Efficacy and safety of a structured de-escalation from antipseudomonal ß-lactams in bloodstream infections due to Enterobacterales (SIMPLIFY): an open-label, multicentre, randomised trial.

BACKGROUND: De-escalation from broad-spectrum to narrow-spectrum antibiotics is considered an important measure to reduce the selective pressure of antibiotics, but a scarcity of adequate evidence is a barrier to its implementation. We aimed to determine whether de-escalation from an antipseudomonal ß-lactam to a narrower-spectrum drug was non-inferior to continuing the antipseudomonal drug in patients with Enterobacterales bacteraemia. METHODS: An open-label, pragmatic, randomised trial was performed in 21 Spanish hospitals. Patients with bacteraemia caused by Enterobacterales susceptible to one of the de-escalation options and treated empirically with an antipseudomonal ß-lactam were eligible. Patients were randomly assigned (1:1; stratified by urinary source) to de-escalate to ampicillin, trimethoprim-sulfamethoxazole (urinary tract infections only), cefuroxime, cefotaxime or ceftriaxone, amoxicillin-clavulanic acid, ciprofloxacin, or ertapenem in that order according to susceptibility (de-escalation group), or to continue with the empiric antipseudomonal ß-lactam (control group). Oral switching was allowed in both groups. The primary outcome was clinical cure 3-5 days after end of treatment in the modified intention-to-treat (mITT) population, formed of patients who received at least one dose of study drug. Safety was assessed in all participants. Non-inferiority was declared when the lower bound of the 95% CI of the absolute difference in cure rate was above the -10% non-inferiority margin. This trial is registered with EudraCT (2015-004219-19) and ClinicalTrials.gov (NCT02795949) and is complete. FINDINGS: 2030 patients were screened between Oct 5, 2016, and Jan 23, 2020, of whom 171 were randomly assigned to the de-escalation group and 173 to the control group. 164 (50%) patients in the de-escalation group and 167 (50%) in the control group were included in the mITT population. 148 (90%) patients in the de-escalation group and 148 (89%) in the control group had clinical cure (risk difference 1·6 percentage points, 95% CI -5·0 to 8·2). The number of adverse events reported was 219 in the de-escalation group and 175 in the control group, of these, 53 (24%) in the de-escalation group and 56 (32%) in the control group were considered severe. Seven (5%) of 164 patients in the de-escalation group and nine (6%) of 167 patients in the control group died during the 60-day follow-up. There were no treatment-related deaths. INTERPRETATION: De-escalation from an antipseudomonal ß-lactam in Enterobacterales bacteraemia following a predefined rule was non-inferior to continuing the empiric antipseudomonal drug. These results support de-escalation in this setting. FUNDING: Plan Nacional de I+D+i 2013-2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Ciencia, Innovación y Universidades, Spanish Network for Research in Infectious Diseases; Spanish Clinical Research and Clinical Trials Platform, co-financed by the EU; European Development Regional Fund "A way to achieve Europe", Operative Program Intelligence Growth 2014-2020.

Efficacy and safety of different antimicrobial DURATions for the treatment of Infections associated with Osteosynthesis Material implanted after long bone fractures (DURATIOM): Protocol for a randomized, pragmatic trial.

