David G. Welkie, Benjamin E. Rubin, Spencer Diamond, Rachel D. Hood, David F. Savage, Susan S. Golden

Cyanobacteria are photosynthetic prokaryotes that are influential in global geochemistry and are promising candidates for industrial applications. Because the livelihood of cyanobacteria is directly dependent upon light, a comprehensive understanding of metabolism in these organisms requires taking into account the effects of day–night transitions and circadian regulation. These events synchronize intracellular processes with the solar day. Accordingly, metabolism is controlled and structured differently in cyanobacteria than in heterotrophic bacteria.

Harrison, O. J., Linehan, J. L., Shih, H.-Y., Bouladoux, N., Han, S.-J., Smelkinson, M., Sen, S. K., Byrd, A. L., Enamorado, M., Yao, C., Tamoutounour, S., Van Laethem, F., Hurabielle, C., Collins, N., Paun, A., Salcedo, R., OShea, J. J., Belkaid, Y.

Barrier tissues are primary targets of environmental stressors and home to the largest number of antigen-experienced lymphocytes in the body, including commensal-specific T cells. Here, we show that skin-resident commensal-specific T cells harbor a paradoxical program characterized by a type-17 program associated with a poised type-2 state. Thus, in the context of injury and exposure to inflammatory mediators such as IL-18, these cells rapidly release type-2 cytokines, thereby acquiring contextual functions. Notably, such acquisition of a type-2 effector program promotes tissue repair. Aberrant type-2 responses can also be unleashed in the context of local defects in immunoregulation. Thus, commensal-specific T cells co-opt tissue residency and cell-intrinsic flexibility as a means to promote both local immunity and tissue adaptation to injury.…

Abstract Background The malaria Eradication Research Agenda (malERA) has identified human-to-mosquito transmission of Plasmodium falciparum as a major target for eradication. The cornerstone for identifying and evaluating transmission in the laboratory is standard membrane feeding assays (SMFAs) where mature gametocytes of P. falciparum generated in vitro are offered to mosquitoes as part of a blood-meal. However, propagation of “infectious” gametocytes requires 10–12 days with considerable physico-chemical demands imposed on host RBCs and thus, “fresh” RBCs that are ≤ 1-week old post-collection are generally recommended. However, in addition to the costs, physico-chemical characteristics unique to RBC donors may confound reproducibility and interpretation of SMFAs. Cryogenic storage of RBCs (“cryo-preserved RBCs”) is accepted by European and US FDAs as an alternative to refrigeration (4 °C) for preserving RBC “quality” and while cryo-preserved RBCs have been used for in vitro cultures of other Plasmodia and the asexual stages of P. falciparum, none of the studies required RBCs to support parasite development for > 4 days. Results Using the standard laboratory strain, P. falciparum NF54, 11 SMFAs were performed with RBCs from four separate donors to demonstrate that RBCs cryo-preserved in the gaseous phase of liquid nitrogen (− 196 °C) supported gametocytogenesis in vitro and subsequent gametogenesis in Anopheles stephensi mosquitoes. Overall levels of sporogony in the mosquito, as measured by oocyst and sporozoite prevalence, as well as oocyst burden, from each of the four donors thawed after varying intervals of cryopreservation (1, 4, 8, and 12 weeks) were comparable to using ≤ 1-week old refrigerated RBCs. Lastly, the potential for cryo-preserved RBCs to serve as a suitable alternative substrate is demonstrated for a Cambodian isolate of P. falciparum across two independent SMFAs. Conclusions Basic guidelines are presented for integrating cryo-preserved RBCs into an existing laboratory/insectary framework for P. falciparum SMFAs with significant potential for reducing running costs while achieving greater reliability. Lastly, scenarios are discussed where cryo-preserved RBCs may be especially useful in enhancing the understanding and/or providing novel insights into the patterns and processes underlying human-to-mosquito transmission.…

