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Antoni Torres,1 Alex Soriano,2 Simone Rivolo,3 Edit Remak,4 Carmen Peral,5 Michal Kantecki,6 Wajeeha Ansari,7 Claudie Charbonneau,8 Jennifer Hammond,9 Santiago Grau,10 Mark Wilcox11 1Servei de Pneumologia Hospital Clinic, University of Barcelona, IDIPAPS, CIBERES, ICREA, Barcelona, Spain; 2Hospital Clínic of Barcelona,University of Barcelona, IDIBAPS, Barcelona, Spain; 3Modeling and Simulation, Evidera, London, UK; 4Formerly Modeling and Simulation, Evidera, Budapest, Hungary; 5Health Economics and Outcomes Research, Pfizer, Madrid, Spain; 6Global Medical Affairs, Pfizer, Paris, France; 7Patient & Health Impact, Pfizer, New York, NY, USA; 8Patient & Health Impact, Pfizer, Paris, France; 9Global Product Development, Pfizer, Collegeville, PA, USA; 10Hospital del Mar,Universitat Pompeu Fabra, Barcelona, Spain; 11University of Leeds, Leeds, UKCorrespondence: Wajeeha Ansari, Tel +1 212 733 5001, Email wajeeha.ansari@pfizer.comPurpose: Complicated skin and soft tissue infections (cSSTI) are associated with high healthcare resource use and costs. The emergency nature of cSSTI hospitalizations requires starting immediate empiric intravenous (IV) antibiotic treatment, making the appropriate choice of initial antibiotic therapy crucial.Patients and Methods: The use of ceftaroline fosamil (CFT) as an alternative to other IV antibiotic therapies for the empiric treatment of hospitalized adults with cSSTI (vancomycin, linezolid, daptomycin, cloxacillin, tedizolid) was evaluated through cost consequences analysis. The model structure was a decision tree accounting for four different pathways: patients demonstrating early response (ER) either discharged early (with oral antibiotic) or remaining in hospital to continue the initial therapy; non-responders either remaining on the initial IV therapy or switching to a second-line antibiotic. The model perspective was the Spanish National Health System.Results: CFT resulted in average percentage of patients discharged early (PDE) of 24.6% (CI 19.49– 30.2%) with average total cost per patient of € 6763 (€ 6268–€ 7219). Vancomycin, linezolid, daptomycin and tedizolid resulted in average PDE of 22% (17.34– 27.09%), 26.4% (20.5– 32.32%), 28.6% (22.08– 35.79%) and 26.5% (20.39– 33.25%), respectively, for a total cost per patient of € 6,619 (€ 5,902–€ 6,929), € 6,394 (€ 5,881–€ 6,904), € 6,855 (€ 5,800–€ 7,410) and € 7,173 (€ 6,608–€ 7,763), respectively. Key model drivers were ER and antibiotic treatment duration, with hospital costs accounting for over 83% of the total expenditures.Conclusion: Given its clinical and safety profile, CFT is an acceptable choice for cSSTI empiric therapy providing comparable ER and costs to other relevant antibiotic options.Keywords: complicated skin and soft tissue infection, cost-consequences, Spain, ceftaroline fosamil

In vitro models of the human colon have been used extensively in developing understanding of the human gut microbiome and how internal and external factors affect the residing bacterial populations. Such models can be highly predictive of in vivo effects of antibiotics, and indeed more so than animal models. The complexity required by current in vitro models to closely mimic the physiology of the colon poses practical limits on their scalability. MiGut allows considerable expansion of model runs, increasing the capacity to test reproducibility or parameters under investigation. The MiGut platform has been assessed against a well-studied triple-stage chemostat model in a demanding nine-week study, with exposure to multiple antibiotics inducing a state of dysbiosis in the microbiome. A good correlation is found, both between individual MiGut models and against the triple-stage chemostat. Together with high-throughput molecular techniques for sample analysis, it is now conceivable that tens of in vitro models could be run simultaneously, allowing complex microbiome-xenobiotic interactions to be explored in far greater detail. MiGut is a unique platform whereby multiple colonic models can be run simultaneously with minimal added resource and complexity to support our understanding of the cause-effect relationships that govern the gut microbiome. This model system expands the capacity to generate clinically relevant data that can optimize interventions which target the gut microbiome directly or indirectly.

