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Existing mRNA COVID-19 vaccines have shown efficacy in reducing severe cases and fatalities. However, their effectiveness against infection caused by emerging SARS-CoV-2 variants has waned considerably, necessitating the development of variant vaccines. Ideally, next-generation vaccines will be capable of eliciting broader and more sustained immune responses to effectively counteract new variants. Additionally, in vitro assays that more closely represent virus neutralization in humans would greatly assist in the analysis of protective vaccine-induced antibody responses. Here, we present findings from a SARS-CoV-2 VLP vaccine encompassing three key structural proteins: Spike (S), Envelope (E), and Membrane (M). The VLP vaccine effectively produced neutralizing antibodies as determined by surrogate virus neutralization test, and induced virus-specific T-cell responses: predominantly CD4+, although CD8+ T cell responses were detected. T cell responses were more prominent with vaccine delivered with AddaVax compared to vaccine alone. The adjuvanted vaccine was completely protective against live virus challenge in mice. Furthermore, we utilized air–liquid-interface (ALI)-differentiated human nasal epithelium (HNE) as an in vitro system, which authentically models human SARS-CoV-2 infection and neutralization. We show that immune sera from VLP-vaccinated mice completely neutralized SARS-CoV-2 virus infection, demonstrating the potential of ALI-HNE to assess vaccine induced Nab.

Abstract Objectives Type 1 laryngeal clefts (LC1) and deep interarytenoid grooves contribute to pediatric feeding disorders. Management of these defects remains heterogeneous among surgeons and interarytenoid injection augmentation (IIA) is not always offered as a treatment option. This study evaluated IIA outcomes among a pediatric patient cohort comprised mostly of those with deep interarytenoid grooves. Methods A single‐institution retrospective chart review featured children under the age of 5 years presenting for aspiration, dysphagia, or choking. Over the period of 7 years (January 2014–October 2021), 39 met inclusion criteria and had sufficient follow‐up data. Descriptive statistics and subgroup analyses were performed. Results Of the 39 included patients, 76.92% had clinical improvement post‐injection, with the mean time to follow‐up being 47 days. Within the deep interarytenoid groove group, improvement rates were 82.76%. Bronchoscopy findings revealed 29 (74.36%) patients with a DIG, 3 (7.69%) with LC1, 3 (7.69%) with no anatomic abnormality, and 4 (10.26%) with vocal cord paralysis. There were no adverse events. There were no associations with the outcomes based on subgroup analysis and logistic regression. Conclusions IIA is an effective and safe treatment for pediatric feeding disorders. No covariates were associated with symptom improvement. Within the deep interarytenoid groove diagnosis subgroup, IIA effectively improved symptoms. Further investigations are needed to explore predictors of success with IIA in this population. Level of Evidence VI.

Understanding the dynamic behaviour of ice shelves, specifically the controls on their ability to buttress the flow of ice into the ocean, is critical for predicting future ice-sheet contributions to sea level rise. Many large ice shelves, which are predominantly composed of meteoric ice, have a basal layer of marine ice (formed from accumulated platelets at the ice–ocean interface), comprising up to 40% of their thickness locally. Differences in temperature, chemistry and microstructure between marine and meteoric ice mean the rheological properties of the ice vary throughout the ice shelf. These differences are not explicitly accounted for in ice-sheet modelling applications, and may have an important influence on ice shelf dynamics. We tested the sensitivity of a model of an idealised ice shelf to variations in temperature distribution and flow enhancement, and found that incorporating a realistic thermal profile (where the marine ice layer is isothermal) had an order of magnitude greater effect on ice mass flux and thinning than incorporating the mechanical properties of the marine ice. The presence of marine ice at the ice shelf base has the potential to significantly increase deviatoric stresses at the surface and ice mass flux across the front of an ice shelf.