Klompas, Michael; Rhee, Chanu

No abstract available…

Abstract Background Malaria is still a major public health concern in Bangladesh in spite of mass distribution of long-lasting insecticide-treated nets (LLINs) as a key preventive strategy. There might be a considerable gap between coverage and actual use of nets by the population in endemic areas. This study intended to assess the gap between coverage, access to and use of LLINs among the households in malaria-endemic settings in Bangladesh. Methods This cross-sectional study collected data from 2640 households of 13 endemic districts of Bangladesh through three-stage cluster random sampling. The gap between coverage, access and use of LLINs were calculated using the procedure established by the Roll Back Malaria Monitoring and Evaluation Reference Group. To support the quantitative findings, qualitative data were also collected through in-depth interview, focus group discussion and key informant interview and analysed accordingly. Results Of 2640 total households, 77.4% (n = 2044) possessed at least two LLINs, 56.8% (n = 1499) had insufficient access, and 18.8% (n = 495) had excess LLINs. Members of 77.9% (n = 2056) households had used LLINs the previous night and 6.0% (n = 68) did not use LLINs despite having sufficient access. LLIN use was lower in non-hill track areas, in Bengali community, in richer households and households with more than four members. Moreover, qualitative findings revealed that the major reasons behind not using LLINs were insufficient access, sleeping outside the home, migration, perceived low efficacy of LLINs, or fear of physical side effects. Conclusion Closing the access gap by providing enough nets through solid investment and well-designed behavioural change interventions are crucial for achieving and sustaining universal coverage.…

Meng, Lingzhong; Wang, Yingwei; Zhang, Lina; McDonagh, David L.

Objectives: Pressure autoregulation is an organ’s intrinsic ability to maintain blood flow despite changes in perfusion pressure. The purpose of this review is to discuss autoregulation’s heterogeneity among different organs and variability under different conditions, a very clinically relevant topic. Data Sources: Systematic search of Ovid MEDLINE; nonsystematic search of PubMed, Google Scholar, and reference lists. Study Selection: Animal or human studies investigating the potency or variation of pressure autoregulation of any organs or the association between autoregulation and outcomes. Data Extraction: Two authors screened the identified studies independently then collectively agreed upon articles to be used as the basis for this review. Data Synthesis: Study details, including subjects, organ investigated, methods of blood pressure intervention and blood flow measurement, and values of the lower limit, upper limit, and plateau were examined. Comparative canine studies were used to demonstrate the heterogeneity of pressure autoregulation among different organs and validate the proposed scale for organ categorization by autoregulatory capacity. Autoregulatory variability is discussed per organ. The association between cerebral autoregulation and outcome is summarized. Conclusions: The organs with robust autoregulation are the brain, spinal cord, heart, and kidney. Skeletal muscle has moderate autoregulation. Nearly all splanchnic organs including the stomach, small intestine, colon, liver, and pancreas possess weak autoregulation. Autoregulation can be readily affected by a variety of clinically relevant factors. Organs with weak or weakened autoregulation are at a greater risk of suboptimal perfusion when blood pressure fluctuates. Cerebral autoregulation and outcomes are closely related. These lessons learned over 100+ years are instructive in clinical care. Drs. Meng and Wang planning and study designing the article. All authors writing and revising the article. 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). Support was provided solely from institutional and/or departmental sources. Dr. Meng is a consultant to CAS Medical Systems, and Dr. McDonagh has research support from Lungpacer Medical. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: lingzhong.meng@yale.edu; wangyingwei@yahoo.com Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Chen, Han; Menon, David K.; Kavanagh, Brian P.

