Intra-abdominal infections survival guide: a position statement by the Global Alliance For Infections In Surgery.

Intra-abdominal infections (IAIs) are an important cause of morbidity and mortality in hospital settings worldwide. The cornerstones of IAI management include rapid, accurate diagnostics; timely, adequate source control; appropriate, short-duration antimicrobial therapy administered according to the principles of pharmacokinetics/pharmacodynamics and antimicrobial stewardship; and hemodynamic and organ functional support with intravenous fluid and adjunctive vasopressor agents for critical illness (sepsis/organ dysfunction or septic shock after correction of hypovolemia). In patients with IAIs, a personalized approach is crucial to optimize outcomes and should be based on multiple aspects that require careful clinical assessment. The anatomic extent of infection, the presumed pathogens involved and risk factors for antimicrobial resistance, the origin and extent of the infection, the patient's clinical condition, and the host's immune status should be assessed continuously to optimize the management of patients with complicated IAIs.

High data-rate communication link supported through the exploitation of optical channels in a characterized turbulent underwater environment.

Underwater turbulence presents a myriad of challenges for underwater optical systems through wavefront distortion and beam deflection. In this work, an underwater turbulence emulator is developed and thoroughly characterized to experimentally test the proposed underwater turbulence mitigation technique. This technique applies a modified HOBBIT system introduced in atmospheric turbulence to the relatively unknown underwater turbulence domain. By varying a beam's spatial position and relative phase gradient, a volume of turbulence is rapidly probed to determine the beam state for optimal propagation. This probe and control method is applied in multiple facets, including improved optical power transmission as well as supporting a 25-Gbps communication link through a dynamic environment.

Sulbactam-durlobactam: A Step Forward in Treating Carbapenem-Resistant Acinetobacter baumannii (CRAB) Infections.

Antimicrobial resistance in gram-negative pathogens, such as Acinetobacter baumannii, is a serious threat to human health. Sulbactam-durlobactam, a unique ß-lactam and a ß-lactamase inhibitor combination, is a novel agent targeted against carbapenem-resistant A. baumannii. This supplement provides a summary of the development of SUL-DUR, discussing its unique features and role in treating infections caused by CRAB pathogens.

Pathogen-Targeted Clinical Development to Address Unmet Medical Need: Design, Safety, and Efficacy of the ATTACK Trial.

There is a crucial need for novel antibiotics to stem the tide of antimicrobial resistance, particularly against difficult to treat gram-negative pathogens like Acinetobacter baumannii-calcoaceticus complex (ABC). An innovative approach to addressing antimicrobial resistance may be pathogen-targeted development programs. Sulbactam-durlobactam (SUL-DUR) is a ß-lactam/ß-lactamase inhibitor combination antibiotic that is being developed to specifically target drug-resistant ABC. The development of SUL-DUR culminated with the Acinetobacter Treatment Trial Against Colistin (ATTACK) trial, a global, randomized, active-controlled phase 3 clinical trial that compared SUL-DUR with colistin for treating serious infections due to carbapenem-resistant ABC. SUL-DUR met the primary noninferiority endpoint of 28-day all-cause mortality. Furthermore, SUL-DUR had a favorable safety profile with a statistically significant lower incidence of nephrotoxicity compared with colistin. If approved, SUL-DUR could be an important treatment option for infections caused by ABC, including carbapenem-resistant and multidrug-resistant strains. The development program and the ATTACK trial highlight the potential for pathogen-targeted development programs to address the challenge of antimicrobial resistance.

Gepotidacin: a novel, oral, 'first-in-class' triazaacenaphthylene antibiotic for the treatment of uncomplicated urinary tract infections and urogenital gonorrhoea.

