Irving, Adam; Higgins, Alisa; Ady, Bridget; Bellomo, Rinaldo; Cooper, D. James; French, Craig; Gantner, Dashiell; Harris, Anthony; Irving, David O.; Murray, Lynne; Nichol, Alistair; Petrie, Dennis; McQuilten, Zoe K.; on behalf of the Standard Issue Transfusion versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) Investigators and Australian and New Zealand Int

Objectives: Trials comparing the effects of transfusing RBC units of different storage durations have considered mortality or morbidity as outcomes. We perform the first economic evaluation alongside a full age of blood clinical trial with a large population assessing the impact of RBC storage duration on quality-of-life and costs in critically ill adults. Design: Quality-of-life was measured at 6 months post randomization using the EuroQol 5-dimension 3-level instrument. The economic evaluation considers quality-adjusted life year and cost implications from randomization to 6 months. A generalized linear model was used to estimate incremental costs (2016 U.S. dollars) and quality-adjusted life years, respectively while adjusting for baseline characteristics. Setting: Fifty-nine ICUs in five countries. Patients: Adults with an anticipated ICU stay of at least 24 hours when the decision had been made to transfuse at least one RBC unit. Interventions: Patients were randomized to receive either the freshest or oldest available compatible RBC units (standard practice) in the hospital transfusion service. Measurements and Main Results: EuroQol 5-dimension 3-level utility scores were similar at 6 months—0.65 in the short-term and 0.63 in the long-term storage group (difference, 0.02; 95% CI, –0.00 to 0.04; p = 0.10). There were no significant differences in resource use between the two groups apart from 3.0 fewer hospital readmission days (95% CI, –5.3 to –0.8; p = 0.01) during follow-up in the short-term storage group. There were no significant differences in adjusted total costs or quality-adjusted life years between the short- and long-term storage groups (incremental costs, –$2,358; 95% CI, –$5,586 to $711) and incremental quality-adjusted life years: 0.003 quality-adjusted life years (95% CI, –0.003 to 0.008). Conclusions: Without considering the additional supply cost of implementing a freshest available RBC strategy for critical care patients, there is no evidence to suggest that the policy improves quality-of-life or reduces other costs compared with standard transfusion practice. This work was performed at the Centre for Health Economics, Monash Business School, Monash University, Caulfield, VIC, Australia. 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). The full list of board members of the Standard Issue Transfusion versus Fresher Red-Cell Use in Intensive Care (TRANSFUSE) Investigators is provided in the Supplementary Appendix (Supplemental Digital Content 1, http://links.lww.com/CCM/E540). The TRANSFUSE trial was supported, in part, by grants from the Australian National Health and Medical Research Council (APP102064 and APP1040971), the Health Research Council of New Zealand (12/575), and the Irish Health Research Board (HRA-DI-2015–589 and CTN-2014-012) and by funding from the Australian Red Cross Blood Service. Ms. Higgins’s and Ms. Murray’s institutions received funding from Australian National Health and Medical Research Council (NHMRC) and Australian Red Cross Blood Service. Drs. Cooper’s and Gantner’s institutions received funding from NHMRC, Health Research Council of New Zealand, and Irish Health Research Board, and they received other support from Australian Red Cross Blood Service. Dr. Cooper received funding from Eustralis Pharmaceuticals (consulting) and National Blood Authority, Australia. Dr. French’s institution received funding from NHMRC. Dr. Irving’s institution received funding from the Australian Government (via the National Blood Authority). Dr. McQuilten’s institution received funding from Abbvie, Celgene, Janssen-Cilag, CSL Biotherapies, and Gilead Sciences (for research undertaken by the Transfusion Research Unit). The remaining authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Zoe K. McQuilten, PhD, Department of Epidemiology and Preventive Medicine, Monash University, 553 St Kilda Rd, Melbourne, VIC 3004, Australia. E-mail: zoe.mcquilten@monash.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Doritchamou, J., Teo, A., Morrison, R., Arora, G., Kwan, J., Manzella-Lapeira, J., Medina-Maldonado, S., Langhorne, J., Hviid, L., Narum, D. L., Dicko, A., Fried, M., Duffy, P. E.

