The Lancet

More than 500 participants will gather in Hong Kong on June 2–5 for the sixth World Conference on Research Integrity (WCRI). One of the ambitions of the WCRIs is to advance research integrity globally by setting standards and agreeing on principles of organising and conducting research. The Singapore Statement, an outcome of the second WCRI in 2010, highlighted four principles and 14 professional responsibilities for researchers and others involved in the research enterprise. The Montreal Statement, developed as part of the third WCRI in 2013, focused on specific challenges for research collaborations.

The Lancet

The Chinese characters for doctor also refer to scholar-bureaucrats, which was the highest aspiration for intellectuals in ancient China. Doctors were then respected as much as Confucian elites who were supposed to have high moral standards and be well educated, altruistic, and dedicated to serving the country. However, in modern China, medicine is no longer seen as a noble or an attractive profession. Last week, four officials were removed from their posts on the basis of their negligence in reviewing and approving an anti-gang brochure in which doctors were portrayed as gangs and listed as first among the top ten gang categories in China.

The Lancet

Despite considerable progress, the Pan American Health Organization (PAHO) estimates that 30% of the population of the Americas still do not have access to the health care they need because of multifaceted barriers. On April 9, leaders, including Mexico's President Andrés Manuel López Obrador, PAHO director Carissa Etienne, and UN High Commissioner for Human Rights Michelle Bachelet, gathered with academics, activists, and representatives of social movements in Mexico City to hear the report of the Commission on Universal Health in the 21st Century.

Helble, J. D., Starnbach, M. N.

Antigen-specific CD4+ T cells against Chlamydia are crucial for driving bacterial clearance and mediating protection against reinfection. Although the C. trachomatis protein Cta1 has been identified as a dominant murine CD4+ T cell antigen, its level of expression during the bacterial developmental cycle and precise localization within the host cell is unknown. Newly developed tools for Chlamydia genetic manipulation have allowed us to generate a C. trachomatis strain expressing a heterologous CD4+ T cell epitope from ovalbumin, OVA323-339. By tagging proteins expressed in C. trachomatis with OVA323-339, we can begin to understand how protein expression, developmental regulation, and subcellular compartmentalization affect the potential of those proteins to serve as antigens. When OVA323-339 was expressed as a fusion with GFP, we found that we were able to elicit an OT-II T cell response in an antigen-dependent manner but surprisingly these T cells were unable to reduce bacterial burden in mice. These data suggest that subcellular localization of antigen, level of antigen expression, or the timing of expression within the developmental cycle of Chlamydia may play a crucial role in eliciting a protective CD4+ T cell response.…

Mira Laajala, Varpu Marjomäki

It has remained a puzzle why infants, during the first weeks of life, are especially prone to enterovirus infections. New work (Proc. Natl. Acad. Sci. U. S. A. 2019;116: 3758–3763) shines light on this matter by showing that the neonatal Fc receptor, prevalent in several tissues, acts as a pan receptor for several echoviruses.

Broitman M, Sox HC, Slutsky J.

This Viewpoint describes the peer review processes of the Patient-Centered Outcomes Research Institute, the yield since 2010 of publicly posted final reports of funded comparative effectiveness studies, and speculates that the benefits of the legislatively mandated process may someday outweigh its many current procedural challenges.

Addetia, A., Greninger, A. L., Adler, A., Yuan, S., Makhsous, N., Qin, X., Zerr, D. M.

Chlorhexidine gluconate (CHG) is a topical antiseptic widely used in healthcare settings. In Staphylococcus spp., the pump QacA effluxes CHG, while the closely related QacB cannot due to a single amino acid substitution. We characterized 1,050 cutaneous Staphylococcus isolates obtained from 173 pediatric oncology patients enrolled in a multicenter CHG bathing trial. CHG susceptibility testing revealed 63 (6%) of these isolates had elevated CHG MICs (≥4 μg/mL). Screening of all 1,050 isolates for qacA/B by restriction fragment length polymorphism (RFLP) yielded 56 isolates with a novel qacA/B RFLP pattern, qacAB273. The CHG MIC was significantly higher for qacAB273-positive isolates (MIC50: 4 μg/mL, [lsqb]range: 0.5–4 μg/mL[rsqb]) compared to other qac groups: qacA-positive (n=559, 1 μg/mL, [lsqb]0.5–4 μg/mL[rsqb]), qacB-positive (n=17, 1 μg/mL, [lsqb]0.25–2 μg/mL[rsqb]), and qacA/B-negative (n=418, 1 μg/mL, [lsqb]0.125–2 μg/mL[rsqb], p=0.001). The qacAB273-positive isolates also displayed a high proportion of methicillin resistance (96.4%) compared to other qac groups (24.9–61.7%, p=0.001). Whole genome sequencing revealed that qacAB273-positive isolates encoded a variant of QacA with 2 amino acid substitutions. This new allele, named qacA4, was carried on the novel plasmid pAQZ1. The qacA4-carrying isolates belonged to the highly resistant S. epidermidis ST2 clone. By searching available sequence datasets, we identified 39 additional qacA4-carrying S. epidermidis strains from 5 countries. Curing an isolate of qacA4 resulted in a four-fold decrease in the CHG MIC, confirming the role of qacA4 in the elevated CHG MIC. Our results highlight the importance of further studying qacA4 and its functional role in clinical staphylococci.…

Carlos A.M. Silva, Barbara Graham Andre, Kristofor Webb, Laura Vari Ashton, Marisa Harton, Annie Luetkemeyer, Samantha Bokatzian, Reem Almubarak, Sebabrata Mahapatra, Laura Hovind, Michelle A. Kendall, Diane Havlir, John T. Belisle, Mary Ann De Groote

The human immunodeficiency virus (HIV) causes functional disruption of the immune response and impairs host ability to control infection by Mycobacterium tuberculosis (Walker et al., 2013) - the etiological agent of tuberculosis (TB). In 2014, there were 9.6 million cases of TB, of which 1.2 million (12.5%) were co-infected with HIV (WHO, 2016). The World Health Organization recommends that all persons with HIV and active TB be promptly treated with antiretroviral therapy (ART) in order to reduce morbidity and mortality (WHO, 2017).