The ongoing spread of antimicrobial resistance has made the treatment of uncomplicated urinary tract infections (UTIs) and urogenital gonorrhoea increasingly difficult. New oral treatment options are urgently needed. Gepotidacin (previously GSK2140944) is a novel, bactericidal, oral, 'first-in-class' triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by blocking two essential topoisomerase enzymes. Mutations in both enzymes would likely be necessary for resistance to occur, thus raising hopes that the drug will be able to maintain long-term effectiveness. Data from Phase II clinical trials of gepotidacin in UTIs and urogenital gonorrhoea appear promising, and Phase III trials are underway. In this review we summarize the development of gepotidacin and discuss its potential role in clinical practice. If approved, gepotidacin will be the first new oral antibiotic for UTIs in more than 20 years.

Sensing and coupling of optical channels in dynamic atmospheric turbulence using OAM beamlets for improved power and data transmission.

Propagation of laser light is distorted in the presence of atmospheric turbulence. This poses an issue for sensing, free-space optical communications, and transmission of power. The presented system offers a novel solution to mitigate the effects of turbulence. By rapidly probing a turbulent volume by varying a beam's spatial and phase characteristics, the best transmission mode can be determined and updated in real time. Unlike a traditional tip-tilt system, this scheme is fully electronic, and has a scalable architecture to leverage multiple optical transmission paths simultaneously. This optical control system greatly improves power efficiency and successful recovery of data through environments with strong turbulence.

Update on the Pathogenesis, Virulence, and Treatment of Candida auris.

Candida auris is an emerging, multidrug resistant fungal pathogen that causes considerable morbidity and mortality. First identified in Japan in 2009, it has since been reported in more than 40 countries. C. auris can persist for long periods on different environmental surfaces as well as the skin. Clinical isolates are typically resistant to commonly prescribed antifungal drugs. Increasingly recognized as a cause of infections and outbreaks in nosocomial settings, C. auris is difficult to identify using traditional microbiological methods. One of the main reasons for the ongoing spread of C. auris is the multitude of virulence factors it possesses and uses against its human host that enables fungal persistence on the skin surface. Yet, many of the virulence mechanismsare unknown or remain incompletely understood. In this review, we summarize the evolution of virulence of C. auris, offer recommendations for combating this important human pathogen, and suggest directions for further research.

OAM-based optical wavelet using a single pixel detection system for probing dynamic environments with application to real-time measurements of strong atmospheric turbulence.

This paper presents a novel method for optical probing by generating optical fields with characteristics of wavelets. The optical wavelets form a basis of rotated asymmetric beams with scaled orbital angular momentum (OAM) and beam sizes. The probing method was used experimentally to measure the continuous wavelet transform of a turbulent propagation path, giving insight into the angular properties about a fixed radius. The wavelet transform of a three-dimensional turbulence distribution was measured; the measurements are much faster than the turbulence changes, allowing characterization of an instantaneous realization of turbulence over time. Results show highly localized regions of OAM in space through the turbulence and characteristics of the turbulence can be extracted from the wavelet transforms.

Distance to Health Care Facilities, Lifestyle Risk Factors, and Stage at Diagnosis in relation to Geographic Pattern of Esophageal Cancer in Tanzania, 2006-2016.

Esophageal cancer is an aggressive, often deadly disease globally that represents a significant health problem in Tanzania. The WHO reported 604,100 new esophageal cancer cases worldwide during 2020 and 544,076 deaths (Sung, 2021; World Health Organization, 2020). In Eastern Africa, 16,137 cases and 15,188 deaths were related to this disease in 2020. Esophageal cancer is associated with various etiologic risk factors, and access to the disease treatment is a major barrier to survival. This study examined associations between the prevalence of four geographically stratified, population-level, etiologic risk factors (tobacco use, unprotected water use, solid fuel source use, and poverty), as well as two access-to-care predictors (persons per hospital and distance from residence to where esophageal cancer treatment occurs). Regional- and coarser-scale zonal incidence rates were calculated for 2006 through 2016 and evaluated for geographic differences in relation to risk factors and access to care predictors using Poisson regression. Differences in the geographic distribution of esophageal cancer were observed. Distance from the region of residence to the treatment center (Ocean Road Cancer Institute) was statistically associated with the geographic pattern of esophageal cancer incidence. Further research into etiologic risk factors, dietary practices, and nutrition is needed to better understand the associations with esophageal cancer in Tanzania and other parts of Eastern Africa.