C. difficile, an anaerobic spore-forming intestinal pathogen, produces up to three toxins that cause host cell damage resulting in disease, C. difficileinfection (CDI). Therapies include antibiotic treatment; however, up to 30% of cases fail primary therapy, resulting in recurrent disease, which increases patient morbidity and places a burden on worldwide healthcare systems. We have little understanding of why these therapies fail. Using a clinically validated in vitro gut model, we assess the contribution of biofilms towards recurrent disease and to investigate biofilm microbiota-C. difficile interactions. During induction of simulated CDI, C. difficile spores and vegetative cells became associated with the colonic biofilm microbiota. Vancomycin treatment did not effectively remove the biofilm C. difficile cells and recurrent infection was observed. Additionally, vancomycin therapy followed by faecal microbiota transplant did resolve the recurrent infection, but the biofilm C. difficile cells remained unaffected. In a biofilm transfer experiment, we showed that transferring biofilm encased C. difficile cells into a C. difficile naïve (but CDI susceptible model) induced CDI. Furthermore, we show that members of the biofilm community can impact C. difficile biofilm formation either acting in an antagonistic or synergistic manner. We highlight the importance of biofilms as a reservoir for C. difficile, which can be a cause for recurrent infections.

Many factors shape the human intestinal microbiota, some of which can confer a deleterious effect on the microbiota, e.g. antibiotic therapy. Disruption to the microbiota has been implicated in the progression of C. difficile infection (CDI), multiplication of multi-drug resistant organisms and many extra-intestinal diseases. Thus, determining the off-target effects of antibiotics is essential to determine a patient’s risk of these diseases, particularly for new therapies. Here we characterise the effect of sarecycline, a novel tetracycline antibiotic for the treatment of moderate to severe acne vulgaris; and compared its effect to the gut microbiota with other acne treatments. Using four independent in vitro gut models, we exposed the human microbiota to either sarecycline, minocycline, doxycycline, or clindamycin, and monitored the changes to the bacterial populations, and whether these changes were sufficient to induce CDI. Sarecycline or doxycycline exposure caused a temporary reduction in the bacterial diversity upon initial exposure. Sarecycline exposure was characterised by a transient increase in Enterococcus spp. and Enterobacteriaceae, and a decrease in Bifidobacterium spp. Doxycycline exposure caused longer-term changes to the Lactobacillaceae and Ruminococcaceae populations. Minocycline exposure resulted in a dramatic reduction to the bacterial diversity, with extensive expansions to the Enterococcus spp. and Enterobacteriaceae populations, whilst the Lactobacillaceae and Ruminococcaceae populations contracted. Whilst clindamycin did induce simulated CDI, neither sarecycline, minocycline, nor doxycycline created a niche conducive for CDI. These data show that long-term sarecycline use has a lower potential for disruption of the colonic microbiota, compared with the current treatments for acne vulgaris.

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0-1 at 90-120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than -5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63-83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2·1% [95% CI - 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment INTERPRETATION: Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

The failure of depleted bivalve populations to recover naturally is often due to a breakdown in recruitment processes, such as a lack of larvae or suitable settlement substrate. The identification of these recruitment limitations are a critical initial step for determining an appropriate strategy for restoration. A lack of larval supply and settlement substrate have both been suggested as possible causes of the failure of natural recovery in the green‐lipped mussel population in the Hauraki Gulf, New Zealand, and were therefore examined in this study. Larval mussels settled throughout most of the year directly onto artificial collectors placed within restored adult mussel beds and in the immediate vicinity of the beds at comparatively lower levels than for remnant populations throughout New Zealand. This low settlement coupled with a lack of recruitment to the restored mussel beds suggests larval supply may be limited in the Hauraki Gulf and warrants further examinations into larval dispersal and retention. Larval settlement was also higher on collectors within mussel beds, suggesting the presence of adults enhances larval settlement and highlights the importance of transplanting adult mussels for reestablishing mussel populations.