Shelby Daniel-Wayman

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 947-951, April 15, 2019. …

Sancar F.

As lab-to-table beef and poultry products inch closer to reality, the FDA announced a formal agreement to jointly regulate them.

Friedrich MJ.

Experts continue to find zoonotic bacteria with high levels of antimicrobial resistance in humans, animals, and food, according to a new report from the European Food Safety Authority and the European Centre for Disease Prevention and Control.

Lum E, Jimenez G, Huang Z, et al.

This study characterizes the proportion of apps available in 2018 for self-management of type 2 diabetes that included goal-setting features, reminders to measure blood glucose, hypoglycemia and hyperglycemia alerts, and action prompts.

Ziegler, Katherine M.; Haywood, Jonathan D.; Sontag, Marci K.; Mourani, Peter M.

Objectives: We sought to compare the performance of the 2008 Centers for Disease Control and Prevention Pediatric criteria for ventilator-associated pneumonia, the 2013 Adult Ventilator-Associated Condition criteria, the new Draft Pediatric Ventilator-Associated Condition criteria, and physician-diagnosed ventilator-associated pneumonia in a cohort of PICU patients. Design: Secondary analysis of a previously conducted prospective observational study. Setting: PICU within a tertiary care children’s hospital between April 1, 2010, and April 1, 2011. Patients: Patients between 31 days and 18 years old, mechanically ventilated via endotracheal tube for more than 72 hours and no limitations of care. Interventions: None. Measurements and Main Results: Ventilator-associated pneumonia criteria applied in real time and ventilator-associated condition criteria applied retrospectively. Outcomes assessed between cases and noncases within criteria. Of the 133 eligible participants, 24 (18%) had ventilator-associated pneumonia by 2008 Pediatric criteria and 27 (20%) by physician diagnosis. Sixteen (12%) and 10 (8%) had ventilator-associated condition by 2013 Adult and Draft Pediatric criteria, respectively. We found significant overlap between cases identified with 2008 Pediatric criteria and physician diagnosis (p = 0.549), but comparisons between the other definitions revealed that the newer criteria identify different patients than previous Centers for Disease Control and Prevention ventilator-associated pneumonia criteria and physician diagnosis (p < 0.01). Although 20 participants were diagnosed with ventilator-associated pneumonia by 2008 Pediatric criteria and physician diagnosis, only three participants were identified by all four criteria. Three subjects uniquely identified by the Draft Pediatric criteria were noninfectious in etiology. Cases identified by all criteria except Draft Pediatric had higher ratios of actual ICU length of stay to Pediatric Risk of Mortality III-adjusted expected length of stay compared with noncases. Conclusions: The Draft Pediatric criteria identify fewer and different patients than previous ventilator-associated pneumonia criteria or physician diagnosis, potentially missing patients with preventable harms, but also identified patients with potentially preventable noninfectious respiratory deteriorations. Further investigations are required to maximize the identification of patients with preventable harms from mechanical ventilation. New address for Dr. Sontag: Center for Public Health Innovation at CI International, Littleton, CO 80120. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by grant from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute R01HL124103; NIH/National Center for Advancing Translational Sciences Colorado Clinical Translational Sciences Award grant number UL1 TR001082. This project was supported by NIH/National Center for Research Resources Colorado Clinical & Translational Science Institute grant number UL1 RR025780. Its contents are the authors’ sole responsibility and do not necessarily represent official NIH views. Ms. Ziegler’s institution received funding from National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) R01HL124103 and NIH/National Center for Advancing Translational Sciences (NCATS) Colorado Clinical Translational Sciences Award (CTSA) grant number UL1 TR001082. Ms. Ziegler and Drs. Sontag and Mourani received support for article research from the NIH. Dr. Sontag’s institution received funding from NHLBI/NIH, Maternal Child Health Bureau of the Health Resources and Services Administration, and the Cystic Fibrosis Foundation, and she received funding from Research Triangle Institute (External Advisory Board for the Early Check Study). Dr. Mourani’s institution received funding from NHLBI/NIH and NCATS/NIH. Dr. Haywood disclosed that he does not have any potential conflicts of interest. This work was performed at the following institutions: Children’s Hospital Colorado, Aurora, CO and the University of Colorado Denver, Aurora, CO. Corresponding Author: Katie.Ziegler@ucdenver.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Ákos T. Kovács

Bacillus subtilis became the most studied species in the genus Bacillus due to its natural competence for uptake of extracellular DNA that facilitates simple genetic modification and occurrence of sporulation, one of the first studied bacterial cell differentiation processes. The dormant spores can survive harsh circumstances (high temperature, desiccation, UV, and γ-radiation), predation by microorganisms and macroorganisms, or even extraterrestrial conditions. B. subtilis can be isolated from various environments, from soil to marine habitats, and utilized in various applications from enzyme production and food fermentation to plant biocontrol.

Yang, X.-M., Leroux, S., Storme, T., Zhang, D.-L., de Beaumais, T. A., Shi, H.-Y., Yang, Y.-L., Wang, X.-L., Zhao, W., Jacqz-Aigrain, E.