During pregnancy, Plasmodium falciparum infected erythrocytes (IE) accumulate in the intervillous spaces of the placenta by binding to chondroitin sulfate A (CSA), and elicit inflammatory responses that are associated with poor pregnancy outcomes. Primigravid women lack immunity to IE that sequester in the placenta, and thus are susceptible to placental malaria (PM). Women become resistant to PM over successive pregnancies as antibodies to placental IE are acquired. Here, we assayed plasma collected at delivery from Malian and Tanzanian women of different parities for total antibody levels against recombinant VAR2CSA antigens (FCR3 allele), and for surface reactivity, binding-inhibition and opsonizing functional activities against IE using two CSA-binding laboratory isolates (FCR3 and NF54).Overall, antibody reactivity to VAR2CSA recombinant proteins and to CSA-binding IE was higher in multigravidae than primigravidae. However, plasma from Malian gravidae reacted more strongly with FCR3 whereas Tanzanian plasma preferentially reacted with NF54. Further, acquisition of functional antibodies was variant-dependent: binding-inhibition of P. falciparum strain NF54 (p

Qingsong Qin, Yun Li

Abstract Accumulating evidence suggests that infections by herpesviruses might be closely linked to Alzheimer's disease (AD). Pathological hallmarks of AD brains include senile plaques induced by amyloid β peptide (Aβ) in the extracellular space and intracellular neurofibrillary tangles (NFTs) consisting of phosphorylated tau protein. The prevailing hypothesis for the mechanism of AD is amyloid cascade reaction. Recent studies revealed that infections by herpesviruses induce the similar pathological hallmarks of AD, including Aβ production, phosphorylation of tau (P‐tau), oxidative stress, neuroinflammation, etc. Aβ peptide is regarded as one of the antimicrobial peptides, which inhibits HSV‐1 replication. In the elderly, reactivation of herpesviruses might act as an initiator for amyloid cascade reaction in vulnerable individuals, triggering the neurofibrillary formation of phosphorylated tau and inducing oxidative stress and neuroinflammation, which can further contribute to the accumulation of Aβ and P‐tau by impairing mitochondria and autophagosome. Epidemiological studies have shown AD susceptibility genes, such as APOE‐ε4 allele, are highly linked to infections by herpesviruses. Interestingly, anti‐herpesviral therapy significantly reduced the risk of AD in a large population study. Given that herpesviruses are arguably the most prevalent opportunistic pathogens and often reactivate in the elderly, it is reasonable to argue reactivation of herpesviruses might be major culprits for initiating AD in individuals carrying AD susceptibility genes. In this review, we summarize epidemiological and molecular evidence that support for a hypothesis of herpesviral infections and antimicrobial protection in the development of AD, and discuss the implications for future prevention and treatment of the disease.

Abstract Background Naturally acquired immunity to malaria across the globe varies in intensity and protective powers. Many of the studies on immunity are from hyperendemic regions of Africa. In Asia, particularly in India, there are unique opportunities for exploring and understanding malaria immunity relative to host age, co-occurrence of Plasmodium falciparum and Plasmodium vivax infections, varying travel history, and varying disease severity. Variation in immunity in hospital settings is particularly understudied. Methods A US NIH ICEMR (South Asia) team examined the level of immunity in an Indian malaria patient population visiting or admitted to Goa Medical College and Hospital in Goa, India. Sera from 200 patients of different ages, in different seasons, infected with P. falciparum or P. vivax or both species, and with different clinical severity were applied to an established protein array system with over 1000 P. falciparum and P. vivax antigens. Differential binding of patient IgG to different antigens was measured. Results Even though Goa itself has much more P. vivax than P. falciparum, IgG reactivity towards P. falciparum antigens was very strong and comparable to that seen in regions of the world with high P. falciparum endemicity. Of 248 seropositive P. falciparum antigens, the strongest were VAR, MSP10, HSP70, PTP5, AP2, AMA1, and SYN6. In P. vivax patients, ETRAMPs, MSPs, and ApiAP2, sexual stage antigen s16, RON3 were the strongest IgG binders. Both P. falciparum and P. vivax patients also revealed strong binding to new antigens with unknown functions. Seropositives showed antigens unique to the young (HSP40, ACS6, GCVH) or to non-severe malaria (MSP3.8 and PHIST). Conclusion Seroreactivity at a major hospital in Southwest India reveals antibody responses to P. falciparum and P. vivax in a low malaria transmission region with much migration. In addition to markers of transmission, the data points to specific leads for possible protective immunity against severe disease. Several, but not all, key antigens overlap with work from different settings around the globe and from other parts of India. Together, these studies confidently help define antigens with the greatest potential chance of universal application for surveillance and possibly for disease protection, in many different parts of India and the world.…

Frida Ben-Ami

In most species, variation in age among individuals is the strongest and most visible form of phenotypic variation. Individual-level age effects on disease traits, caused by differences in the age at exposure of the host or its parents, have been widely documented in invertebrates. They can influence diverse traits, such as host susceptibility, virulence, parasite reproduction and further transmission, and may cascade to the population level, influencing disease prevalence and within-host competition.