Murashige-Skoog medium solutions have been used in a variety of plant plate growth assays, yet most research uses Arabidopsis thaliana as the study organism. For larger seeds such as maize (Zea mays), most protocols employ a paper towel roll method for experiments, which often involves wrapping maize seedlings in wet, sterile germination paper. What the paper towel roll method lacks, however, is the ability to image the roots over time without risk of contamination. Here, we describe a sterile plate growth assay that contains Murashige-Skoog medium to grow seedlings starting two days after germination. This protocol uses a section of a paper towel roll method to achieve uniform germination of maize seedlings, which are sterilely transferred onto large acrylic plates for the duration of the experiment. The media can undergo modification to include an assortment of plant hormones, exogenous sugars, and other chemicals. The acrylic plates allow researchers to freely image the plate without disturbing the seedlings and control the environment in which the seedlings are grown, such as modifications in temperature and light. Additionally, the protocol is widely adaptable for use with other cereal crops.Key features• Builds upon plate growth methods routinely used for Arabidopsis seedlings but that are inadequate for maize.• Real-time photographic analysis of seedlings up to two weeks following germination.• Allows for testing of various growth conditions involving an assortment of additives and/or modification of environmental conditions.• Samples are able to be collected for genotype screening.Graphical overview

Abstract Background SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials. Methods ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined. Discussion This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions. Trial registration Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

Adaptive clinical trials have designs that evolve over time because of changes to treatments or changes to the chance that participants will receive these treatments. These changes might introduce confounding that biases crude comparisons of the treatment arms and makes the results from standard reporting methods difficult to interpret for adaptive trials. To deal with this shortcoming, a reporting framework for adaptive trials was developed based on concurrently randomised cohort reporting. A concurrently randomised cohort is a subgroup of participants who all had the same treatments available and the same chance of receiving these treatments. The reporting of pre-randomisation characteristics and post-randomisation outcomes for each concurrently randomised cohort in the study is recommended. This approach provides a transparent and unbiased display of the degree of baseline balance and the randomised treatment comparisons for adaptive trials. The key concepts, terminology, and recommendations underlying concurrently randomised cohort reporting are presented, and its routine use in adaptive trial reporting is advocated.

The development of virus-like particle (VLP) based vaccines for human papillomavirus, hepatitis B and hepatitis E viruses represented a breakthrough in vaccine development. However, for dengue and COVID-19, technical complications, such as an incomplete understanding of the requirements for protective immunity, but also limitations in processes to manufacture VLP vaccines for enveloped viruses to large scale, have hampered VLP vaccine development. Selecting the right adjuvant is also an important consideration to ensure that a VLP vaccine induces protective antibody and T cell responses. For diseases like COVID-19 and dengue fever caused by RNA viruses that exist as families of viral variants with the potential to escape vaccine-induced immunity, the development of more efficacious vaccines is also necessary. Here, we describe the development and characterisation of novel VLP vaccine candidates using SARS-CoV-2 and dengue virus (DENV), containing the major viral structural proteins, as protypes for a novel approach to produce VLP vaccines. The VLPs were characterised by Western immunoblot, enzyme immunoassay, electron and atomic force microscopy, and in vitro and in vivo immunogenicity studies. Microscopy techniques showed proteins self-assemble to form VLPs authentic to native viruses. The inclusion of the glycolipid adjuvant, α-galactosylceramide (α-GalCer) in the vaccine formulation led to high levels of natural killer T (NKT) cell stimulation in vitro, and strong antibody and memory CD8+ T cell responses in vivo, demonstrated with SARS-CoV-2, hepatitis C virus (HCV) and DEN VLPs. This study shows our unique vaccine formulation presents a promising, and much needed, new vaccine platform in the fight against infections caused by enveloped RNA viruses.