A Systems-Based Analysis of Mono- and Combination Therapy for Carbapenem-Resistant Klebsiella pneumoniae Bloodstream Infections.

Antimicrobial resistance is a global threat. As "proof-of-concept," we employed a system-based approach to identify patient, bacterial, and drug variables contributing to mortality in patients with carbapenem-resistant Klebsiella pneumoniae (CRKp) bloodstream infections exposed to colistin (COL) and ceftazidime-avibactam (CAZ/AVI) as mono- or combination therapies. Patients (n = 49) and CRKp isolates (n = 22) were part of the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE-1), a multicenter, observational, prospective study of patients with carbapenem-resistant Enterobacterales (CRE) conducted between 2011 and 2016. Pharmacodynamic activity of mono- and combination drug concentrations was evaluated over 24 h using in vitro static time-kill assays. Bacterial growth and killing dynamics were estimated with a mechanism-based model. Random Forest was used to rank variables important for predicting 30-day mortality. Isolates exposed to COL+CAZ/AVI had enhanced early bacterial killing compared to CAZ/AVI alone and fewer incidences of regrowth compared to COL and CAZ/AVI. The mean coefficient of determination (R2) for the observed versus predicted bacterial counts was 0.86 (range: 0.75 - 0.95). Bacterial subpopulation susceptibilities and drug mechanistic synergy were essential to describe bacterial killing and growth dynamics. The combination of clinical (hypotension), bacterial (IncR plasmid, aadA2, and sul3) and drug (KC50) variables were most predictive of 30-day mortality. This proof-of-concept study combined clinical, bacterial, and drug variables in a unified model to evaluate clinical outcomes.

Antibiotic stewardship in the era of precision medicine.

Antimicrobial resistance (AMR) continues to spread at an alarming rate worldwide. Novel approaches are needed to mitigate its deleterious impact on antibiotic efficacy. Antibiotic stewardship aims to promote the appropriate use of antibiotics through evidence-based interventions. One paradigm is precision medicine, a medical model in which decisions, practices, interventions, and therapies are adapted to the individual patient based on their predicted response or risk of disease. Precision medicine approaches hold promise as a way to improve outcomes for patients with myriad illnesses, including infections such as bacteraemia and pneumonia. This review describes the latest advances in precision medicine as they pertain to antibiotic stewardship, with an emphasis on hospital-based antibiotic stewardship programmes. The impact of the COVID-19 pandemic on AMR and antibiotic stewardship, gaps in the scientific evidence, and areas for further research are also discussed.

Using Precision Medicine for the Diagnosis and Treatment of Viral Pneumonia.

The COVID-19 pandemic has drawn considerable attention to viral pneumonia from clinicians, public health authorities, and the general public. With dozens of viruses able to cause pneumonia in humans, differentiating viral from bacterial pneumonia can be very challenging in clinical practice using traditional diagnostic methods. Precision medicine is a medical model in which decisions, practices, interventions, and therapies are adapted to the individual patient on the basis of their predicted response or risk of disease. Precision medicine approaches hold promise as a way to improve outcomes for patients with viral pneumonia. This review describes the latest advances in the use of precision medicine for diagnosing and treating viral pneumonia in adults and discusses areas where further research is warranted.

Imipenem/Relebactam Resistance in Clinical Isolates of Extensively Drug Resistant Pseudomonas aeruginosa: Inhibitor-Resistant ß-Lactamases and Their Increasing Importance.