STUDY QUESTION What is the association between serum progesterone levels on the day of frozen embryo transfer (FET) and the probability of live birth in women undergoing different FET regimens? SUMMARY ANSWER Overall, serum progesterone levels WHAT IS KNOWN ALREADY Progesterone is essential for pregnancy success. A recent systematic review showed that in FET cycles using vaginal progesterone for endometrial preparation, lower serum progesterone levels ( STUDY DESIGN, SIZE, DURATION This was a multicentre (n = 8) prospective cohort study conducted in the UK between January 2020 and February 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS We included women having NC-FET or HRT-FET treatment with progesterone administration by any available route. Women underwent venepuncture on the day of embryo transfer. Participants and clinical personnel were blinded to the serum progesterone levels. We conducted unadjusted and multivariable logistic regression analyses to investigate the association between serum progesterone levels on the day of FET and treatment outcomes according to the type of cycle and route of exogenous progesterone administration. Our primary outcome was the live birth rate per participant. MAIN RESULTS AND THE ROLE OF CHANCE We studied a total of 402 women. The mean (SD) serum progesterone level was 14.9 (7.5) ng/ml. Overall, the mean adjusted probability of live birth increased non-linearly from 37.6% (95% CI 26.3–48.9%) to 45.5% (95% CI 32.1–58.9%) as serum progesterone rose between the 10th (7.8 ng/ml) and 90th (24.0 ng/ml) centiles. In comparison to participants whose serum progesterone level was ≥7.8 ng/ml, those with lower progesterone ( LIMITATIONS, REASONS FOR CAUTION The final sample size was smaller than originally planned, although our study was adequately powered to confidently identify a difference in live birth between optimal and inadequate progesterone levels. Furthermore, our cohort did not include women receiving oral or rectal progestogens. WIDER IMPLICATIONS OF THE FINDINGS Our results corroborate existing evidence suggesting that lower serum progesterone levels hinder FET success. However, the relationship between serum progesterone and the probability of live birth appears to be non-linear in women receiving exclusively subcutaneous progesterone, suggesting that in this subgroup of women, high serum progesterone may also be detrimental to treatment success. STUDY FUNDING/COMPETING INTERESTS This work was supported by CARE Fertility and a doctoral research fellowship (awarded to P.M.) by the Tommy’s Charity and the University of Birmingham. M.J.P. is supported by the NIHR Birmingham Biomedical Research Centre. S.F. is a minor shareholder of CARE Fertility but has no financial or other interest with progesterone testing or manufacturing companies. P.L. reports personal fees from Pharmasure, outside the submitted work. G.P. reports personal fees from Besins Healthcare, outside the submitted work. M.W. reports personal fees from Ferring Pharmaceuticals, outside the submitted work. The remaining authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER ClinicalTrials.gov: NCT04170517.

Background: Various factors, including treatment protocols, can influence the outcomes of frozen embryo transfers (FETs). The study objectives were to compare different endometrial preparation protocols of FET cycles and to evaluate the factors, including the endometrial thickness (ET), that affect outcomes. Methods: This observational cohort study involved 5037 women undergoing FETs at eight tertiary clinics in the UK between January 2016 and March 2019. The endometrial preparation protocols used were natural cycle (NC-FETs), artificial hormone support cycle with oestradiol valerate but without pituitary downregulation (AC-FETs) and artificial hormone support cycle with agonist downregulation (ACDR-FETs). Results: The mean (±SD) ages across NC-FET, AC-FET and ACDR-FET groups were 36.5 (±4.2), 35.9 (±5.0) and 36.4(±4.9) years, respectively. LBRs were comparable (40.7%, 175/430; 36.8%, 986/2658; and 36.7%, 716/1949, respectively) across the three groups. Clinical pregnancy, implantation, multiple pregnancies, miscarriage and ectopic pregnancy rates were also similar. In the regression analysis of variables including age, duration of infertility, number of embryos transferred, protocol type and endometrial thickness, age was the only significant predictor of LBRs, although its predictive ability was poor (AUC: 0.55). With the overall LBR of the study population being 37.1%, the post-test probability of a live birth at an ET of

In three phase III randomized controlled trials, ceftaroline fosamil was shown to be non-inferior to vancomycin plus aztreonam for the treatment of complicated skin and soft tissue infections (cSSTIs). This exploratory analysis evaluated the impact of underlying comorbidities on clinical outcomes in patients with cSSTI pooled from these three studies.CANVAS 1 and 2 and COVERS evaluated ceftaroline fosamil (600 mg every 12 h [q12h]; 600 mg every 8 h [q8h; COVERS]) versus vancomycin plus aztreonam (1 g q12h each [CANVAS 1 and 2]; vancomycin 15 mg/kg q12h and aztreonam 1 g q8h [COVERS]) in hospitalized adults with cSSTI. The primary efficacy variable in each trial was clinical response at the test-of-cure (TOC) visit. Subgroup analyses were performed on the pooled clinically evaluable (CE) population, exploring the impact of age and various baseline comorbidities.Overall, 1808 patients were included in the CE population (1005 ceftaroline fosamil; 803 vancomycin plus aztreonam). Clinical cure rates at TOC were 89.7% (ceftaroline fosamil) and 90.8% (vancomycin plus aztreonam) (difference [95% confidence interval] - 1.13 [- 3.87, 1.67]). Clinical response rates were similar between treatment groups, regardless of age (≤ 65 years or 65 years), and in subgroups of patients with and without diabetes mellitus, peripheral vascular disease, cancer/malignancy, renal impairment, and obesity; within these subgroups, efficacy and safety results were generally consistent with those of the overall cSSTI population.This analysis provides supportive evidence of the efficacy of ceftaroline fosamil in patients with cSSTI and underlying comorbidities.CANVAS 1, NCT00424190 and CANVAS 2, NCT00423657 (both trials first posted on ClinicalTrials.gov 18/01/2007); COVERS, NCT01499277 (first posted on ClinicalTrials.gov 26/12/2011).