Loggerhead turtles are a globally vulnerable species of marine turtle. Broad-scale patterns of distribution and abundance can provide regional managers a tool to effectively conserve and manage this species at basin and sub-basin scales. In this study, combined aerial and shipboard line transect survey data collected between 2003 and 2018 were used to estimate distribution and abundance throughout the Mediterranean Sea. Approximately 230,000 linear kilometers of survey effort, from seven different surveying organizations were incorporated into a generalized additive model to relate loggerhead density on survey segments to environmental conditions. Two spatial density models estimating loggerhead density, abundance, and distribution were generated – one a long-term annual average covering 2003-2018 and another covering the summer of 2018, when a basin-wide aerial survey, the Agreement on the Conservation of Cetaceans of the Black Sea, Mediterranean Sea and Contiguous Atlantic Area Survey Initiative, was performed. Both models were adjusted for availability bias using dive data from loggerhead turtles tagged with time depth recorders. Mean abundance for the long-term average model was estimated as 1,201,845 (CV=0.22). The summer 2018 abundance estimate was 789,244 turtles and covered a smaller area than the long-term average. These estimates represent the first basin-wide estimates of abundance for loggerhead turtles in the Mediterranean not based on demographic models. Both models predicted similar distributions, with higher abundance predicted in the northern Adriatic Sea, central Mediterranean basin, Tyrrhenian Sea, and south of the Balearic Islands. Lower densities were predicted in the eastern Mediterranean Sea and the Aegean Sea. The highest density areas generally did not coincide with previously established adult loggerhead turtle foraging areas, which are typically neritic, indicating the models are predominantly predicting oceanic distributions, where most of the survey effort occurred. Juvenile loggerhead turtles are predominantly oceanic and comprise most of the population, but care must be taken when using these models as they may not accurately predict distribution of neritic foraging areas, where subadult and adult loggerheads can often be found. Despite this limitation, these models represent a major step forward for conservation planning and understanding basin-wide distribution and abundance patterns of this species.

Objective:. Middle to distal-third clavicular shaft fractures are commonly treated with precontoured anterior plating. Some surgeons use mini-fragment plate fixation and position these plates on the anterior clavicle. Recent studies demonstrated the advantages of anterior clavicle plating, including a possible biomechanical advantage with cantilever bending forces and less subsequent implant removal. The insertion and positioning of anteriorly based clavicle plates requires the release of a portion of the anterior deltoid origin from the lateral clavicle. The purpose of this study is to evaluate the anatomy of the deltoid in relation to the clavicle and to determine the percentage of the deltoid origin released to place modern anterior precontoured plates. Methods:. Six right and 4 left cadaver shoulders were dissected, each from separate cadaveric specimens (6 male and 4 female). All measurements were made with digital calipers. The length of the clavicle was measured from the acromioclavicular joint to the sternoclavicular joint. The length of deltoid origin on the lateral clavicle was measured from the acromioclavicular joint to the most medial attachment of the deltoid on the clavicle. Percentage of clavicle with deltoid origin was subsequently calculated. Results:. The average length of the cadaveric clavicles was 164.4 mm with a range from 134.3 to 178.1 mm. The average amount of deltoid origin on the clavicle was 58.7 mm with a range from 43.4 to 69 mm. On average 35.5% of the clavicle had deltoid origin, with a range from 30.2% to 38.8%. Conclusion:. On average, 35.5% of the clavicular osseous anatomy contains deltoid origin. This should be taken into consideration when performing anterior plating for clavicle fractures. With a significant portion of deltoid origin elevated, surgeons may consider altering postoperative protocols until some interval healing has occurred to this anterior head of the deltoid.

Optical biosensing is being actively investigated for minimally-invasive monitoring of key biomarkers both $in~ vitro$ and $in~ vivo$ . However, typical benchtop instruments are not portable and are not well suited to high-throughput, real-time analysis. This paper presents a versatile multichannel instrument for measurement of emission intensity and lifetime values arising from luminescent biosensor materials. A detailed design description of the opto-electronic hardware as well as the control software is provided, elaborating a flexible, user-configurable system that may be customized or duplicated for a wide range of applications. This article presents experimental measurements that prove the $in~ vitro$ and $in ~vivo$ functionality of the system. Such tools may be adopted for many research and development purposes, including evaluation of new biosensor materials, and may also serve as prototypes for future miniaturized handheld or wearable devices.