BACKGROUND: Infection associated with osteosynthesis material (IOM) is one of the most feared and challenging complications of trauma surgery and can cause significant functional loss, requiring multiple interventions and excessive consumption of antimicrobials. Evidence is needed about the best surgical procedure and the duration of antibiotic treatment according to the age of the implant or onset of infection symptoms, as it considers the biofilm formation and the state of fracture healing. There were not clinical trials evaluating the optimal duration of antibiotic therapy in IOM when implant is retained. Because there are antibiotics that have proven to be effective for the treatment of infection associated to implant, mainly in PJI, these antibiotics could be used in these infections. Investigating whether shorter duration of treatment is a priority in infectious diseases, as a way to reduce the exposure to antibiotics and help in controlling antimicrobial resistance and avoiding unnecessary adverse events and cost. We aim to describe the hypothesis, objectives, design, variables and procedures for a pragmatic randomized controlled trial comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. METHODS AND DESIGN: This is a multicenter, open-label, non-inferiority, randomized, controlled, pragmatic phase 3 trial, comparing different durations of antibiotic treatment in IOM after long bone fractures treated with debridement and implant retention. Patients with microbiologically confirmed IOM will be included. Eligible patients are those older than 14 years, with early IOM (up to 2 weeks after the implant surgery) and delayed IOM (between 3 and 10 weeks after the implant surgery) with stabilized fracture and absence of bone exposure who sign the informed consent. Randomization will be 1:1 to receive a short-term antibiotic treatment (8 weeks in early IOM and 12 weeks in delayed IOM) or a long-term antibiotic treatment (12 weeks in early IOM or until fracture healing or implant removal in delayed IOM). The antibiotic treatment will be that used in routine practice by the specialist in infectious diseases. The primary outcome is the composited variable "cure" that includes clinical cure, radiological healing, and definitive soft tissue coverage, which will be evaluated in the test of cure at 12 months after the end of antibiotic therapy. Adverse events, resistance development during therapy and functional status will be collected. A total of 364 patients are needed to show a 10% non-inferiority margin, with 80% power and 5% one-sided significance level. DISCUSSION: If the hypothesis of non-inferiority of short vs. long antibiotic treatments is demonstrated, and the efficacy of antibiotics with less ecological impact in long treatments, the impact on reduction of bacterial resistance, toxicity and health costs will be observed. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT05294796) on Jan 26th 2022 and at the European Union Drug Regulating Authorities Clinical Trials (EUDRACT) (2021-003914-38) on Jul 16th 2021. The Sponsor Study Code is DURATIOM.

Investors' confidence in the crowdlending platform and the impact of Covid-19.

Crowdlending platforms have gained importance in recent years due to digitalization. The Covid-19 pandemic has severely impacted the entire economy, including repercussions on digital transactions. Investors considering transactions on these platforms require confidence in both the platform and the project in order to make the right decision. For this reason, this study analyzes the links between the parties involved in the process. A survey was sent to 135 investors on the Colectual platform in January 2022, and the research method adopted is Fuzzy Set Qualitative Comparative Analysis (fsQCA). The study examines the connections between the platform, the investors, and the project developers, to assess the influence exerted by the platform on the confidence of the parties seeking and providing investment. The main result is that Covid-19 has been a key factor in the confidence of investors in the platform, and it has had a significant influence on the investments made.

I Quit! Effects of Work-Family Policies on the Turnover Intention.

The retention of key human resources is a challenge and a necessity for any organisation. This paper analyses the impact of the existence and accessibility of work-family policies on the well-being of workers and their intention to leave the organisation. To test the proposed hypotheses, we applied a structural equation model based on the partial least squares path modelling (PLS-SEM) approach to a sample of 558 service sector workers. The results show that the existence and accessibility of work-family policies directly reduce the intention to leave the organisation. Moreover, this relationship also occurs indirectly, by mediating the well-being that is generated by these work-family policies. We also analysed the moderating role that gender and hierarchy could have in the above relationships. In addition to the above theoretical implications, this study has practical implications. The findings show that employees with family and work balance problems experience lower emotional well-being, more health problems and eventually higher turnover rates. To avoid these problems, management must focus not only on the implementation of work-family policies but also on their accessibility, without subsequent retaliation or prejudice to employees. Additionally, management should pay special attention to female managers, given their greater difficulty in balancing work and family life.

Harnessing inter-disciplinary collaboration to improve emergency care in low- and middle-income countries (LMICs): results of research prioritisation setting exercise.