Jessica T. Lee

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 935-936, April 15, 2019. …

Nance R, Trejo M, Whitney B, et al.

AbstractBackgroundSubstance use is common among people living with HIV (PLWH) and a barrier to achieving viral suppression.ObjectiveAmong PLWH who report illicit drug use, we evaluated associations between HIV viral load (VL) and reduced use of illicit opioids, methamphetamine/crystal, cocaine/crack, and marijuana, regardless of whether or not abstinence was achieved.DesignLongitudinal cohort studySetting/participantsPLWH in clinical care at 8 HIV clinics or 5 clinical studiesMeasurementsWe used joint longitudinal and survival models to examine the impact of decreasing drug use and of abstinence for each drug on viral suppression. We repeated analyses using linear mixed models to examine associations between change in frequency of drug use and VL.ResultsThe number of PLWH who were using each drug at baseline ranged from n=568 (illicit opioids) to n=4272 (marijuana). Abstinence was associated with higher odds of viral suppression (OR 1.4-2.2) and lower relative VL (ranging from 21-42% by drug) for all four drug categories. Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with VL suppression (OR 2.2, 1.6 respectively). Reducing frequency of illicit opioid or methamphetamine/crystal use without abstinence was associated with lower relative VL (47%, 38% respectively).LimitationsObservational data have limitations with causal inference.ConclusionsAbstinence was associated with viral suppression. In addition, reducing use of illicit opioids or methamphetamine/crystal, even without abstinence, was also associated with viral suppression. Findings highlight the impact of reducing substance use even when abstinence is not achieved and the potential benefits of medications, behavioral interventions, and harm-reduction interventions.

Morrissey, I., Magnet, S., Hawser, S., Shapiro, S., Knechtle, P.

Enmetazobactam, formerly AAI101, is a novel penicillanic acid sulfone extended-spectrum β-lactamase inhibitor. The combination of enmetazobactam with cefepime has entered clinical trials to assess safety and efficacy in patients with complicated urinary tract infections. Here, the in vitro activity of cefepime-enmetazobactam was determined for 1,993 clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa collected in the US and Europe during 2014 and 2015. Enmetazobactam at a fixed concentration of 8 μg/ml lowered the cefepime MIC90 from 16 to 0.12 μg/ml for Escherichia coli, >64 to 0.5 μg/ml for Klebsiella pneumoniae, 16 to 1 μg/ml for Enterobacter cloacae, and 0.5 to 0.25 μg/ml for Enterobacter aerogenes. Enmetazobactam did not enhance the potency of cefepime against P. aeruginosa. Applying the CLSI ‘susceptible-dose dependent’ (SDD) breakpoint of 8 μg/ml to cefepime-enmetazobactam for comparative purposes resulted in cumulative inhibitions of 99.9% for E. coli, 96.4% for K. pneumoniae, 97.0% for E. cloacae, 100% for E. aerogenes, 98.1% for all Enterobacteriaceae surveilled, and 82.8% for P. aeruginosa. Comparator susceptibilities for all Enterobacteriaceae were 99.7% for ceftazidime-avibactam, 96.2% for meropenem, 90.7% for ceftolozane-tazobactam, 87% for cefepime (SDD breakpoint), 85.7% for piperacillin-tazobactam, and 81.2% for ceftazidime. For the subset of ESBL-producing K. pneumoniae isolates, addition of 8 μg/ml enmetazobactam to cefepime lowered the MIC90 from >64 to 1 μg/ml, whereas the shift for 8 μg/ml tazobactam was from >64 to 8 μg/ml. Cefepime-enmetazobactam may represent a novel carbapenem-sparing option for empiric treatment of serious Gram-negative infections in settings where ESBL-producing Enterobacteriaceae are expected.…

In the Diagnostic Test Interpretation entitled “Vibration-Controlled Transient Elastography for Diagnosing Cirrhosis and Staging Hepatic Fibrosis,” published in the November 20, 2018, issue of JAMA, a value reported in the Application to This Patient section was incorrect. The third sentence should have read “VCTE is 93% specific for cirrhosis when LSM is greater than the threshold and consistent with other findings of cirrhosis (ie, thrombocytopenia).” This article was corrected online.