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections are a major clinical challenge. Many isolates are carbapenem resistant, which severely limits treatment options; thus, novel therapeutic combinations, such as imipenem-relebactam (IMI/REL), ceftazidime-avibactam (CAZ/AVI), ceftolozane-tazobactam (TOL/TAZO), and meropenem-vaborbactam (MEM/VAB) were developed. Here, we studied two extensively drug-resistant (XDR) P. aeruginosa isolates, collected in the United States and Mexico, that demonstrated resistance to IMI/REL. Whole-genome sequencing (WGS) showed that both isolates contained acquired GES ß-lactamases, intrinsic PDC and OXA ß-lactamases, and disruptions in the genes encoding the OprD porin, thereby inhibiting uptake of carbapenems. In one isolate (ST17), the entire C terminus of OprD deviated from the expected amino acid sequence after amino acid G388. In the other (ST309), the entire oprD gene was interrupted by an ISPa1328 insertion element after amino acid D43, rendering this porin nonfunctional. The poor inhibition by REL of the GES ß-lactamases (GES-2, -19, and -20; apparent Ki of 19 ± 2 µM, 23 ± 2 µM, and 21 ± 2 µM, respectively) within the isolates also contributed to the observed IMI/REL-resistant phenotype. Modeling of REL binding to the active site of GES-20 suggested that the acylated REL is positioned in an unstable conformation as a result of a constrained Ω-loop.

The UK stand together trial: protocol for a multicentre cluster randomised controlled trial to evaluate the effectiveness and cost-effectiveness of KiVa to reduce bullying in primary schools.

BACKGROUND: Reducing bullying is a public health priority. KiVa, a school-based anti-bullying programme, is effective in reducing bullying in Finland and requires rigorous testing in other countries, including the UK. This trial aims to test the effectiveness and cost-effectiveness of KiVa in reducing child reported bullying in UK schools compared to usual practice. The trial is currently on-going. Recruitment commenced in October 2019, however due to COVID-19 pandemic and resulting school closures was re-started in October 2020. METHODS: Design: Two-arm pragmatic multicentre cluster randomised controlled trial with an embedded process and cost-effectiveness evaluation. PARTICIPANTS: 116 primary schools from four areas; North Wales, West Midlands, South East and South West England. Outcomes will be assessed at student level (ages 7-11 years; n = approximately 13,000 students). INTERVENTION: KiVa is a whole school programme with universal actions that places a strong emphasis on changing bystander behaviour alongside indicated actions that provide consistent strategies for dealing with incidents of bullying. KiVa will be implemented over one academic year. COMPARATOR: Usual practice. PRIMARY OUTCOME: Student-level bullying-victimisation assessed through self-report using the extensively used and validated Olweus Bully/Victim questionnaire at baseline and 12-month follow-up. SECONDARY OUTCOMES: student-level bullying-perpetration; student mental health and emotional well-being; student level of, and roles in, bullying; school related well-being; school attendance and academic attainment; and teachers' self-efficacy in dealing with bullying, mental well-being, and burnout. SAMPLE SIZE: 116 schools (58 per arm) with an assumed ICC of 0.02 will provide 90% power to identify a relative reduction of 22% with a 5% significance level. RANDOMISATION: recruited schools will be randomised on 1:1 basis stratified by Key-Stage 2 size and free school meal status. Process evaluation: assess implementation fidelity, identify influences on KiVa implementation, and examine intervention mechanisms. Economic evaluation: Self-reported victimisation, Child Health Utility 9D, Client Service Receipt Inventory, frequency of services used, and intervention costs. The health economic analysis will be conducted from a schools and societal perspective. DISCUSSION: This two-arm pragmatic multicentre cluster randomised controlled trial will evaluate the KiVa anti-bullying intervention to generate evidence of the effectiveness, cost-effectiveness and scalability of the programme in the UK. Our integrated process evaluation will assess implementation fidelity, identify influences on KiVa implementation across England and Wales and examine intervention mechanisms. The integrated health economic analysis will be conducted from a schools and societal perspective. Our trial will also provide evidence regarding the programme impact on inequalities by testing whether KiVa is effective across the socio-economic gradient. TRIAL REGISTRATION: Trials ISRCTN 12300853 Date assigned 11/02/2020.

Managing sepsis in the era of precision medicine: challenges and opportunities.