BACKGROUND: More than half of deaths in low- and middle-income countries (LMICs) result from conditions that could be treated with emergency care - an integral component of universal health coverage (UHC) - through timely access to lifesaving interventions. METHODS: The World Health Organization (WHO) aims to extend UHC to a further 1 billion people by 2023, yet evidence supporting improved emergency care coverage is lacking. In this article, we explore four phases of a research prioritisation setting (RPS) exercise conducted by researchers and stakeholders from South Africa, Egypt, Nepal, Jamaica, Tanzania, Trinidad and Tobago, Tunisia, Colombia, Ethiopia, Iran, Jordan, Malaysia, South Korea and Phillipines, USA and UK as a key step in gathering evidence required by policy makers and practitioners for the strengthening of emergency care systems in limited-resource settings. RESULTS: The RPS proposed seven priority research questions addressing: identification of context-relevant emergency care indicators, barriers to effective emergency care; accuracy and impact of triage tools; potential quality improvement via registries; characteristics of people seeking emergency care; best practices for staff training and retention; and cost effectiveness of critical care - all within LMICs. CONCLUSIONS: Convened by WHO and facilitated by the University of Sheffield, the Global Emergency Care Research Network project (GEM-CARN) brought together a coalition of 16 countries to identify research priorities for strengthening emergency care in LMICs. Our article further assesses the quality of the RPS exercise and reviews the current evidence supporting the identified priorities.

Lethal Influenza in Two Related Adults with Inherited GATA2 Deficiency.

The pathogenesis of life-threatening influenza A virus (IAV) disease remains elusive, as infection is benign in most individuals. We studied two relatives who died from influenza. We Sanger sequenced GATA2 and evaluated the mutation by gene transfer, measured serum cytokine levels, and analyzed circulating T- and B-cells. Both patients (father and son, P1 and P2) died in 2011 of H1N1pdm IAV infection at the ages of 54 and 31 years, respectively. They had not suffered from severe or moderately severe infections in the last 17 (P1) and 15 years (P2). A daughter of P1 had died at 20 years from infectious complications. Low B-cell, NK- cell, and monocyte numbers and myelodysplastic syndrome led to sequence GATA2. Patients were heterozygous for a novel, hypomorphic, R396L mutation leading to haplo-insufficiency. B- and T-cell rearrangement in peripheral blood from P1 during the influenza episode showed expansion of one major clone. No T-cell receptor excision circles were detected in P1 and P3 since they were 35 and 18 years, respectively. Both patients presented an exuberant, interferon (IFN)-γ-mediated hypercytokinemia during H1N1pdm infection. No data about patients with viremia was available. Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood. However, a role of other genetic variants involved in immune responses cannot be ruled out. Patients with GATA2 deficiency can reach young adulthood without severe infections, including influenza, despite long-lasting complete B-cell and natural killer (NK) cell deficiency, as well as profoundly diminished T-cell thymic output.

In vitro assessment of competitive and time-dependent inhibition of the nevirapine metabolism by nortriptyline in rats.

Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) widely used as a component of High Active Antiretroviral Therapy (HAART) since it is inexpensive, readily absorbed after oral administration and non-teratogenic. In the present work, the mechanism of a previously described pharmacokinetic interaction between NVP and the antidepressant drug nortriptyline (NT) was studied using rat hepatic microsomes. The obtained results showed a competitive inhibition of the NVP metabolism by NT. The three main NVP metabolites (2-OH-NVP, 3-OH-NVP and 12-OH-NVP) where competitively inhibited with similar inhibitory constant values (Ki = 4.01, 3.97 and 4.40 µM, respectively). Time-dependent inhibition of the NVP metabolism was also detected, with a 2.5-fold reduction in the IC50 values of NT for 2-, 3-, and 12-OH-NVP formation when NT was preincubated with the microsomal suspension in the presence of an NADPH-generating system. A concentration-dependent inhibition of the formation of NVP metabolites by the main NT metabolite (10-OH-NT) was also observed, however, the inhibitory potency of 10-OH-NT was much lower than that of the parent drug. The apparent hepatic intrinsic clearance of NVP determined in these in vitro experiments was used to predict the in vivo clearance of NVP using the "well-stirred" and the "parallel-tube" models, resulting in values close to those previously observed in vivo clearance. Finally, a good prediction of the increase in the plasma concentrations of NVP when co-administered with NT was obtained employing the inhibitory constant of NT determined in vitro and the estimated plasma concentration of NT entering the liver.