Laura C. Multini, Mauro T. Marrelli, John C. Beier, André B.B. Wilke

Extra-Amazonian malaria has been reported to be endemic in Brazil since the end of the 19th century. Currently, only a few cases are reported annually. However, recent findings of unexpected Plasmodium infections with uncertain transmission cycles in the Extra-Amazonian region could pose a threat to the malaria elimination agenda in Brazil.

Dunbar A, Schauwvlieghe A, Rijnders B.

Abstract Background Invasive Salmonella infections result in significant morbidity and mortality in developing countries. In Asia, typhoid and paratyphoid fever are reported to be the major invasive Salmonella infections, while invasive non-typhoidal Salmonella (iNTS) infections are believed to be uncommon. Data from Sarawak, in Malaysian Borneo, are limited. Methods A retrospective study identifying all children aged

Abstract Background Endograft infection is a rare but extremely dangerous complication of aortic repair (25–100% of mortality). We describe here the first case of Listeria monocytogenes abdominal periaortitis associated with a vascular graft. We also discuss the differential diagnosis of periaortitis and provide a literature review of L. monocytogenes infectious aortitis. Case presentation Nine months after endovascular treatment of an abdominal aortic aneurysm (abdominal stent graft), a 76-year-old man was admitted for severe abdominal pain radiating to the back. Laboratory tests were normal apart from elevated C-reactive protein (CRP). Injected abdominal computed tomography (CT) showed infiltration of the fat tissues around the aortic endoprosthesis and aneurysmal sac expansion; positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography (18F-FDG PET/CT) showed a hypermetabolic mass in contact with the endoprosthesis. Blood cultures were negative. At surgical revision, an infra-renal peri-aortic abscess was evident; post-operative antibiotic therapy with ciprofloxacin and doxycycline was started. Cultures of intraoperative samples were positive for L. monocytogenes. Results were further confirmed by a broad-range polymerase chain reaction (PCR) and next-generation sequencing. Antibiotic treatment was switched to intravenous amoxicillin for 6 weeks. Evolution was uneventful with decrease of inflammatory parameters and regression of the abscess. Conclusion An etiologic bacterial diagnosis before starting antibiotic therapy is paramount; nevertheless, culture-independent methods may provide a microbiological diagnosis in those cases where antimicrobials are empirically used and when cultures remain negative.…

Piedra P.

respiratory syncytial viruschildrendomino effecthealthcare costlong-term sequelae…

Abstract Background Conflicting results exist on the added benefit of combining long-lasting insecticidal nets (LLINs) with indoor residual spraying (IRS) to control malaria infection. The main study objective was to evaluate whether the combined use of LLINs and IRS with propoxur provides additional protection against Plasmodium falciparum and/or Plasmodium vivax among all age groups compared to LLINs or IRS alone. Methods This cluster-randomized, controlled trial was conducted in the Rift Valley area of Ethiopia from September 2014 to January 2017 (121 weeks); 44 villages were allocated to each of four study arms: LLIN + IRS, IRS, LLIN, and control. Each week, 6071 households with 34,548 persons were surveyed by active and passive case detection for clinical malaria. Primary endpoints were the incidence of clinical malaria and anaemia prevalence. Results During the study, 1183 malaria episodes were identified, of which 55.1% were P. falciparum and 25.3% were P. vivax, and 19.6% were mixed infections of P. falciparum and P. vivax. The overall malaria incidence was 16.5 per 1000 person-years of observation time (PYO), and similar in the four arms with 17.2 per 1000 PYO in the LLIN + IRS arm, 16.1 in LLIN, 17.0 in IRS, and 15.6 in the control arm. There was no significant difference in risk of anaemia among the trial arms. Conclusions The clinical malaria incidence and anaemia prevalence were similar in the four study groups. In areas with low malaria incidence, using LLINs and IRS in combination or alone may not eliminate malaria. Complementary interventions that reduce residual malaria transmission should be explored in addition to LLINs and IRS to further reduce malaria transmission in such settings. Trial registration PACTR201411000882128 (08 September 2014)…

Adibi A, Sin D, Sadatsafavi M.

To the Editor Mr Wayant and colleagues evaluated the effect of lowering the significance threshold from .05 to .005 on major randomized clinical trials (RCTs) published in 2017. The authors reported that 70.7% of primary end points remained significant and suggested that lowering the threshold might address statistical issues such as P-hacking.

Wayant C, Scott J, Vassar M.

In Reply Mr Adibi and colleagues raise salient points about the prior probability of replication of late-phase RCTs and the increased sample size requirements necessary for a P value threshold of .005. Although we agree that the .005 threshold would require adjustments to funding strategies and trial design, we remain unconvinced that the .005 threshold would come with “little added benefit.” Ultimately, we remain supportive of the new .005 threshold, for this proposal was meant to serve as a temporizing measure while improved statistical frameworks are developed.