Background: There is a growing body of recent literature regarding the occurrence of pseudotumors associated with modular junctions and various bearing surfaces after total hip arthroplasty (THA). Revision surgery is often technically challenging and high complication rates have been reported. The optimal management of these patients and outcomes after operative treatment remain poorly understood. Methods: We report the case of a 77-year-old male with progressive unilateral lower extremity swelling, pain, and neuropathy 9 years after revision THA for polyethylene liner wear. Imaging and biopsy confirmed a massive intrapelvic pseudotumor exerting compressive effects. Radiographs demonstrated extensive femoral and pelvic osteolysis without evidence of component loosening. Debulking of the intrapelvic portion of the pseudotumor was performed via the lateral window of the ilioinguinal approach with component retention. Results: Debulking of the intrapelvic mass resulted in resolution of symptoms. One year postoperatively the patient reported pain free ambulation using a walker and no recurrence of symptoms. Radiographs demonstrated stable THA components in comparison with preoperative films. Discussion and Conclusion: This case demonstrates a rare finding of intrapelvic pseudotumor causing neurovascular compression after revision THA. Clinicians should be aware of intrapelvic pseudotumor as a possible cause of limb swelling and neuropathy, and that debulking of the mass is a potential treatment option in the setting of well-fixed implants.

Populations of invasive alien plants create disruptive plant communities that are extremely adaptable, imposing severe ecological impacts on agriculture, biodiversity and human activities. To minimise these impacts, prevention and effective weed management strategies are urgently required, including the identification of satellite populations before they invade new areas. This is a critical element that allows weed management practices to become both successful and cost-effective. Mimosa pigra L. (Giant sensitive plant) is an invasive weed that has spread across various environments around the world and is considered one of the world’s top 100 most invasive plant species. Being adaptable to a wide range of soil types, in addition to its woody protective prickles and low palatability, M. pigra has quickly spread and established itself in a range of habitats. Current control methods of this species include biological, chemical and physical methods, together with attempts of integrated application. Reports suggest that integrated management appears to be the most effective means of controlling M. pigra since the use of any single method has not yet proved suitable. In this regard, this review synthesises and explores the available global literature and current research gaps relating to the biology, distribution, impacts and management of M. pigra. The contribution of this work will help guide land managers to design appropriate and sustainable management programs to control M. pigra.

Objective: Describe primary pharmacokinetic/pharmacodynamic (PK/PD) parameters of vancomycin and meropenem in pediatric patients undergoing ECMO and analyze utilized dosing to reach PK/PD target.Design: Prospective, multicentric, population PK analysis.Setting: Two hospitals with pediatric intensive care unit.Patients: Pediatric patients (1 month - 15 years old) receiving vancomycin and meropenem for empiric or definitive infection treatment while ECMO support.Measurements and Main Results: Four serum concentration were obtained for patients receiving vancomycin (n = 9) and three for meropenem (n = 9). The PK/PD target for vancomycin was a ratio of the area under the curve to the minimal inhibitory concentration (AUC/MIC) of >400, and for meropenem was 4 times above MIC for 50% of the dosing interval (fT50% > 4xMIC). Pharmacokinetic modeling was performed using PMetrics 1.5.0. We included nine patients, with 11 PK profiles for each antimicrobial. The median age of patients was 4 years old (2 months - 13 years) and 45% were male. Creatinine clearance (CL) was 183 (30–550) ml/min/1.73 m2. The median dose was 13.6 (range 10–15) mg/kg every 6–12 h and 40 mg/kg every 8–12 h for vancomycin and meropenem, respectively. Two compartment models were fitted. Weight was included as a covariate on volume of the central compartment (Vc) for meropenem. Weight was included as a covariate on both Vc and clearance (CL) and serum creatinine was also included as a covariate on CL for vancomycin. The pharmacokinetic parameters CL and Vc were 0.139 ± 0.102 L/h/kg and 0.289 ± 0.295 L/kg for meropenem and 0.060 ± 0.055 L/h/kg and 0.419 ± 0.280 L/kg for vancomycin, respectively. Across each dosing interval 91% of patients achieved the PK/PD targets for adequate exposure for meropenem and 63.6% for vancomycin.Conclusion: Pharmacokinetic/pharmacodynamic objectives for vancomycin were achieved partially with conventional doses and higher dosing with extended infusion were needed in the case of meropenem.