Out-of-Hospital Cardiac Arrest Resuscitation Systems of Care: A Scientific Statement From the American Heart Association.

The American Heart Association previously recommended implementation of cardiac resuscitation systems of care that consist of interconnected community, emergency medical services, and hospital efforts to measure and improve the process of care and outcome for patients with cardiac arrest. In addition, the American Heart Association proposed a national process to develop and implement evidence-based guidelines for cardiac resuscitation systems of care. Significant experience has been gained with implementing these systems, and new evidence has accumulated. This update describes recent advances in the science of cardiac resuscitation systems and evidence of their effectiveness, as well as recent progress in dissemination and implementation throughout the United States. Emphasis is placed on evidence published since the original recommendations (ie, including and since 2010).

The use of ertapenem for the treatment of community-acquired pneumonia in routine hospital practice: a matched cohort study / Uso de ertapenem en la neumonía adquirida en la comunidad en la práctica clínica diaria: estudio de cohortes pareadas

Background. The clinical response to ertapenem in community-acquired pneumonia (CAP) at the setting of routine hospital practice has been scarcely evaluated. Methods. We retrospectively compared CAP cases treated with ertapenem or with other standard antimicrobials (controls) at a tertiary 1,434-bed center from 2005 to 2014. Results. Out of 6,145 patients hospitalized with CAP, 64 (1%) ertapenem-treated and 128 controls were studied (PSI IV-V 72%, mean age 73 years.). A significant higher proportion of bedridden patients (41% vs. 21%), residence in nursing homes (19% vs. 7%), previous use of antibiotics (39% vs. 29%) and necrotizing (13% vs. 1%) or complicated (36% vs. 19%) pneumonia, was observed in the ertapenem vs. non-ertapenem patients. Initial treatment with ertapenem was independently associated with an earlier resolution of signs of infection. In patients aged 65 or older the independent risks factors for mortality were: PSI score (7.0, 95%CI 1.8-27.7), bedridden status (4.6, 95%CI 1.1-20.9) and Health Care Associated Pneumonia (HCAP) (4.6, 95%CI 1.3-16.5). First-line treatment with ertapenem was an independent protector factor in this subgroup of patients (0.1, 95%CI 0.1-0.7). Conclusions. Ertapenem showed a superior clinical response in frail elderly patients with complicated community- acquired pneumonia, and it may be considered as a firstline therapeutic regimen in this setting (AU)

Introducción. La respuesta clínica a ertapenem en la neumonía adquirida en la comunidad (NAC) en el contexto de la práctica clínica diaria ha sido evaluada de forma insuficiente. Material y Métodos. Estudio retrospectivo, comparativo de pacientes con NAC tratados con ertapenem o con otros antimicrobianos en un hospital terciario de 1.434 camas en el período 2005-2014. Resultados. De los 6.145 pacientes hospitalizados con NAC, 64 (1%) tratados con ertapenem y 128 controles fueron incluidos en el estudio (PSI IV-V 72%, edad media 73 años). Se observó una proporción significativamente mayor de pacientes encamados (41% vs. 21%), institucionalizados (19% vs. 7%), con antibioterapia previa (39% vs. 29%) y con neumonías necrotizantes (13% vs. 1%) o complicadas (36% vs. 19%) en el grupo de ertapenem vs. no-ertapenem. El tratamiento inicial con ertapenem se asoció de forma independiente con una resolución más temprana de los signos de infección. En el subgrupo de pacientes con 65 años o más, los factores independientes de riesgo de mortalidad fueron: PSI score (7,0 IC95% 1,8-27,7), encamamiento (4,6 IC95% 1,1-20,9) y la Neumonía Asociada a Cuidados Sanitarios (NACS) (4,6 IC95% 1,3-16,5). El tratamiento en primera línea con ertapenem fue un factor protector independiente en este grupo de pacientes (0,1 IC95% 0,1-0,7). Conclusiones. El tratamiento con ertapenem se asoció a una respuesta clínica superior en el paciente anciano frágil con NAC complicada y se podría considerar como un régimen terapéutico de primera línea en este contexto (AU)