Sharfstein JM, Olsen Y.

With the opioid epidemic now claiming nearly 2000 lives from overdose in the United States each month, the medical profession is increasingly accepting the assessment of noted surgeon and writer Atul Gawande, MD: “We started it.” Specialty societies such as the American Academy of Family Physicians and American College of Physicians are offering tools to reduce the unnecessary use of opioids for pain and the risk of addiction. The Federation of State Medical Boards has released guidelines for the treatment of chronic pain, and many state medical boards have adopted their own policies. Physicians are responding. Since peaking in 2012, opioid prescriptions have declined by more than one-fourth.

Emanuele Durante-Mangoni, Roberto Andini, Rosa Zampino

Carbapenem resistance is defined as in vitro nonsusceptibility to any carbapenem and/or documented production of a carbapenemase. This feature has rapidly spread worldwide among clinical isolates of Enterobacteriaceae, mostly Klebsiella spp, and is associated with diverse molecular mechanisms. Carbapenem resistance is often associated with resistance to all traditional beta-lactams and other classes of antibiotics, denoting a typical example of extensively drug-resistant phenotype.

Dia A, Cifu AS, Shah AP.

This JAMA Clinical Guidelines Synopsis summarizes the 2017 focused update of the American College of Cardiology/American Heart Association (AHA/ACC) guideline on management of patients with severe aortic stenosis focusing on surgical vs transcatheter valve replacement (TAVR).

Larry Lutwick, Amal Saif Al-Maani, Shaheen Mehtar, Ziad Memish, Victor Daniel Rosenthal, Angela Dramowski, Grace Lui, Tamer Osman, Andre Bulabula, Gonzalo Bearman

Kazuo Tsuchiya

American Journal of Respiratory and Critical Care Medicine, Volume 199, Issue 8, Page 1031-1033, April 15, 2019. …

De Wolfe, T. J., Kates, A. E., Barko, L., Darien, B. J., Safdar, N.

Probiotics may represent a promising approach for reducing Clostridioides (Clostridium) difficile infections (CDI). A clinical trial conducted by our group demonstrated CDI patients undergoing adjunctive treatment with Lactobacillus and Bifidobacterium probiotics had reduction in diarrhea duration and compositional changes in their stool microbiome. Here we modified a CDI mouse model to represent clinical outcomes observed in patients and employ this model to identify evidence for prevention of primary CDI and relapse with the same probiotic. Mice (n = 80) were administered 0.25 mg/mL cefoperazone over five days and subsequently challenged with 102 C. difficile VPI 10463 spores. A subset of mice (n = 40) were administered 108 CFU of probiotics daily alongside cefoperazone pre-treatment and until experimental endpoints were reached. Clinical scoring was performed daily on mice and used to evaluate CDI onset and severity. Moderate CDI mice were defined by survival beyond day 3 post-infection while severe CDI mice were those who succumbed to infection prior to day 3 post-infection. Sequencing and analysis of 16S rRNA from stool content was performed to determine compositional alterations to the microbiota. Using total clinical scores we identified an association between probiotic treatment and delayed onset of primary CDI and relapse by approximately 12-24 hours (p < 0.001). The stool microbiome of moderate CDI mice receiving probiotic treatment was significantly enriched with Lachnospiraceae during primary CDI (p < 0.05). The outcomes observed present an opportunity to use this modified CDI mouse model to examine the efficacy of non-antibiotic options for CDI management.…

Friedrich MJ.

An intense El Niño event in 2015-2016 fueled outbreaks of chikungunya, hantavirus, Rift Valley fever, cholera, and plague around the world, according to a new report from US investigators. The National Oceanic and Atmospheric Administration ranked this El Niño among the top 3 strongest events in nearly 70 years.

Kawahara, R., Fujiya, Y., Yamaguchi, T., Khong, D. T., Nguyen, T. N., Tran, H. T., Yamamoto, Y.

Colistin is recognized as the last resort for treatment of life-threatening infections caused by multidrug-resistant bacteria; however, the increasing prevalence of colistin-resistant bacteria harboring the mobile colistin resistance gene (mcr) poses a threat to the treatment (1)....…

SHAFI Humaira, HIPOLITO Louie Galang

Patients with rickettsial infection usually present with a febrile illness, headache, arthromyalgia and various biochemical abnormalities. Neurologic involvement is rare in murine typhus. Here, we report a case of a patient who presented with status epilepticus secondary to Rickettsia typhi infection.