We evaluated the population pharmacokinetics of caspofungin in children (2–12 years old). The real-world data from 48 children were best fit by a two-compartment model with first-order elimination. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics compared to body weight. The population pharmacokinetics of caspofungin confirmed that adjustment of caspofungin based on body surface area is most appropriate for paediatric use.…

Friedrich MJ.

Almost half of all children around the world with cancer—the vast majority of whom live in low- and middle-income countries—are not diagnosed or treated, US researchers have reported.

Kathleen J. Ramos

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 938-940, April 15, 2019. …

Tong, J., Song, Z., Kim, D. H., Chen, X., Chen, C., Palmstrom, A. F., Ndione, P. F., Reese, M. O., Dunfield, S. P., Reid, O. G., Liu, J., Zhang, F., Harvey, S. P., Li, Z., Christensen, S. T., Teeter, G., Zhao, D., Al-Jassim, M. M., van Hest, M. F. A. M., Beard, M. C., Shaheen, S. E., Berry, J. J., Yan, Y., Zhu, K.

All-perovskite-based polycrystalline thin-film tandem solar cells have the potential to deliver efficiencies of > 30%. However, the performance of all-perovskite-based tandem devices have been limited by the lack of high-efficiency, low-band-gap Sn-Pb mixed-perovskite solar cells (PSCs). We report on using guanidinium thiocyanate (GuaSCN) to dramatically improve the structural and optoelectronic properties of Sn-Pb mixed, low-band-gap (~1.25 electron volt) perovskite films that have 10-times lower defect density, leading to carrier lifetimes of greater than 1 microsecond and diffusion lengths of 2.5 micrometer. These improved properties enable our demonstration of >20%-efficient, 1.25-eV, low-band-gap PSCs. When combined with wider bandgap PSCs, we achieve 25%-efficient 4-terminal and 23.1%-efficient 2-terminal all-perovskite-based polycrystalline thin-film tandem solar cells.…

Colaianni C.

In this narrative medicine essay an otolaryngologist remembers a patient who identifies her physicians as characters in the television show Grey’s Anatomy, a playful reference that makes her advanced cancer hospitalizations bearable and disarms her physicians through diversion and humor.

Souli M, Ruffin F, Choi S, et al.

AbstractBackgroundWe conducted a longitudinal study to evaluate changes in the clinical presentation and epidemiology of Staphylococcus aureus bacteremia (SAB) in an academic, US medical center.MethodsConsecutive patients with monomicrobial SAB were enrolled from January 1995 to December 2015. Each person’s initial bloodstream S. aureus isolate was genotyped using spa typing. Clonal complexes (CCs) were assigned using Ridom StaphType software. Changes over time in both the patient and bacterial characteristics were estimated with linear regression. Associations between genotypes or clinical characteristics and complications were estimated using multivariable regression models.ResultsAmong the 2348 eligible participants, 54.2% had an implantable, foreign body of some type. This proportion increased significantly during the 21-year study period, by 0.96% annually (P = .002), as did comorbid conditions and acquisition outside of the hospital. Rates of any metastatic complication also significantly increased, by 0.94% annually (P = .019). Among the corresponding bloodstream S. aureus isolates, spa-CC012 (multi-locus sequence type [MLST] CC30), -CC004 (MLST CC45), -CC189 (MLST CC1), and -CC084 (MLST CC15) all significantly declined during the study period, while spa-CC008 (MLST CC8) significantly increased. Patients with SAB due to spa-CC008 were significantly more likely to develop metastatic complications in general, and abscesses, septic emboli, and persistent bacteremia in particular. After adjusting for demographic, racial, and clinical variables, the USA300 variant of spa-CC008 was independently associated with metastatic complications (odds ratio 1.42; 95% confidence interval 1.02–1.99).ConclusionsSystematic approaches for monitoring complications of SAB and genotyping the corresponding bloodstream isolates will help identify the emergence of hypervirulent clones and likely improve clinical management of this syndrome.

Sancar F.

This Medical News feature summarizes a recent study exploring the link between childhood lead exposure and mental health and personality in adulthood.

Tapia, Pablo; Gatica, Sebastian; Cortés-Rivera, Cristian; Otero, Carolina; Becerra, Alvaro; Riedel, Claudia A.; Cabello-Verrugio, Claudio; Kalergis, Alexis M.; Simon, Felipe

Objectives: To determine whether circulating endothelial cells from septic shock patients and from nonseptic shock patients are transformed in activated fibroblast by changing the expression level of endothelial and fibrotic proteins, whether the level of the protein expression change is associated with the amount of administered resuscitation fluid, and whether this circulating endothelial cell protein expression change is a biomarker to predict sepsis survival. Design: Prospective study. Setting: Medical-surgical ICUs in a tertiary care hospital. Patients: Forty-three patients admitted in ICU and 22 healthy volunteers. Interventions: None. Measurements and Main Results: Circulating mature endothelial cells and circulating endothelial progenitor cells from septic shock and nonseptic shock patients showed evidence of endothelial fibrosis by changing the endothelial protein expression pattern. The endothelial proteins were downregulated, whereas fibroblast-specific markers were increased. The magnitude of the expression change in endothelial and fibrotic proteins was higher in the septic shock nonsurvivors patients but not in nonseptic shock. Interestingly, the decrease in the endothelial protein expression was correlated with the administered resuscitation fluid better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in the septic shock nonsurvivors patients but not in nonseptic shock. Notably, the significant difference between endothelial and fibrotic protein expression indicated a nonsurvival outcome in septic shock but not in nonseptic shock patients. Remarkably, area under the receiver operating characteristic curve analysis showed that endothelial protein expression levels predicted the survival outcome better than the Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores in septic shock but not in nonseptic shock patients. Conclusions: Circulating endothelial cells from septic shock patients are acutely converted into fibroblasts. Endothelial and fibrotic protein expression level are associated with resuscitation fluid administration magnitude and can be used as biomarkers for an early survival diagnosis of sepsis. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by research grants from Fondo Nacional de Desarrollo Científico y Tecnológico—Fondecyt 1161288, 21171566, and 1161646. Millennium Institute on Immunology and Immunotherapy P09-016-F. UNAB DI-741-15/N. Drs. Gatica, Riedel, and Cabello-Verrugio received funding from Fondo Nacional de Desarrollo Científico y Tecnológico—Fondecyt. Dr. Kalergis received funding from Millennium Institute on Immunology and Immunotherapy. Dr. Simon’s institution received funding from Fondo Nacional de Desarrollo Científico y Tecnológico—Fondecyt, and he received support from Millennium Institute on Immunology and Immunotherapy P09-016-F. UNAB DI-741-15/N. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: fsimon@unab.cl Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Jiao, Y., Moya, B., Chen, M.-J., Zavascki, A. P., Tsai, H., Tao, X., Sutaria, D. S., Louie, A., Boyce, J. D., Lucas, D. D., Kim, T. H., Tsuji, B. T., Bonomo, R. A., Drusano, G. L., Bulitta, J. B.