We aimed to characterize Clostridioides difficile isolates cultured during a six-month single-center study from stool samples of patients with C. difficile infection (CDI) genotyped by the Xpert® C. difficile/Epi assay by polymerase chain reaction (PCR) ribotyping, toxin genes’ detection and multi-locus variable number tandem repeats analysis (MLVA). The susceptibility to metronidazole, vancomycin and moxifloxacin was determined by agar dilution. In addition, the presence of Thr82Ile in the GyrA and a single nucleotide deletion at position (Δ117) in the tcdC gene were investigated. Between January 1 and June 30, 2016, of 114 CDIs, 75 cases were genotyped as presumptive PCR ribotype (RT) 027 infections using a commercial assay. C. difficile isolates cultured from presumptive RT027 stool samples belonged to RT176. These isolates carried genes for toxin A (tcdA), B (tcdB), binary (cdtA/B) and had Δ117 in the tcdC gene. Using MLVA, the 71/75 isolates clustered into two clonal complexes (CCs). Of these, 39 isolates (54.9%) were from patients hospitalized in acute care and 32 isolates (45.1%) were isolated from patients hospitalized in the long-term care department. All isolates were susceptible to metronidazole and vancomycin, and 105 isolates were resistant to moxifloxacin (92%) carrying Thr83Ile in the GyrA. An outbreak of RT176 CDIs, suspected as RT027, was recognized in a Slovakian hospital. In order to monitor the emergence and spread of RT027-variants, the identification of a presumptive RT027 CDI should be confirmed at a strain level by PCR ribotyping.

Predation by sea stars has the potential to cause elevated levels of mortality in reestablished populations of bivalves relative to levels of recruitment. Recent efforts to restore beds of the nearly extirpated green‐lipped mussel within the Hauraki Gulf, New Zealand, resulted in high abundances of sea stars occupying those beds and it is unknown whether predation poses a potential limitation to the success of restoration in this bivalve species. The contribution of predation by sea stars to the mortality of mussels across four experimental mussel beds over a 2‐year period was estimated using data from regular assessments of sea star abundance and an experimentally determined consumption rate of sea stars upon mussels. In addition, the potential size selection of mussels by sea stars was assessed to determine if large sea stars selected for recent settlers. Sea stars' abundance within the mussel beds grew to an average of 0.57 sea stars/m² within 9 months, remaining at similar levels throughout the study. These predominantly large sea stars were estimated to have consumed 30.1% of the mussels over a 25‐month period, representing a contribution of 40.4% of the mussel mortality. Sea stars predominantly selected for larger mussels, and their predation likely contributes little to any lack in mussel recruitment. Sea star predation is clearly a limiting factor on the survival of transplanted adult mussels and the present study highlights the need to continually assess predation risk to determine if remediation is necessary for the persistence of the restored beds.

It is unknown whether the presence of hard substrate is a necessary prerequisite for the attachment and establishment of mussels, especially on soft-sediment habitats where hard substrates are scarce. Therefore, we examined the importance of natural attachment substrates in the form of mussel shell and adult conspecifics for the establishment of juvenile and adult green-lipped mussels (Perna canaliculus) on soft-sediment. In field experiments where shell material was added as substrate to soft-sediment it made no difference to the subsequent retention of adult mussels. Laboratory experiments showed that juvenile mussels preferentially sought out, and attached to adult mussels compared to remaining on unmodified soft-sediment. Furthermore, juvenile mussels attached to live adult mussels had higher survival in the presence of a common sea star predator compared to juveniles on unmodified soft-sediment or attached to mussel shell. The results suggest that establishment of mussel beds on soft-sediment requires only adult mussels, which receive sufficient anchorage through attachment to neighbouring adults and in so doing, providing a stable, complex substrate suitable for improving the survival of establishing juvenile mussels by protecting them from sea star predators.