Baude J, Bastien S, Gillet Y, et al.

AbstractBackgroundNecrotizing Soft Tissue Infections (NSTIs) caused by group A Streptococcus (GAS) and occasionally by Staphylococcus aureus (SA) frequently involve the deep fascia and often lead to muscle necrosis.MethodsTo assess the pathogenicity of GAS and SA for muscles in comparison to keratinocytes, adhesion and invasion of NSTI-GAS and NSTI-SA isolates were assessed on these cells, Bloodstream infections (BSI-SA) and non-invasive coagulase negative Staphylococci (CNS) isolates were used as controls.ResultsNSTI-SA and BSI-SA exhibited stronger internalization into human keratinocytes and myoblasts than NSTI-GAS or CNS. SA internalization reached over 30% in human myoblasts due to a higher percentage of infected myoblasts (>11%) as compared to keratinocytes (

Sancar F.

The FDA has approved esketamine nasal spray as an adjunctive therapy for adults with treatment-resistant depression (TRD), which affects approximately 30% of patients with major depressive disorder. It’s the first regulatory approval of esketamine, the s-enantiomer of ketamine, for any psychiatric condition worldwide.

Batool, M., Hillhouse, A. E., Ionov, Y., Kochan, K. J., Mohebbi, F., Stoica, G., Threadgill, D. W., Zelikovsky, A., Waghela, S. D., Wiener, D. J., Rogovskyy, A. S.

Borrelia burgdorferi is a tick-borne bacterium responsible for approximately 300,000 annual cases of Lyme disease (LD) in the USA with increasing incidents in other parts of the world. The debilitating nature of LD is mainly attributed to the ability of B. burgdorferi to persist in patients for many years despite strong anti-Borrelia antibody responses. Antimicrobial treatment of persistent infection is challenging. Similar to humans, B. burgdorferi establishes long-term infection in various experimental animal models except in New Zealand White (NZW) rabbits, which clear the spirochete within 4-12 weeks. LD spirochetes have a highly evolved antigenic variation vls system, on the lp28-1 plasmid, where gene conversion results in surface expression of antigenically variable VlsE protein. VlsE is required for B. burgdorferi to establish persistent infection by continually evading otherwise potent antibody. Since the clearance of B. burgdorferi is mediated by humoral immunity in NZW rabbits, the previously published results that LD spirochetes lose lp28-1 during the rabbit infection could potentially explain the failure of B. burgdorferi to persist. However, the present study unequivocally disproves that prior finding by demonstrating that LD spirochetes retain the vls system. Yet, despite the vls system being fully functional, the spirochete fails to evade anti-Borrelia antibody of the NZW rabbit. In addition to being protective against homologous and heterologous challenge, the rabbit antibody significantly ameliorate LD-induced arthritis in persistently infected mice. Overall, the current data indicate that NZW rabbits develop a protective antibody repertoire, whose specificities once defined will identify potential candidates for a much-anticipated LD vaccine.…

Ivaska L, Christensen A, Waris M, et al.

AbstractHuman bocavirus 1 (HBoV1) can persist in nasopharynx and tonsils. Using HBoV1 serology, reverse-transcription polymerase chain reaction (PCR) for detecting messenger RNA (mRNA) and quantitative PCR for HBoV1 genome load count, we studied in what extent the HBoV1 DNA loads in nasopharynx correlates with acute infection markers. Tonsillar tissue, nasopharyngeal aspirate and serum were obtained from 188 elective adeno-/tonsillectomy patients. Relatively high loads of HBoV1 DNA were detected in the nasopharynx of 14 (7%) primarily asymptomatic subjects with negative mRNA and/or serodiagnostic results. Quantitative HBoV1 DNA PCR may have lower specificity than HBoV1 mRNA detection for diagnosing symptomatic infection.

Lee, Robert Y.; Engelberg, Ruth A.; Curtis, J. Randall; Hough, Catherine L.; Kross, Erin K.