Telephone CPR Instructions in Emergency Dispatch Systems: Qualitative Survey of 911 Call Centers.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death. The 2010 American Heart Association Emergency Cardiovascular Care (ECC) Guidelines recognize emergency dispatch as an integral component of emergency medical service response to OHCA and call for all dispatchers to be trained to provide telephone cardiopulmonary resuscitation (T-CPR) pre-arrival instructions. To begin to measure and improve this critical intervention, this study describes a nationwide survey of public safety answering points (PSAPs) focusing on the current practices and resources available to provide T-CPR to callers with the overall goal of improving survival from OHCA. METHODS: We conducted this survey in 2010, identifying 5,686 PSAPs; 3,555 had valid e-mail addresses and were contacted. Each received a preliminary e-mail announcing the survey, an e-mail with a link to the survey, and up to three follow-up e-mails for non-responders. The survey contained 23 primary questions with sub-questions depending on the response selected. RESULTS: Of the 5,686 identified PSAPs in the United States, 3,555 (63%) received the survey, with 1,924/3,555 (54%) responding. Nearly all were public agencies (n=1,888, 98%). Eight hundred seventy-eight (46%) responding agencies reported that they provide no instructions for medical emergencies, and 273 (14%) reported that they are unable to transfer callers to another facility to provide T-CPR. Of the 1,924 respondents, 975 (51%) reported that they provide pre-arrival instructions for OHCA: 67 (3%) provide compression-only CPR instructions, 699 (36%) reported traditional CPR instructions (chest compressions with rescue breathing), 166 (9%) reported some other instructions incorporating ventilations and compressions, and 92 (5%) did not specify the type of instructions provided. A validation follow up showed no substantial difference in the provision of instructions for OHCA by non-responders to the survey. CONCLUSION: This is the first large-scale, nationwide assessment of the practices of PSAPs in the United States regarding T-CPR for OHCA. These data showing that nearly half of the nation's PSAPs do not provide T-CPR for OHCA, and very few PSAPs provide compression-only instructions, suggest that there is significant potential to improve the implementation of this critical link in the chain of survival for OHCA.

Part 2: Evidence Evaluation and Management of Conflicts of Interest: 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations.

The process for evaluating the resuscitation science has evolved considerably over the past 2 decades. The current process, which incorporates the use of the GRADE methodology, culminated in the 2015 CoSTR publication, which in turn will inform the international resuscitation councils' guideline development processes. Over the next few years, the process will continue to evolve as ILCOR moves toward a more continuous evaluation of the resuscitation science.

Surfactant protein A genetic variants associate with severe respiratory insufficiency in pandemic influenza A virus infection.