Objectives: A narrative review of the pathophysiology linking altered airway pressure and intracranial pressure and cerebral oxygenation. Data Sources: Online search of PubMed and manual review of articles (laboratory and patient studies) of the altered airway pressure on intracranial pressure, cerebral perfusion, or cerebral oxygenation. Study Selection: Randomized trials, observational and physiologic studies. Data Extraction: Our group determined by consensus which resources would best inform this review. Data Synthesis: In the normal brain, positive-pressure ventilation does not significantly alter intracranial pressure, cerebral oxygenation, or perfusion. In injured brains, the impact of airway pressure on intracranial pressure is variable and determined by several factors; a cerebral venous Starling resistor explains much of the variability. Negative-pressure ventilation can improve cerebral perfusion and oxygenation and reduce intracranial pressure in experimental models, but data are limited, and mechanisms and clinical benefit remain uncertain. Conclusions: The effects of airway pressure and ventilation on cerebral perfusion and oxygenation are increasingly understood, especially in the setting of brain injury. In the face of competing mechanisms and priorities, multimodal monitoring and individualized titration will increasingly be required to optimize care. Drs. Chen, Menon, and Kavanagh helped with conception and design, and drafting the article for important intellectual content. 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 funds (to Dr. Kavanagh) from the Canadian Institutes of Health Research. Dr. Chen is supported by National Natural Science Foundation of China (Grant Number: 81701942). Dr. Menon received support for article research from National Institute for Health Research, United Kingdom. He is a Professorial Fellow, Queens’ College, Cambridge, United Kingdom, and a Senior Investigator, National Institute for Health Research, United Kingdom. Dr. Kavanagh disclosed that he has a patent pending for a device for mechanical ventilation. He holds the Dr Geoffrey Barker Chair in Critical Care Research. For information regarding this article, E-mail: brian.kavanagh@utoronto.ca Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Mori M, Leitman E, Walker B, et al.

AbstractBackgroundHLA class I contributes to HIV immune control through antigen presentation to both cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. However, by contrast with investigations of CTL, studies of NK cells in HIV control through HLA-killer immunoglobulin-like receptor (KIR) interactions remain sparse in African cohorts.Methods312 treatment naïve, chronically HIV-infected adults were recruited from South Africa, and the effects of HLA-KIR pairs on clinical outcome were statistically analyzed.ResultsThere was no significant difference in viral load among all subjects with HLA alleles from the HLA-C1 group (p=0.1). However, differences in HLA-C type significantly influenced viremia among 247 KIR2DL3 positives (p=0.04), suggesting that specific HLA-KIR interactions contribute to immune control. Higher viral load (p=0.02) and lower CD4+ T cell counts (p=0.008) were observed in subjects with HLA-C*16:01+KIR2DL3+. Longitudinal analysis showed more rapid progression to AIDS among HLA-C*16:01+KIR2DL3+ positives (aHR 1.9, p=0.03) than in subjects without this genotype, independent of CD4+ T cell count and viral load.ConclusionsThese highlight the existence of unique anti-HIV innate immunity within distinct populations and the contribution of KIR on NK cells and some CTLs to the well-described HLA-mediated impact on HIV disease progression.

Abstract Background Plasmodium falciparum haemozoin, a detoxification product of digested haemoglobin from infected erythrocytes, is released into the bloodstream upon schizont rupture and accumulates in leukocytes. High levels of haemozoin correlate with disease severity. Some studies have shown that concentrations of the substrate of inducible nitric oxide synthase (iNOS), l-arginine, as well as nitric oxide are low in patients infected with P. falciparum malaria. The present study investigates, in vitro, the role of P. falciparum haemozoin on nitric oxide production, iNOS expression in macrophages, and the possible interaction between l-arginine and haemozoin. Methods Plasmodium falciparum haemozoin was obtained from in vitro cultures through magnetic isolation. Phagocytosis of haemozoin by immortalized bone marrow derived macrophages was detected by confocal reflection combined with fluorescence microscopy. Nitrite concentrations in the supernatants was evaluated by Griess assay as a standard indication of nitric oxide production, while iNOS expression was detected on cell extracts by western blotting. Detection of l-arginine in haemozoin-treated or untreated media was achieved by liquid chromatography–tandem mass spectrometry (LC–MS/MS). Results Haemozoin synergizes in vitro with interferon-gamma to produce nitric oxide. However, when mouse macrophages were stimulated with haemozoin, a proportional increase of nitric oxide was observed up to 25 μM of haemozoin, followed by a decrease with doses up to 100 μM, when nitric oxide release was completely abrogated. This was not due to reactive oxygen species production, nor to an effect on iNOS activity. Interestingly, when at 24 h, haemozoin-treated macrophages were washed and incubated in fresh medium for further 24 h, the nitric oxide production was restored in a dose–response manner. Similar results were seen when l-arginine-enriched media was used in the stimulation. Moreover, muramyldipeptide, a strong nitric oxide inducer, was unable to activate macrophages to release nitric oxide in the presence of haemozoin-treated medium. By LC–MS/MS a complete depletion of l-arginine was observed in this haemozoin-treated, conditioned medium. Conclusions It is proposed that haemozoin interacts with l-arginine reducing its availability for iNOS, and thus decreasing nitric oxide production. The clinical (or pathological) implications of these results are discussed.…