Objectives: Family members of ICU survivors report long-term psychologic symptoms of posttraumatic stress disorder. We describe patient- and family-member risk factors for posttraumatic stress disorder symptoms among family members of survivors of acute respiratory distress syndrome. Design: Prospective cohort study of family members of acute respiratory distress syndrome survivors. Setting: Single tertiary care center in Seattle, Washington. Subjects: From 2010 to 2015, we assembled an inception cohort of adult acute respiratory distress syndrome survivors who identified family members involved in ICU and post-ICU care. One-hundred sixty-two family members enrolled in the study, corresponding to 120 patients. Interventions: None. Measurements and Main Results: Family members were assessed for self-reported psychologic symptoms 6 months after patient discharge using the Posttraumatic Stress Disorder Checklist-Civilian Version, the Patient Health Questionnaire 9-item depression scale, and the Generalized Anxiety Disorder 7-item scale. The primary outcome was posttraumatic stress disorder symptoms, and secondary outcomes were symptoms of depression and anxiety. We used clustered multivariable logistic regression to identify patient- and family-member risk factors for psychologic symptoms. Posttraumatic stress disorder symptoms were present in 31% (95% CI, 24–39%) of family participants. Family member risk factors for posttraumatic stress disorder symptoms included preexisting mental health disorders (adjusted odds ratio, 3.22; 95% CI, 1.42–7.31), recent personal experience of serious physical illness (adjusted odds ratio, 3.07; 95% CI, 1.40–6.75), and female gender (adjusted odds ratio, 5.18; 95% CI, 1.74–15.4). Family members of previously healthy patients (Charlson index of zero) had higher frequency of posttraumatic stress disorder symptoms (adjusted odds ratio, 2.25; 95% CI, 1.06–4.77). Markers of patient illness severity were not associated with family posttraumatic stress disorder symptoms. Conclusions: The prevalence of long-term posttraumatic stress disorder symptoms among family members of acute respiratory distress syndrome survivors is high. Family members with preexisting mental health disorders, recent experiences of serious physical illness, and family members of previously healthy patients are at increased risk for posttraumatic stress disorder symptoms. This study was performed at Harborview Medical Center, 325 Ninth Ave, Campus Box 359762, Seattle, WA 98104. Drs. Lee, Engelberg, Curtis, Hough, and Kross received support for article research from the National Institutes of Health (NIH). Dr. Lee’s institution received funding from National Heart, Lung, and Blood Institute (NHLBI) (NIH T32 HL125195). Dr. Kross’ institution received funding from the NHLBI (NIH K23 HL098745). Drs. Engelberg’s and Cross' institutions also received funding from the Cambia Health Foundation, Cystic Fibrosis Foundation, and UW Medicine. For information regarding this article, E-mail: rlee06@uw.edu Copyright © by 2019 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Tianhui Liu, Yameng Sun, Jialing Zhou, Fang Yang, Xia Zou, Lin Wang, Xiaoning Wu, Yongpeng Chen, Hongxin Piao, Lungen Lu, Wei Jiang, Youqing Xu, Bo Feng, Yuemin Nan, Wen Xie, Guofeng Chen, Huanwei Zheng, Hai Li, Huiguo Ding, Hui Liu, Tailing Wang, Xiaojuan Ou, Shanshan Wu, Yuanyuan Kong, Ping Wang, Min Cong, Yan Zhang, Hong You, Jidong Jia

Abstract Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein (M2BP) has been identified as a predictor for the response of interferon α (IFN‐α) in patients with viral hepatitis. However, whether serum glycosylation isomer of M2BP (M2BPGi) was associated with the regression of liver fibrosis in patients with chronic hepatitis B (CHB) during IFN‐α add‐on therapy is still unknown. CHB patients were treated with entecavir for 26 weeks followed by entecavir plus pegylated IFN‐α for 52 weeks. Liver biopsies were taken at baseline and treatment week 78. The regression of fibrosis was identified according to Ishak standard or Ishak plus Progressive‐Indeterminate‐Regressive (P‐I‐R) standard. Serum M2BPGi and liver function tests were measured at baseline and every 26 weeks of treatment. A total of 72 CHB patients were included in the present study. Serum M2BPGi was correlated with fibrosis and necroinflammation both at baseline and week 78. If Ishak standard was used as the reference, only the percent change of M2BPGi at week 52 from week 26 (Δ%M2BPGi26w‐52W) was independently associated with fibrosis regression at treatment week 78, the area under the ROC curve (AUROC) of Δ%M2BPGi26w‐52W for predicting fibrosis regression was 0.705. As for Ishak plus P‐I‐R standard, the AUROC of the predictive model for fibrosis regression (0.896*M2BPGi52W + 0.363*necroinflammation score0w + 2.051*Ishak score0w – 4.489) was 0.888. These data indicated that dynamic changes of serum M2BPGi were associated with fibrosis regression in CHB patients on IFN‐α add‐on therapy.

Kandasamy R, Voysey M, Collins S, et al.