Abstract Objectives To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. Trial design ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. Participants Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently. Intervention and comparator Participants will be randomised 1:1:1:1 to: Group 1: standard of care; Group 2: lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form; Group 3: hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days; Group 4: lopinavir /ritonavir plus hydroxychloroquine. Main outcomes Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated. Randomisation The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have individual participant allocation provided through a web-based trial enrolment platform. Blinding (masking) This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required. Numbers to be randomised (sample size) We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required sample size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 2440. Trial Status ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021. Trial registration Australian New Zealand Clinical Trials Registry ( ACTRN12620000445976 ). Prospectively registered April 6, 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

ABSTRACT The severity of diseases, the complexity of treatment, and the use of medical devices in the intensive care unit (ICU) may change the pharmacokinetics (PK) profile of antibiotics among critically ill patients.This narrative review aims to explain the PK profile of critically ill patients compared to other group of patients and to describe the pharmacokinetic-pharmacidynamic (PK-PD) target attainment among this group of patients. Only articles published less than 10 years ago were included in this narrative review. Evidences have indicated that critically ill patients have relatively larger volume distribution (Vd) of hydrophilic antibiotics compared to patients with stable conditions. The fluid shifting to interstitial space, hypoalbuminemia, and aggressive fluid treatment may contribute to the increase value of Vd in critically ill patients. The clearance (CL) of hydrophilic antibiotics in critically ill patients is highly determined by dynamic changing of renal function compared to patients in other wards. The phenomenon of augmented renal clearance and the use of high intensity of renal replacement therapy can increase the CL of hydrophilic antibiotics. The different PK profile of antibiotics may lead to the failure of attaining the PK-PD target if the dose of antibiotics is not adjusted according to such differences. ABSTRAK Tingkat keparahan penyakit yang relatif tinggi dibandingkan pasien di bangsal rawat lain dan penggunaan terapi serta alat medis yang relatif lebih kompleks di ruang intensive care unit (ICU) dapat berdampak pada perubahan profil farmakokinetik (PK) antibiotik pada pasien kritis. Tujuan utama kajian naratif ini adalah untuk memaparkan profil PK dan ketercapaian target farmakokinetik-farmakodinamik (PK-PD) pasien kritis di ICU. Hanya artikel yang diterbitkan dalam kurun waktu 10 tahun terakhir yang digunakan dalam kajian naratif ini. Bukti penelitian menunjukkan bahwa volume distribusi (Vd) antibiotik hidrofilik pada pasien kritis lebih besar dibandingkan dengan pasien yang relatif lebih stabil atau subyek sehat. Perpindahan cairan intravaskuler ke daerah interstitial, hipoalbuminemia, dan terapi cairan khususnya yang diberikan secara agresif merupakan faktor yang berkontribusi terhadap peningkatan Vd pada pasien kritis. Clearance (CL) antibiotik hidrofilik pada pasien kritis ditentukan oleh perubahan fungsi ginjal yang relatif lebih dinamis dibandingkan dengan pasien di ruang rawat inap lain. Fenomena augmented renal clearance yang umum dijumpai pada pasien kritis dan penggunaan renal replacement therapy dengan intensitas yang tinggi dapat meningkatkan CL antibiotik hidrofilik. Perbedaan profil PK tersebut berpotensi menyebabkan kegagalan untuk mencapai target PK-PD apabila tidak dilakukan penyesuaian dosis antibiotik pada pasien kritis. Identifikasi profil PK perlu diupayakan sebagai langkah awal untuk mengoptimalkan pemberian antibiotik pada kelompok pasien kritis.