There is a great need for efficacious therapies against Gram-negative bacteria. Double β-lactam combinations (DBL) are relatively safe and preclinical data are promising; however, their clinical role has not been well defined. We conducted a meta-analysis of the clinical and microbiological efficacy of DBL compared to β-lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge and Cochrane Controlled Trials Register were searched until July 2018. We included randomized controlled clinical trials which compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response of Gram-negative bacteria as secondary outcome; sensitivity analyses were performed for Pseudomonas aeruginosa, Klebsiella spp. and Escherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly better clinical response (risk ratio 1.05, CI [0.99-1.11]) and microbiological response in Gram-negatives (risk ratio 1.11, CI [0.99-1.25]) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% vs. 8.8%, p=0.0338) and ototoxicity (0.7 vs. 3.1%, p=0.0137). Other adverse events were largely comparable. Overall, empirically-designed DBL showed comparable clinical and microbiological responses across different Gram-negative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via latest translational approaches leveraging mechanistic insights and newer β-lactams for future evaluation in clinical trials.…

Pais, G. M., Avedissian, S. N., O'Donnell, J. N., Rhodes, N. J., Lodise, T. P., Prozialeck, W. C., Lamar, P. C., Cluff, C., Gulati, A., Fitzgerald, J. C., Downes, K. J., Zuppa, A. F., Scheetz, M. H.

Introduction: Urinary biomarkers are superior to serum creatinine for defining onset and extent of kidney injury. This study classifies the temporal predictive ability of biomarkers for vancomycin-induced kidney injury (VIKI) as defined by histopathologic damage.Methods: Male Sprague-Dawley rats (n=125) were randomized to receive 150 to 400 mg/kg/day vancomycin via once or twice daily intraperitoneal injection over 1, 3, or 6 days. Urine was collected once during the 24 hours prior to euthanasia or twice for rats treated for 6 days. Receiver operating characteristic curves (ROC) were employed to assess urinary biomarker performance of kidney injury molecule 1 (KIM-1), clusterin, osteopontin (OPN), cystatin C, and neutrophil gelatinase-associated lipocalin (NGAL) to predict histopathologic defined VIKI (using a national standard pathologic assessment scheme from hematoxylin and eosin stained kidneys).Results: Urinary KIM-1, clusterin, and OPN outperformed cystatin C and NGAL according to sensitivity and specificity. For the earliest injury, urinary KIM-1 (AUC 0.662, p

Bashor, C. J., Patel, N., Choubey, S., Beyzavi, A., Kondev, J., Collins, J. J., Khalil, A. S.

Eukaryotic genes are regulated by multivalent transcription factor complexes. Through cooperative self-assembly, these complexes perform non-linear regulatory operations involved in cellular decision-making and signal processing. Here, we apply this design principle to synthetic networks, testing whether engineered cooperative assemblies can program non-linear gene circuit behavior in yeast. Using a model-guided approach, we show that specifying strength and number of assembly subunits enables predictive tuning between linear and non-linear regulatory response for single- and multi-input circuits. We demonstrate that assemblies can be adjusted to control circuit dynamics. We harness this capability to engineer circuits that perform dynamic filtering, enabling frequency-dependent decoding in cell populations. Programmable cooperative assembly provides a versatile way to tune nonlinearity of network connections, dramatically expanding the engineerable behaviors available to synthetic circuits.…

Following publication of the original article [1], the author has flagged errors that affect the scientific content of the article.…

Following publication of the original article [1], it was flagged that the name of the author Lisa Ranford-Cartwright had been (incorrectly) given as ‘Lisa-Ranford Cartwright.…

In the 1 September 2016 issue of the Journal, in the article by Khoury et al (Khoury DS, Cromer D, Möhrle JJ, McCarthy JS, Davenport MP. Defining the effectiveness of antimalarial chemotherapy: investigation of the lag in parasite clearance following drug administration. J Infect Dis 2016; 214:753–61), the authors stated on page 755 that “Two subjects were excluded [from analyses in the subsection “Timing of Treatment Affects Parasite Kinetics in the Lag Phase After Therapy”] because they were treated in the afternoon….” However, 2 errors were made by the authors subsequently in the article. First, although both subjects were excluded from the analysis in this subsection, they were included in analyses summarized in subsequent subsections of Results. Second, 11 other subjects were mistakenly classified as having been treated in the morning despite having been treated in the afternoon. Accordingly, the 11 subjects should have been excluded from analyses, for consistency.