INTRODUCTION: Precision medicine is a medical model in which decisions, practices, interventions and therapies are tailored to the individual patient based on their predicted response or risk of disease. Sepsis is a life-threatening condition characterized by immune system dysregulation whose pathophysiology remains incompletely understood. There is much hope that precision medicine can lead to better outcomes in patients with sepsis. AREAS COVERED: In this review from a comprehensive literature search in PubMed for English-language studies in adults, we highlight recent advances in the diagnosis and treatment of sepsis of bacterial origin using precision medicine approaches including rapid diagnostic tests, predictive biomarkers, genomic methods, rapid antimicrobial susceptibility testing, and monitoring cell mediated immunity. Challenges and directions for future research are also discussed. EXPERT OPINION: Current diagnostic testing in sepsis relies primarily on conventional cultures (e.g. blood cultures), which are time-consuming and may delay critical therapeutic decisions. Nonculture-based techniques including nucleic acid amplification technologies (NAAT), other molecular methods (biomarkers), and genomic sequencing offer promise to overcome some of the inherent limitations seen with culture-based techniques.

Fractional orbital angular momentum conversion in second-harmonic generation with an asymmetric perfect vortex beam.

This Letter demonstrates the nonlinear conversion of asymmetric perfect vortex (APV) beams with fractional orbital angular momentum (OAM). By controlling the amplitude and phase of the fundamental light field, we create APVs whose global OAM demonstrates a one-to-one correspondence of the charge numbers for fractional OAM values. The results show that the OAM of the second-harmonic generation fields follow the OAM conservation law. The nonlinear interactions of multiple OAM beams with the APVs are also investigated as they relate to the nonlinear frequency conversion and are shown to exhibit unique frequencies as a result of the Doppler frequency tagged OAM values.

Approach to the Patient with a Skin and Soft Tissue Infection.

The diagnosis of a skin and soft tissue infection (SSTI) requires careful attention to a patient's history, physical examination, and diagnostic test results. We review for many bacterial, viral, fungal, and parasitic pathogens that cause SSTIs the clues for reaching a diagnosis, including reported past medical history, hobbies and behaviors, travel, insect bites, exposure to other people and to animals, environmental exposures to water, soil, or sand, as well as the anatomic site of skin lesions, their morphology on examination, and their evolution over time. Laboratory and radiographic tests are discussed that may be used to confirm a specific diagnosis.

Overview: The Ongoing Threat of Antimicrobial Resistance.

The effectiveness of antibiotics continues to erode because of the relentless spread of antimicrobial resistance (AMR). Public and private foundations, professional organizations, and international health agencies recognize the threat posed by AMR and have issued calls for action. One of the main drivers of AMR is overprescription of antibiotics, both in human and in veterinary medicine. The One Health concept is a response from a broad group of stakeholders to counter the global health threat posed by AMR. In this article, we discuss current trends in AMR and suggest strategies to mitigate its ongoing dissemination.

Updated guidance on the management of COVID-19: from an American Thoracic Society/European Respiratory Society coordinated International Task Force (29 July 2020).

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a disease caused by severe acute respiratory syndrome-coronavirus-2. Consensus suggestions can standardise care, thereby improving outcomes and facilitating future research. METHODS: An International Task Force was composed and agreement regarding courses of action was measured using the Convergence of Opinion on Recommendations and Evidence (CORE) process. 70% agreement was necessary to make a consensus suggestion. RESULTS: The Task Force made consensus suggestions to treat patients with acute COVID-19 pneumonia with remdesivir and dexamethasone but suggested against hydroxychloroquine except in the context of a clinical trial; these are revisions of prior suggestions resulting from the interim publication of several randomised trials. It also suggested that COVID-19 patients with a venous thromboembolic event be treated with therapeutic anticoagulant therapy for 3 months. The Task Force was unable to reach sufficient agreement to yield consensus suggestions for the post-hospital care of COVID-19 survivors. The Task Force fell one vote shy of suggesting routine screening for depression, anxiety and post-traumatic stress disorder. CONCLUSIONS: The Task Force addressed questions related to pharmacotherapy in patients with COVID-19 and the post-hospital care of survivors, yielding several consensus suggestions. Management options for which there is insufficient agreement to formulate a suggestion represent research priorities.