling at night do not show overlap at the level of the main calling frequency, in contrast to fish calling during the day. This shows that at night, in the absence of visual cues, sound communication is more important.

A well-recognized gap exists between evidence-based recommendations for post-fracture care and actual clinical practice, demonstrated by the high percentage of fragility fracture patients who are neither diagnosed nor treated for osteoporosis. Our purpose is to review fracture liaison service (FLS) models and to evaluate national and international experiences in secondary fracture prevention. We performed a systematic search of publication databases (MEDLINE, SCOPUS) and included randomized controlled trials, meta-analyses, and review articles using the following keywords: Fracture liaison services, Secondary prevention of fracture, Post-fracture healthcare gap, and fragility fractures. References were included from 2001-2015. We subsequently performed reference searches of retrieved articles and available literature was reviewed. The efficacy of secondary fracture prevention programs correlates strongly with their intensity. Type A FLS Models are most successful in initiating diagnostic and treatment plans for fragility fracture patients. Adoption of FLS programs improves care by lowering mortality and refracture rates while also lowering healthcare costs. The quality of evidence supporting associations between FLS programs and improved outcomes was moderately strong due to the availability of longitudinal data from nationalized health systems. As our population ages and challenges to the healthcare system loom ever larger, it is imperative that we fund and champion fracture liaison services. The fracture liaison service has recently emerged as a novel clinical approach that uses coordinated, multidisciplinary care to improve post-fracture outcomes and reduce recurrent fractures. These programs are simple, targeted, high-yield and have the potential to protect our most vulnerable patients. DXA = dual-energy x-ray absorptiometry FLS = fracture liaison service NCQA = National Committee of Quality Assurance NHS = National Health Service PCP = primary care physician PQRS = Physician Quality Reporting System QCDR = Qualified Clinical Data Registry.

To the Editor: A reference range for cerebrospinal fluid (CSF) opening pressure in children undergoing diagnostic lumbar puncture has not been established. 1 The influence of age, body-mass index (BMI), and depth of sedation on opening pressure in children is also uncertain. 2 We conducted a 2-year, single-center prospective study of CSF opening pressure in children undergoing lumbar puncture as part of their routine clinical care. Our objective was to establish a useful, clinically relevant reference range for opening pressure and a threshold value for abnormally elevated opening pressure (in the 90th percentile or higher, defined a priori). Our reference group consisted . . .

Prior work demonstrated differences in basal skin hydration related to skin tone parameter differences that included the melanin index (M), the erythema index (E), and the individual topology angle (ITA). The impact of these parameters on moisturization-induced hydration remains unclear. This study aimed to investigate whether basal skin tone influences moisturizer-related skin hydration. M, E, and ITA were measured bilaterally at multiple anterior forearm sites of 30 young adults. The percentage water content (PWC) was determined by measuring the skin's dielectric constant to depths of 0.5 mm (PWC5) and 2.5 mm. PWC measurements were done before and four hours after applying four different humectant moisturizers. Analyses were conducted using the whole group and subgroups divided according to values below and above the median values for M, E, and ITA. The whole group PWC increased at both depths. At 0.5 mm, it increased from its baseline of 46.4±10.2 to 51.5±9.1 (p < 0.001), a 12.6±11.3% increase. At 2.5 mm, PWC increased from its baseline of 39.1±6.6 to 40.6±6.1 (p < 0.001), a 4.2±5.7% increase. Both subgroups increased at 0.5 mm. However, percentage increases in PWC tended to be greater for subgroups with lower M and E and higher ITA. Considering gender, only males showed a significant positive correlation between the change in PWC5 and ITA (r = 0.584, p = 0.028), whereas females exhibited a uniform, non-skin tone-dependent response. The findings suggest that lighter skin tones (higher ITA) may be associated with greater moisturizer-induced skin hydration. However, the differential gender responses may also indicate that male-female differences are involved and warrant further study.