Rajasingham R, Enns E, Khoruts A, et al.

AbstractBackgroundIn 2018, the Infectious Disease Society of America (IDSA) published guidelines for diagnosis and treatment of Clostridioides difficile infection (CDI). However, there is little guidance regarding which treatments are cost-effective.MethodsWe used a Markov model to simulate a cohort of patients presenting with an initial CDI diagnosis. We used the model to estimate the costs, effectiveness, and cost-effectiveness of different CDI treatment regimens recommended in the recently published 2018 IDSA guidelines. The model includes stratification by the severity of the initial infection, and subsequent likelihood of cure, recurrence, mortality, and outcomes of subsequent recurrences. Data sources were taken from IDSA guidelines and published literature on treatment outcomes. Outcome measures were discounted quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs).ResultsUse of fidaxomicin for non-severe initial CDI, vancomycin for severe CDI, fidaxomicin for first recurrence, and FMT for subsequent recurrence (Strategy 44) cost an additional $478 for 0.009 QALYS gained per CDI patient, resulting in an ICER of $31,751 per QALY, below the willingness-to-pay threshold of $100,000/QALY. This is the optimal, cost-effective CDI treatment strategy.ConclusionsMetronidazole is suboptimal for non-severe CDI as it is less beneficial than alternative strategies. The preferred treatment regimen is fidaxomicin for non-severe CDI, vancomycin for severe CDI, fidaxomicin for first recurrence, and FMT for subsequent recurrence. The most effective treatments, with highest cure rates, are also cost-effective due to averted mortality, utility loss, and costs of re-hospitalization and/or further treatments for recurrent CDI.

Wilcox, M. Elizabeth; Vaughan, Kelsey; Chong, Christopher A. K. Y.; Neumann, Peter J.; Bell, Chaim M.

Objectives: Cost-effectiveness analyses are increasingly used to aid decisions about resource allocation in healthcare; this practice is slow to translate into critical care. We sought to identify and summarize original cost-effectiveness studies presenting cost per quality-adjusted life year, incremental cost-effectiveness ratios, or cost per life-year ratios for treatments used in ICUs. Design: We conducted a systematic search of the English-language literature for cost-effectiveness analyses published from 1993 to 2018 in critical care. Study quality was assessed using the Drummond checklist. Setting: Critical care units. Patients or Subjects: Critical care patients. Interventions: Identified studies with cost-effectiveness analyses. Measurements and Main Results: We identified 97 studies published through 2018 with 156 cost-effectiveness ratios. Reported incremental cost-effectiveness ratios ranged from –$119,635 (hypothetical cohort of patients requiring either intermittent or continuous renal replacement therapy) to $876,539 (data from an acute renal failure study in which continuous renal replacement therapy was the most expensive therapy). Many studies reported favorable cost-effectiveness profiles (i.e., below $50,000 per life year or quality-adjusted life year). However, several therapies have since been proven harmful. Over 2 decades, relatively few cost-effectiveness studies in critical care have been published (average 4.6 studies per year). There has been a more recent trend toward using hypothetical cohorts and modeling scenarios without proven clinical data (2014–2018: 19/33 [58%]). Conclusions: Despite critical care being a significant healthcare cost burden there remains a paucity of studies in the literature evaluating its cost effectiveness. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Dr. Bell disclosed that he is a medical consultant to the Ontario Ministry of Health and Long-Term Care. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: elizabeth.wilcox@mail.utoronto.ca Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Jessica M. Bryant, Sebastian Baumgarten, Lucy Glover, Sebastian Hutchinson, Najma Rachidi

CRISPR/Cas9 technology has been developing rapidly in the field of parasitology, allowing for the dissection of molecular processes with unprecedented efficiency. Optimization and implementation of a new technology like CRISPR, especially in nonmodel organisms, requires communication and collaboration throughout the field. Recently, a ‘CRISPR in Parasitology’ symposium was held at the Institut Pasteur Paris, bringing together scientists studying Leishmania, Plasmodium, Trypanosoma, and Anopheles.

Rodolphe Barrangou, Richard A. Notebaart

The advent of CRISPR-based technologies has revolutionized genetics over the past decade, and genome editing is now widely implemented for diverse medical and agricultural applications, such as correcting genetic disorders and improving crop and livestock breeding. CRISPR-based technologies are also of great potential to alter the genetic content of food bacteria in order to control the composition and activity of microbial populations across the food supply chain, from the farm to consumer products.

Maxime J. Jean, Dawei Zhou, Guillaume Fiches, Weili Kong, Huachao Huang, Andrei Purmal, Katerina Gurova, Netty G. Santoso, Jian Zhu

Abstract A cure for human immunodeficiency virus type‐1 (HIV‐1) has been hampered by the limitation of current combination antiretroviral therapy (cART) to address the latent reservoirs in HIV‐1 patients. One strategy proposed to eradicate these reservoirs is the “shock and kill” approach, where latency‐reversing agents (LRAs) are used to reactivate and promote viral cell death and/or immune killing of reactivated cells. Here, we report that curaxin CBL0137, an anti‐tumor compound, can potentiate TNFα‐mediated reactivation of latently infected HIV‐1cell lines. Additionally, the single use of CBL0137 is sufficient to reactivate HIV‐1 latent reservoirs in peripheral mononuclear cells (PBMCs) isolated from HIV‐1 positive, cART‐treated, aviremic patients. Thus, CBL0137 possesses capabilities as a LRA and could be considered for the “shock and kill” approach. This article is protected by copyright. All rights reserved.