The intrusion of weeds into fertile areas has resulted in significant global economic and environmental impacts on agricultural production systems and native ecosystems, hence without ongoing and repeated management actions, the maintenance or restoration of these systems will become increasingly challenging. The establishment of herbicide resistance in many species and unwanted pollution caused by synthetic herbicides has ushered in the need for alternative, eco-friendly sustainable management strategies, such as the use of bioherbicides. Of the array of bioherbicides currently available, the most successful products appear to be sourced from fungi (mycoherbicides), with at least 16 products being developed for commercial use globally. Over the last few decades, bioherbicides sourced from bacteria and plant extracts (such as allelochemicals and essential oils), together with viruses, have also shown marked success in controlling various weeds. Despite this encouraging trend, ongoing research is still required for these compounds to be economically viable and successful in the long term. It is apparent that more focused research is required for (i) the improvement of the commercialisation processes, including the cost-effectiveness and scale of production of these materials; (ii) the discovery of new production sources, such as bacteria, fungi, plants or viruses and (iii) the understanding of the environmental influence on the efficacy of these compounds, such as atmospheric CO2, humidity, soil water stress, temperature and UV radiation.

Abstract Background Standard dosing of meropenem (2 g t.i.d.) produces CSF concentrations of only 1–2 mg/L which is inferior to the clinical breakpoint for most Gram-negative bacteria. There is therefore concern that dosing must be increased in order to achieve therapeutic CSF concentrations for bacteria with susceptibility close to clinical breakpoints. Yet, the effects of high-dose meropenem on CSF concentrations are not well described in literature. We therefore determined meropenem CSF-levels in a patient who was treated with 15 g/day of meropenem. Case presentation Our patient suffered from a brain trauma and an external ventricular drainage was implanted. Later, a carbapenemase-producing Acinetobacter baumannii (OXA-23, NDM-1) was isolated from blood cultures and CSF. The MIC for meropenem was > 32 mg/L (R), and we opted for a combination therapy of meropenem, colistin and fosfomycin. Meropenem was given at an unusual high-dose (15 g/day) with the aim of achieving high CSF concentrations. CSF concentrations peaked at 64 mg/L. Yet, the patient succumbed to an intracranial bleed into a preexisting cerebral contusion. Conclusions High-dose meropenem can achieve CSF levels largely superior to those achieved with commonly recommended dosing regimens. Though our patient succumbed to an intracranial bleed which could be regarded as a severe adverse event, we suggest that meropenem dosing can be increased when pathogens with increased MICs are found in the CSF. More in vivo data are however needed to determine the safety of high-dose meropenem.

Kenya is highly dependent on precipitation for both food and water security. Farmers and pastoralists rely on rain to provide water for crops and vegetation to feed herds. As such, precipitation forecasts can be useful tools to inform decision makers and potentially allow the preparation for such events as drought. This study assessed the predictability of a seasonal forecast (CFSv2) and a short-term precipitation forecast (CHIRPS-GEFS) over Kenya. The short-term forecast was assessed on its ability to predict the onset date of the rainy season, and the skill of the seasonal forecast in predicting abnormal precipitation patterns. CHIRPS-GEFS provided a useful starting point to estimate the onset date, but during the long rains in the southwest, where agriculture is concentrated, differences between the predicted and actual onset dates were large (over 20 days). Assessments for CFSv2 generally displayed lower forecast skill over highlands and coastal regions at a seasonal scale. The CFSv2 forecast skill varied widely over individual months and lead times, but over whole rainy seasons, CFSv2 was more skillful than a random forecast at all lead times in the major agricultural areas of Kenya. This research fills a critical research and application gap in understanding the forecast precipitation skill for onset and sub-seasonal prediction.