INTRODUCTION: Inherited variability in host immune responses influences susceptibility and outcome of Influenza A virus (IAV) infection, but these factors remain largely unknown. Components of the innate immune response may be crucial in the first days of the infection. The collectins surfactant protein (SP)-A1, -A2, and -D and mannose-binding lectin (MBL) neutralize IAV infectivity, although only SP-A2 can establish an efficient neutralization of poorly glycosylated pandemic IAV strains. METHODS: We studied the role of polymorphic variants at the genes of MBL (MBL2), SP-A1 (SFTPA1), SP-A2 (SFTPA2), and SP-D (SFTPD) in 93 patients with H1N1 pandemic 2009 (H1N1pdm) infection. RESULTS: Multivariate analysis showed that two frequent SFTPA2 missense alleles (rs1965708-C and rs1059046-A) and the SFTPA2 haplotype 1A(0) were associated with a need for mechanical ventilation, acute respiratory failure, and acute respiratory distress syndrome. The SFTPA2 haplotype 1A(1) was a protective variant. Kaplan-Meier analysis and Cox regression also showed that diplotypes not containing the 1A(1) haplotype were associated with a significantly shorter time to ICU admission in hospitalized patients. In addition, rs1965708-C (P = 0.0007), rs1059046-A (P = 0.0007), and haplotype 1A(0) (P = 0.0004) were associated, in a dose-dependent fashion, with lower PaO2/FiO2 ratio, whereas haplotype 1A(1) was associated with a higher PaO2/FiO2 ratio (P = 0.001). CONCLUSIONS: Our data suggest an effect of genetic variants of SFTPA2 on the severity of H1N1pdm infection and could pave the way for a potential treatment with haplotype-specific (1A(1)) SP-A2 for future IAV pandemics.

Hábitos quirúrgicos de los cirujanos zurdos / The surgical habits of left-handed surgeons

Objetivos. Interrogar al personal quirúrgico, médico y de enfermería sobre su conocimiento de los distintos hábitos quirúrgicos de los cirujanos zurdos, sus posibles problemas de adaptación, así como sobre las posibilidades de complementariedad que puede suponer operar con un cirujano zurdo. Sujetos y métodos. Entre enero y mayo de 2003 se encuestó a 145 médicos cirujanos y a 17 enfermeros instrumentistas. La encuesta se componía de 15 preguntas con respuestas múltiples. Se realizó un análisis descriptivo de las respuestas y se comprobó si existían diferencias estadísticamente significativas entre las respuestas de los distintos grupos con el test de chi al cuadrado. Resultados. La muestra presenta igual prevalencia de cirujanos zurdos y ambidextros (6,2% frente a 6,8%). El 100% de la enfermería instrumentista y el 72% de los cirujanos de staff han instrumentado o ayudado a un cirujano zurdo. El 93% de los encuestados opina que los cirujanos zurdos operan igual que los diestros. El 65% opina que el instrumental estándar no es igualmente útil para diestros y zurdos. El 45% de los encuestados desconoce la existencia de instrumental específico para zurdos, si bien el 80% cree que mejoraría su capacidad quirúrgica. Es opinión mayoritaria que la implementación de material específico para zurdos no se produce por problemas de costes. Conclusiones. Existe un desconocimiento notable de la problemática del cirujano zurdo, y no se valoran las posibles ventajas que puede aportar su ayuda. La implementación de instrumental diseñado para cirujanos zurdos sería, en opinión general, una ayuda valiosa (AU)

Aims. To question members of surgical, medical and nursing staff about their knowledge of the different surgical habits of left-handed surgeons, the possible problems they may have as regards adaptation, and also about the chances of complementarity that may be required when operating with a left-handed surgeon. Subjects and methods. Between January and May 2003 a survey was conducted on 145 surgeons and 17 instrument nurses. The survey consisted of 15 questions with multiple-choice answers. Responses were submitted to a descriptive analysis and the chi squared test was use to determine whether there were statistically significant differences between the answers given by the different groups. Results. The prevalence of left-handed and ambidextrous surgeons in the sample was the same (6.2% versus 6.8%). 100% of the instrument nurses and 72% of the staff surgeons have assisted or acted as scrub nurses with a left-handed surgeon. 93% of the respondents stated that left-handed surgeons operate in the same way as their right-handed colleagues. 65% said that standard instruments are not as easy to use for left- and right-handers. 45% of the respondents did not know that there are instruments specifically designed for left-handed users, although 80% thought that they would improve their surgical capacity. The majority said that specific left-handed material was not implemented due to the extra cost involved. Conclusions. The problems left-handed surgeons face are something that is largely unknown and the possible advantages that could be gained by helping them are not taken into account. In general respondents thought that implementing instruments designed for left-handed surgeons would be a valuable aid (AU)