Abstract Background Primaquine, an 8-aminoquinoline with anti-hypnozoite activity against Plasmodium vivax, is metabolized by human cytochrome P450 2D6 (CYP2D6) to its active metabolite. Human CYP2D6 activities may influence the metabolism of primaquine and the risk of experiencing Plasmodium relapses following primaquine anti-relapse therapies (PART). In this study, the CYP2D6 profile and its relationship with outcomes of PART in Australian Defence Force (ADF) personnel is retrospectively investigated. Methods Genomic DNA was isolated from stored and de-identified serum or blood samples from ADF personnel deployed on peacekeeping duties to Papua New Guinea (PNG) (1999) and East Timor (1999–2000) who received PART before returning to Australia and after experiencing relapses. CYP2D6 allelic type was determined by PCR and Sanger sequencing. CYP2D6 allele frequency, predicted phenotypes and activity scores were compared among personnel who did not experience P. vivax (ADF-NR, n = 48) and those who experience at least one (ADF-R, n = 109) relapse, as well as between those who experienced 1 (n = 79), 2 (n = 21) and 3–5 (n = 9) relapses within the ADF-R group. Results 16 CYP2D6 alleles were observed in 157 ADF personnel. Alleles *1, *4, *2 and *41 were major alleles (> 5%). The CYP2D6 allele frequency profile in the ADF-NR group matched that of a European population. There was an increased proportion of non-functional CYP2D6 alleles in the ADF-R group compared to the European population and ADF-NR group. However, frequencies of predicted CYP2D6 phenotype and activity score were not different between the ADF-R and ADF-NR groups, nor among sub-groups experiencing multiple relapses within the ADF-R group. Conclusions CYP2D6 phenotype or activity score based on the allele classification was not a major contributor to P. vivax relapse in this ADF cohort. Other factors such as adherence and/or parasite tolerance to primaquine are likely contributing factors to P. vivax relapses in this cohort.…

Jeremy M. Kahn

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 970-979, April 15, 2019. …

Tess Bright, W. Mulwafu, M. Phiri, R. J. H. Ensink, A. Smith, J. Yip, I. Mactaggart, S. Polack

Abstract Objective To determine whether a non‐specialist health worker can accurately undertake audiometry and otoscopy, the essential clinical examinations in a survey of hearing loss, instead of a highly skilled specialist (i.e. ENT or audiologist). Methods Clinic‐based diagnostic accuracy study in Malawi. Consecutively sampled participants ≥18 years had their hearing tested using a validated tablet‐based audiometer (hearTest) by an audiologist (gold‐standard), an audiology officer, a nurse and a community health worker (CHW). Otoscopy for diagnosis of ear pathologies was conducted by an ENT specialist (gold‐standard), an ENT clinical officer, a CHW, an ENT nurse, and a general nurse. Sensitivity, specificity and kappa (k) were calculated. 80% sensitivity, 70% specificity, and kappa of 0.6 were considered adequate. Results 617 participants were included. High sensitivity (>90%) and specificity (>85%) in detecting bilateral hearing loss was obtained by all non‐specialists. For otoscopy, sensitivity and specificity were >80% for all non‐specialists in diagnosing any pathology except for the ENT nurse. Agreement in diagnoses for the ENT clinical officer was good (k=0.7) in both ears. For other assessors, moderate agreement was found (k=0.5). Conclusion A non‐specialist can be trained to accurately assess hearing using mobile‐based audiometry. However, accurate diagnosis of ear conditions requires at least an ENT clinical officer (or equivalent). Conducting surveys of hearing loss with non‐specialists could lower costs and increase data collection, particularly in low and middle‐income countries, where ENT specialists are scarce. This article is protected by copyright. All rights reserved.

Abstract Background To investigate the diagnostic value of the interferon-γ release assay (IGRA) for detecting tuberculosis (TB) infection in patients with Behçet’s disease (BD). Methods We retrospective analyzed the data collected from 173 BD patients hospitalized between 2010 and 2015. Ninety-nine healthy volunteers were enrolled as a control group. IGRA was performed using T-SPOT.TB. The diagnosis of active TB (ATB) was based on clinical, radiological, microbiological, histopathological information and the response to anti-TB therapy. Latent TB (LTB) infection was defined as asymptomatic patients with positive T-SPOT.TB. Results TB infection was documented in 59 BD patients (34.1%). The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio and negative likelihood ratio of T-SPOT.TB for the diagnosis of ATB were 88.9%, 74.8%, 29.1%, 98.3%, 3.53 and 0.15, respectively. The receiver-operating-characteristic curve demonstrated that spot-forming cells (SFCs) of 70/106 PBMC was the optimal cutoff for diagnosing ATB, with an area under the curve of 0.891. Furthermore, the median SFCs in ATB group was significantly higher than those in LTB infection (466/106 PBMC vs. 68/106 PBMC, p = 0.007) or previous TB infection (466/106 PBMC vs. 96/106 PBMC, p = 0.018). A significant discrepancy between T-SPOT.TB and tuberculin skin test was noted (kappa coefficient = 0.391, p = 0.002). Conclusions T-SPOT.TB, an IGRA, may assist in the diagnosis of ATB in BD patients, and the higher SFCs suggest ATB in BD patients.…

Abstract Background Visceral leishmaniasis is a vector-borne parasitic disease caused by protozoa belonging to the genus Leishmania. The clinical presentation of visceral leishmaniasis strictly depends on the host immunocompetency, whereas depressive conditions of the immune system impair the capability to resolve the infection and allow reactivation from sites of latency of the parasite. Case presentation We describe a case of visceral leishmaniasis (VL) that occurred in a patient with chronic hepatitis C treated with direct-acting antiviral drugs (DAA). The hypothesized mechanism is the alteration of protective inflammation mechanisms secondary to DAA therapy. Downregulation of type II and III IFNs, their receptors, which accompany HCV clearance achieved during treatment with sofosbuvir and ribavirin might have a negative impact on a risk for reactivation of a previous Leishmania infection. We know indeed that IFN-γ is important to enhance killing mechanisms in macrophages, which are the primary target cells of Leishmania. Conclusion Since VL is endemic in Sicily as well as in other countries of the Mediterranean basin, physicians should be aware of the possible unmasking of cryptic Leishmania infection by DAAs.…

Sio TT, Le-Rademacher JG, Leenstra JL, et al.