Abstract Background Antimicrobial Stewardship Programs (ASPs) have been promoted to optimize antimicrobial usage and patient outcomes, and to reduce the emergence of antimicrobial-resistant organisms. However, the best strategies for an ASP are not definitively established and are likely to vary based on local culture, policy, and routine clinical practice, and probably limited resources in middle-income countries. The aim of this study is to evaluate structures and resources of antimicrobial stewardship teams (ASTs) in surgical departments from different regions of the world. Methods A cross-sectional web-based survey was conducted in 2016 on 173 physicians who participated in the AGORA (Antimicrobials: A Global Alliance for Optimizing their Rational Use in Intra-Abdominal Infections) project and on 658 international experts in the fields of ASPs, infection control, and infections in surgery. Results The response rate was 19.4%. One hundred fifty-six (98.7%) participants stated their hospital had a multidisciplinary AST. The median number of physicians working inside the team was five [interquartile range 4–6]. An infectious disease specialist, a microbiologist and an infection control specialist were, respectively, present in 80.1, 76.3, and 67.9% of the ASTs. A surgeon was a component in 59.0% of cases and was significantly more likely to be present in university hospitals (89.5%, p

Jellyfish outbreaks are increasingly viewed as a deterministic response to escalating levels of environmental degradation and climate extremes. However, a comprehensive understanding of the influence of deterministic drivers and stochastic environmental variations favouring population renewal processes has remained elusive. This study quantifies the deterministic and stochastic components of environmental change that lead to outbreaks of the jellyfish Pelagia noctiluca in the Mediterranen Sea. Using data of jellyfish abundance collected at 241 sites along the Catalan coast from 2007 to 2010 we: (1) tested hypotheses about the influence of time-varying and spatial predictors of jellyfish outbreaks; (2) evaluated the relative importance of stochastic vs. deterministic forcing of outbreaks through the environmental bootstrap method; and (3) quantified return times of extreme events. Outbreaks were common in May and June and less likely in other summer months, which resulted in a negative relationship between outbreaks and SST. Cross- and along-shore advection by geostrophic flow were important concentrating forces of jellyfish, but most outbreaks occurred in the proximity of two canyons in the northern part of the study area. This result supported the recent hypothesis that canyons can funnel P. noctiluca blooms towards shore during upwelling. This can be a general, yet unappreciated mechanism leading to outbreaks of holoplanktonic jellyfish species. The environmental bootstrap indicated that stochastic environmental fluctuations have negligible effects on return times of outbreaks. Our analysis emphasized the importance of deterministic processes leading to jellyfish outbreaks compared to the stochastic component of environmental variation. A better understanding of how environmental drivers affect demographic and population processes in jellyfish species will increase the ability to anticipate jellyfish outbreaks in the future.

The escalation of serious infections in critically ill patients over the past 25 years has continued despite advances in contemporary medicine. Ongoing research to reduce the high morbidity and mortality rates is mandated. ?-lactam antibiotics are often used empirically in serious infections. The efficacy of these time-dependent antibiotics is correlated with the time that concentrations are maintained above the minimum inhibitory concentration of the infective pathogen. In critically ill patients, pathophysiological changes can reduce antibiotic concentrations and thus alternative modes of administration such as continuous infusion have been studied and shown to standardize ?-lactam pharmacokinetics and meet pharmacodynamic targets. Clinical data supporting the efficacy of continuous infusion are currently scarce, but data continue to grow. Likewise antibiotic resistance continues to grow. Recent data suggest that poor dosing strategies may be contributing to this problem, which is exacerbated by a lack of development of alternate antibiotics. Suffice to say clinicians must use antibiotic regimens that optimally treat the individual patient and reduce the development of antibiotic resistance. [ABSTRACT FROM AUTHOR]