Abstract Background Previous studies have suggested that Toxoplasma gondii (T. gondii) infection might be associated with fatty liver disease. However, the relationship between non-alcoholic fatty liver disease (NAFLD) and T. gondii infection has not been investigated in a large population. We aimed to study the relationship between those two diseases using a population-based dataset from the United States. Methods The data were collected from the third National Health and Nutrition Examination Survey (NHANES III) between 1988 and 1994. Statistical analysis was applied to compare the prevalence of NAFLD in anti-T. gondii antibody-positive participants with antibody-negative ones. Results A total of 9465 persons with a mean age of 44.33 ± 16.21 years, 46.9% of which were males, were included in the final analysis. Their mean BMI was 27.60 ± 5.96 kg/m2. A total of 2520 participants (26.62%) were positive for the T. gondii antibody. There was an increasing trend of seroprevalence of T. gondii with age (P for trend

Garnacho-Montero, José; Timsit, Jean-François

Purpose of review We reviewed recent data about epidemiology of Acinetobacter baumannii, resistance mechanisms, and therapeutic options for severe infections caused by multidrug-resistant strains. Recent findings A. baumannii is a major cause of nosocomial infections affecting mainly to debilitating patients in the ICU, although the spread to regular wards and to long-term care facilities is increasing. It is characterized by its great persistence in the environment and to have an extraordinary capability to develop resistance to all antimicrobials. Carbapenems may not be considered the treatment of choice in areas with high rates of carbapenem-resistant A. baumannii. Nowadays, polymyxins are the antimicrobials with the greatest level of in-vitro activity against A. baumannii. Colistin is the most widely used in clinical practice although polymyxin B seems to be associated with less renal toxicity. Colistin is administered intravenously as its inactive prodrug colistimethate. A loading dose of 9 million IU and subsequently high, extended-interval maintenance doses (4.5 million IU/12 h) are recommended. Combination therapy instead of monotherapy increases the rates of microbiological eradication although no clinical study has demonstrated a reduction in clinical outcomes (mortality or length of stay). Summary The optimal treatment for multidrug-resistant A. baumannii nosocomial infections has not been established. There are no compelling data to recommend combination therapy for severe A. baumannii infections. Correspondence to José Garnacho-Montero, Unidad Clínica de Cuidados Intensivos, Hospital Universitario Virgen Macarena, Sevilla, Spain. E-mail: jgarnachom@gmail.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Pisanic N, Ballard S, Colquechagua F, et al.

AbstractBackgroundNorovirus is a leading cause of acute gastroenteritis worldwide. Routine norovirus diagnosis requires stool collection. The goal of this study was to develop and validate a noninvasive method to diagnose norovirus to complement stool diagnostics and to facilitate studies on transmission.MethodsA multiplex immunoassay to measure salivary immunoglobulin G (IgG) responses to 5 common norovirus genotypes (GI.1, GII.2, GII.4, GII.6, and GII.17) was developed. The assay was validated using acute and convalescent saliva samples collected from Peruvian children