This phase 3 randomized trial compares the effect of doxepin mouthwash or diphenhydramine-lidocaine-antacid mouthwash on oral mucositis–related pain among patients who underwent definitive head and neck radiotherapy.

Rubin R.

This Medical News article is an interview with the first pediatrician and second woman physician to serve in Congress.

Chirikov V, Simões E, Kuznik A, et al.

AbstractBackgroundThis study evaluates the long-term RSV burden among pre-term and term infants in the US.MethodsInfants with birth hospitalization claim and ≥24 months of continuous enrollment were retrospectively identified in the Truven MarketScan® Commercial Claims and Encounters database 01JAN04–30SEP2015. Infants with RSV in the first year of life (n=38,473) were matched to controls (n=76,825) and remaining imbalances adjusted using propensity score methodology. All-cause, respiratory- and asthma/wheezing-related 5-year average cumulative costs were measured.ResultsEarly premature (n=213), premature (n=397), late premature (n=4446), and full-term (n=33,417) RSV infants were matched to 424, 791, 8875, and 66,735 controls, respectively. At 2-years follow-up, all-cause cumulative costs compared with controls increased by: for early premature, $51,016 (95% CI: $3725, $98,306); premature, $29,226 ($13,285, $45,166); late premature, $11,372 ($9255, $13,490); full-term infants, $6665 ($6301, $7029). The 5-year RSV burden increased to $57,274 (95% CI: $9700, $104,848), $30,484 ($14,400, $46,567), $15,085 ($12,528, $17,643), and $8973 ($8522, $9424), respectively. The RSV burden was higher when stratified by inpatient/outpatient settings and respiratory- and asthma/wheezing-related costs.ConclusionsThe RSV burden extends across cost domains and prematurity with greatest burden incurred by second year of follow-up. Findings are useful in determining the costeffectiveness of RSV agents in development.

Song Z, Baicker K.

This cluster randomized clinical trial evaluates the effects of a workplace wellness program comprising nutrition, physical activity, and stress reduction modules on self-reported lifestyle outcomes (exercise, diet, smoking, alcohol use), clinical measures (eg, cholesterol, blood pressure, body mass index [BMI]), spending and utilization measures, and employment outcomes (absenteeism job tenure, job performance).

Rosenstock J, Allison D, Birkenfeld AL, et al.

This randomized clinical trial compares the effects of 3-, 7-, and 14-mg/d of oral semaglutide vs sitagliptin on glycated hemoglobin in patients with type 2 diabetes uncontrolled with metformin alone or with sulfonylurea.

Lv, X., Alder, J., Li, L., O'Riordan, W., Rybak, M. J., Ye, H., Zhang, R., Zhang, Z., Zhu, X., Wilcox, M. H.

Tedizolid phosphate is approved for the treatment of acute bacterial skin and skin structure infection (ABSSSI) caused by Gram-positive bacteria in the USA, Europe, and other countries.In this multicenter, double-blind, Phase 3 study, 598 adult ABSSSI patients in China, Taiwan, the Philippines, and the USA were randomized to receive tedizolid 200 mg, intravenous (IV)/oral (PO), once daily for 6 days or linezolid 600 mg, IV/PO twice daily for 10 days. The primary endpoint was early clinical response rate at 48–72 hours. Secondary endpoints included programmatic and investigator-assessed outcomes at end-of-therapy (EOT) and post-therapy evaluation (PTE) visits. Safety was also evaluated.In the intent-to-treat (ITT) population, 75.3% of tedizolid-treated patients and 79.9% of linezolid-treated patients were early responders (treatment difference: –4.6%; 95% confidence interval (CI): –11.2; 2.2). After exclusion of patients who never received study drug (tedizolid: n=8; linezolid: n=1; modified ITT), comparable early response rates were observed (tedizolid: 77.4%; linezolid: 80.1%; treatment difference: –2.7%; 95% CI: –9.4; 3.9). Secondary endpoints showed high and similar clinical success rates in the ITT and clinically evaluable (CE) populations at EOT and PTE visits (e.g. CE-PTE: tedizolid: 90.4%; linezolid: 93.5%). Both drugs were well tolerated and no death occurred. Eight patients experienced phlebitis with tedizolid versus none with linezolid, hence, drug-related treatment-emergent adverse events were reported in a slightly higher proportion in the tedizolid (20.9%) arm than linezolid arm (15.8%), respectively.The study demonstrated that tedizolid in a primarily Asian population was an efficacious and well-tolerated treatment option for ABSSSI patients.…

Brendan Elsworth, Caroline D. Keroack, Manoj T. Duraisingh

The malaria parasite must digest host cytoplasm for normal growth, and many studies have revealed the essential role of proteases in hemoglobin digestion. Here, we discuss the results of Jonscher et al. (Cell Host Microbe 2019;25:166–173) who have, for the first time, identified a molecule, VPS45, involved in the uptake and trafficking of host cytoplasm to the digestive vacuole.

Abraham J.