Inter-specific variation in claw morphology of decapod crustaceans is related to the particular dietary niche different species occupy, but very few studies have investigated whether claw variation among populations of a same species is similarly related to diet. We set out to quantify differences in claw morphology between green crabs inhabiting rocky and fine-sediment shores in the southwest Bay of Fundy, Canada, and asked whether these were related to differences in the prevalence of hard- and soft-bodied prey in the crab's diet. We found that claw morphology did not differ between crabs from the two habitat types, but did significantly differ between crabs sampled from different rocky shores and different fine-sediment shores. The absence of significant differences in claw morphology between crabs from rocky and fine-sediment shores was somewhat surprising, given that we did observe significant differences in crab diet between the two habitats. However, these dietary differences were related to the prevalence of soft-bodied prey, and hard-bodied snails and mussels were the most prevalent prey items in the guts of crabs from both rocky and fine-sediment shores. Our results therefore suggest that the prevalence of soft-bodied prey in the diet of green crabs in nature does not affect the morphology of their claw. Given our findings, along with recently published patterns of phenotypic co-variance between green crab claw size and snail shell thickness, we hypothesize that consumption of hard-bodied prey may be more consequential to variation in green crab claw morphology than the diet as a whole. More field studies are needed to complement the rich tradition of lab-based research into the biochemical properties of the decapod claw, and in particular to elucidate the role of diet on intra-specific variation of this appendage in nature.

This article contributes to the theorisation and understanding of the discipline of quality management as it revisits and unfolds the ideas of the quality pioneer W.A. Shewhart. It attempts to fill a gap in the current writings on the history of management thought by uncovering the major conceptual influences on Shewhart’s works, in particular their link with advancements in science in the early twentieth century, as well as with process philosophy and the philosophy of pragmatism. Throughout the discussion, examples are provided of the impact of process thinking and pragmatism on Shewhart’s writings. In the concluding part of the article, comments are made in relation to the relevance of the conceptual underpinnings of Shewhart’s ideas for the present theory and practice of quality management.

International audience; Background. During antibiotic treatments, antibiotics reach the colon and alter the microbiome, resulting in emergence and dissemination of resistant bacteria, antibiotic-associated diarrhea (AAD) and occurrence of Clostridium difficile (Cd) infections (CDI). We developed an oral adsorbent-based product, DAV132, to be co-administered with antibiotics in order to prevent these effects. We report here the results of protection of the microbiome in human volunteers treated with oral moxifloxacin (MOX), and protection against CDI in vitro in a human gut model (HGM) and in vivo in experimental hamsters.Methods. Four groups (MOX [400 mg OD for 5 days], MOX + DAV132 [7.5 g TID for 7 days], DAV132, or control) of healthy volunteers (n = 44) were included in a randomized clinical trial. Feces were collected at screening, daily from D1 to D9 and at D12, D16, D23, D30, D37 and plasma PK assayed at D1and5. Metagenomic analyses were done by shotgun sequencing at screening, D3, D6, D9, D16 and D37. The effect of DAV132 on MOX was also assessed in a HGM inoculated with Cd spores (ribotype 027, MOX MIC 32 mg/L); bacterial counts, toxin production and MOX concentrations were measured over time. MOX dosed hamsters were inoculated with 104 spores of a non-epidemic Cd (TcdA + , TcdB + , cdtB−) and treated ±DAV132. Mortality and Cd counts were assessed over time.Results. In humans, DAV132 was well tolerated and decreased free fecal MOX by > 99% compared to MOX alone: ratio of mean LogAUCD1-D16 = 0.0093 (95% CI 0.0061-0.0144), p = 0.03 × 10−16; MOX plasma PK was not changed significantly. Alterations of the fecal microbiome observed with MOX were prevented. In the HGM, DAV protected the microbiota and prevented Cd overgrowth and toxin production. Hamsters were fully protected by DAV against MOX-induced CDI (dose dependent), with decreased free fecal MOX and Cd counts.Conclusion. DAV132 protects humans against fecal microbiome disruption after oral MOX treatment, without altering its plasma PK. In vitro results in HGM and in vivo results in hamsters suggest that DAV132 should be protective against antibiotic-induced CDI. These results warrant further clinical development of DAV132 to protect the intestinal microbiota, and so prevent AAD and CDI, in patients receiving oral or parenteral antibiotics.