Abstract Background Hand, foot and mouth disease (HFMD) is a major communicable disease in children ≤6 years old, particularly in several countries in the Asia-Pacific Region, including Thailand. HFMD impacts public health and the economy, especially in northern Thailand. Methods A prospective cohort study was conducted to estimate the incidence rate and to identify the serotype and clinical features of HFMD among children in northern Thailand. A validated questionnaire and throat swab were used for data collection. Polymerase chain reaction (PCR) was used to detect human enterovirus and identify its serotypes. Participants were recruited from 14 hospitals in two provinces in northern Thailand, specifically, Chiang Rai and Pha Yao Province, between January 1, 2016, and December 31, 2016. Chi-square or Fisher’s exact test was used to detect the associations of signs and symptoms with HFMD serotype. Logistic regression was used to detect the associations of variables with a positive enterovirus at alpha = 0.05. Result In total, 612 children aged ≤6 years from Chiang Rai and Pha Yao Province who were diagnosed with HFMD by a throat swab were recruited for the analysis. Approximately half of the cohort was male (57.2%), 57.5% was aged  6 months, and children who had mother who worked as farmers, daily wage employees, and unprofessional skilled jobs had a greater chance of enterovirus infection than those who had unemployed mothers. Coxsackievirus-infected children had a higher rate of rashes on the buttocks, knee, and elbow and fever but a lower rate of lethargy and malaise than EV-A71-infected children. Conclusions EV-A71 is a major cause of HFMD in children

Bosch, Nicholas A.; Cohen, David M.; Walkey, Allan J.

Objective: Atrial fibrillation frequently develops in patients with sepsis and is associated with increased morbidity and mortality. Unfortunately, risk factors for new-onset atrial fibrillation in sepsis have not been clearly elucidated. Clarification of the risk factors for atrial fibrillation during sepsis may improve our understanding of the mechanisms of arrhythmia development and help guide clinical practice. Data Sources: Medline, Embase, Web of Science, and Cochrane CENTRAL. Study Selection: We conducted a systematic review and meta-analysis to identify risk factors for new-onset atrial fibrillation during sepsis. Data Extraction: We extracted the adjusted odds ratio for each risk factor associated with new-onset atrial fibrillation during sepsis. For risk factors present in more than one study, we calculated pooled odds ratios (meta-analysis). We classified risk factors according to type and quantified the factor effect sizes. We then compared sepsis-associated atrial fibrillation risk factors with risk factors for community-associated atrial fibrillation. Data Synthesis: Forty-four factors were examined as possible risk factors for new-onset atrial fibrillation in sepsis, 18 of which were included in meta-analyses. Risk factors for new-onset atrial fibrillation included demographic factors, comorbid conditions, and most strongly, sepsis-related factors. Sepsis-related factors with a greater than 50% change in odds of new-onset atrial fibrillation included corticosteroid use, right heart catheterization, fungal infection, vasopressor use, and a mean arterial pressure target of 80–85 mm Hg. Several cardiovascular conditions that are known risk factors for community-associated atrial fibrillation were not identified as risk factors for new-onset atrial fibrillation in sepsis. Conclusions: Our study shows that risk factors for new-onset atrial fibrillation during sepsis are mainly factors that are associated with the acute sepsis event and are not synonymous with risk factors for community-associated atrial fibrillation. Our results provide targets for future studies focused on atrial fibrillation prevention and have implications for several key areas in the management of patients with sepsis such as glucocorticoid administration, vasopressor selection, and blood pressure targets. Dr. Bosch takes responsibility for the integrity of the work as a whole, from inception to published article, and he drafted the article. Drs. Bosch and Walkey substantially contributed to the conception and design of this study. Drs. Bosch and Cohen acquired the data. Drs. Bosch, Cohen, and Walkey were involved in the interpretation of data and revised it critically for important intellectual content. 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 National Heart, Lung, and Blood Institute grants 5K01HL116768-03 and 1R01HL136660-01 (to Dr. Walkey). Dr. Walkey’s institution received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute; he received royalties from UptoDate; and he received support for article research from the NIH. The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: nicholas.bosch@bmc.org Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.