Approximately 4 of 5 large US employers offer a wellness program as part of their employees’ health benefits. Workplace wellness programs include a coordinated set of activities that support employees in making changes to health behaviors that may reduce their risk for certain chronic conditions and enable employees with existing diagnoses to manage them more effectively. Comprehensive, multicomponent programs typically include health assessments and biometric screening to quantify risk factors; education and coaching for lifestyle behavior modification (eg, tobacco cessation, physical activity promotion, stress reduction, and weight management); and in some cases, chronic disease management.

In the JAMA Forum article titled “Teaching Pelvic Examination Under Anesthesia Without Patient Consent,” published in the February 26, 2019, issue of JAMA, there was an error in the sentence “The Association of American Medical Colleges, reversing its prior policy position, offered that ‘performing pelvic examinations on women under anesthesia, without their knowledge or approval…is unethical and unacceptable.’” The Association of American Medical Colleges did not reverse its prior policy position; the organization has been on record in opposing the practice since 2003. This article has been corrected online.

Kahal D.

To the Editor Dr Wilder et al described a patient treated and cured of HCV who subsequently underwent VCTE to restage his liver disease. Vibration-controlled transient elastography or routine monitoring of fibrosis regression is not currently recommended after HCV cure.

Wilder J, Choi SS, Moylan CA.

In Reply Dr Fischer and colleagues highlight 2 important points regarding the decision to perform VCTE. We agree that specificity describes the accuracy of a test in the absence of disease and defines the ability of a test to correctly classify an individual as disease free. We obtained our information regarding 94% specificity of VCTE to rule out cirrhosis from the study by Cardoso et al. Accuracy of VCTE was evaluated in patients with hepatitis B and HCV in whom the presence of cirrhosis was unknown. In their analysis, VCTE was 94% specific in individuals without cirrhosis and an LSM less than 12.5 kPa. The intent of our sentence was to indicate the accuracy of the test and probably should not have used the word specific given the interpretation that this would mean specificity. We have asked that the article be corrected online to the following: “VCTE is 93% accurate for cirrhosis when LSM is greater than the threshold . . . .” We apologize for any confusion.

Rass, Verena; Gaasch, Max; Kofler, Mario; Schiefecker, Alois Josef; Ianosi, Bogdan-Andrei; Steinkohl, Fabian; Beer, Ronny; Pfausler, Bettina; Gizewski, Elke R.; Thomé, Claudius; Schmutzhard, Erich; Helbok, Raimund

Objectives: Optimal fluid management is important in patients with acute brain injury, including subarachnoid hemorrhage. We aimed to examine the relationship between daily fluid intake and fluid balance with hospital complications and functional outcome. Design: Retrospective observational cohort study. Setting: Neurocritical care unit at a tertiary academic medical center. Patients: Two-hundred thirty-seven consecutive nontraumatic subarachnoid hemorrhage patients admitted to the neurologic ICU between 2010 and 2016. Interventions: Total daily amount of fluids and fluid balance were calculated over 15 days. Using multivariate generalized estimating equation models the association of daily fluid intake and fluid balance with disease severity, hospital complications and poor functional outcome (3-mo modified Rankin Score ≥ 3) was investigated. Additionally, we described the composition of fluids given. Measurements and Main Results: Patients presented with a median admission Hunt and Hess grade of 3 (interquartile range, 1–5) and were 57 years old (interquartile range, 47–67 yr old). A higher daily fluid intake was associated with higher admission Hunt and Hess grade (odds ratio, 1.61; 95% CI, 1.47–1.76; p < 0.001), increased pulmonary fluid accumulation (adjusted odds ratio, 1.11; 95% CI, 1.01–1.21; p = 0.033), prolonged mechanical ventilation (Wald statistic = 20.08; degrees of freedom = 1; p < 0.001), higher daily Subarachnoid hemorrhage Early Brain Edema Score (adjusted odds ratio, 1.11; 95% CI, 1.01–1.22; p = 0.034), occurrence of anemia (adjusted odds ratio, 1.36; 95% CI, 1.20–1.54; p < 0.001), delayed cerebral ischemia (adjusted odds ratio, 1.31; 95% CI, 1.14–1.51; p < 0.001), and poor functional outcome (adjusted odds ratio, 1.25; 95% CI, 1.10–1.41; p < 0.001). Daily fluid balance was associated with higher admission Hunt and Hess grade (odds ratio, 1.09; 95% CI, 1.05–1.13; p < 0.001) and anemia (adjusted odds ratio, 1.17; 95% CI, 1.03–1.33; p = 0.019). The main contributors to fluids were nutritional compounds (31%), IV drugs (30%), and volume substitution (17%). Conclusions: Our study demonstrates a significant association of fluid intake but not fluid balance with hospital complications and poor functional outcome in subarachnoid hemorrhage patients. A larger prospective study is needed to confirm our results. Drs. Rass and Gaasch have contributed equally to this work. Drs. Beer and Helbok (under project number KLI 375) received support for article research from the Austrian Science Fund (FWF). Dr. Beer’s institution received funding from FWF. Dr. Thomé’s institution received funding from BrainLab, DepuySynthes, Intrinsic Therapeutics, Pfizer, Signus Medical, BIT Pharma GmBh, Tissue Engineering Technologies AG, and Edge Therapeutics, and he received funding from BrainLab, DepuySynthes, Intrinsic Therapeutics, Signus Medical, Medtronic, Icotec, Edge Therapeutics, and Zeiss. The remaining authors have disclosed that they do not have any potential conflicts of interest. This work was performed at Neurological Intensive Care Unit, Department of Neurology, Medical University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. For information regarding this article, E-mail: raimund.helbok@tirol-kliniken.at Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.