AbstractBackgroundFollowing programmatic introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), there is residual carriage and disease due to PCV13 covered serotypes.Methods988 PCV13-immunised children aged 13-48 months were enrolled between February 2014 and August 2015 (late-PCV13), and had nasopharyngeal pneumococcal carriage compared with 567 PCV7-immunised children enrolled into a study between November 2010 and September 2011 (early-PCV13). Nasopharyngeal pneumococci were molecular-serotyped by microarray. Invasive pneumococcal disease (IPD) cases were identified through enhanced national surveillance. Blood collected from the late-PCV13 cohort was assessed for levels of serotype-specific serum IgG by multiplex immunoassay.ResultsCompared with PCV7-immunised children, carriage among PCV13-immunised children was significantly lower for serotypes 19A (OR=0.08, 95% CI 0.02-0.25), 6C (OR=0.11, 95% CI 0.03-0.32) and 7F (8 vs 0 cases).IPD incidence in children

Anand K, Shoba Mammen, Rajesh Kannangai, Asha Mary Abraham

Pilishvili T.

Kovanda, L. L., Sullivan, S. M., Smith, L. R., Desai, A. V., Bonate, P. L., Hope, W. W.

VL-2397, a novel, systemic antifungal agent, has potent in vitro and in vivo fungicidal activity against Aspergillus species. Plasma concentrations from a Phase 1 study were used to construct a population pharmacokinetic (PPK) model for VL-2397.Methods: Healthy subjects aged 18 to 55 years received single doses of VL-2397 ranging from 3 to 1200mg, multiple daily doses of 300, 600, or 1200mg for 7 days, or 300mg three-times/day for 7 days followed by 600mg daily for 21 days. Plasma samples were collected throughout the dosing intervals.Results: Sixty-six subjects provided 1,908 concentrations. Drug concentrations over time increased less than dose proportional for doses above 30mg. Dose-normalized concentrations plotted over time did not overlap. A 3-compartment non-linear saturable binding model fit the data well. Clearance increased with dose, mean values ranged from 0.4 L/h at 3mg and 8.5 L/h at 1200mg. Mean volume in the central compartment ranged from 4.8 to 6.9 L across doses. In the first 24 hours, once daily dosing results in a rapid decrease in concentrations by hour 16 to approximately 1 mg/L, regardless of dose, with slow clearance over time. Administration of 300mg every 8 hours achieved concentrations above 1 mg/L over an entire 24-hour period. There was a significant relationship of body surface area to clearance.The data suggests that VL-2397 has non-linear saturable binding kinetics. Protein binding is the likely primary source of the non-linearity. The PPK model can now be used to optimize dosing by bridging the kinetics to efficacious pharmacodynamic targets.…

Abstract Background The World Health Organization (WHO) recommends combinations of an artemisinin derivative plus an anti-malarial drug of longer half-life as treatment options for uncomplicated Plasmodium falciparum infections. In Africa, artesunate–mefloquine (ASMQ) is an infrequently used artemisinin-based combination therapy (ACT) because of perceived poor tolerance to mefloquine. However, the WHO has recommended reconsideration of the use of ASMQ in Africa. In this large clinical study, the pharmacokinetics (PK) of a fixed dose combination of ASMQ was investigated in an African paediatric population to support dosing recommendations used in Southeast Asia and South America. Methods Among the 472 paediatric patients aged 6–59 months from six African centres included in the large clinical trial, a subset of 50 Kenyan children underwent intensive sampling to develop AS, its metabolite dihydroartemisinin (DHA) and MQ PK models. The final MQ PK model was validated using sparse data collected in the remaining participants (NONMEM®). The doses were one or two tablets containing 25/55 mg AS/MQ administered once a day for 3 days according to patients’ age. A sensitive LC–MS/MS method was used to quantify AS, DHA and MQ concentrations in plasma. An attempt was made to investigate the relationship between the absence/presence of malaria recrudescence and MQ area under the curve (AUC) using logistic regression. Results AS/DHA concentration–time profiles were best described using a one-compartment model for both compounds with irreversible AS conversion into DHA. AS/DHA PK were characterized by a significant degree of variability. Body weight affected DHA PK parameters. MQ PK was characterized by a two-compartment model and a large degree of variability. Allometric scaling of MQ clearances and volumes of distribution was used to depict the relationship between MQ PK and body weight. No association was found between the model predicted AUC and appearance of recrudescence. Conclusions The population pharmacokinetic models developed for both AS/DHA and MQ showed a large variability in drug exposure in the investigated African paediatric population. The largest contributor to this variability was body weight, which is accommodated for by the ASMQ fixed dose combination (FDC) dosing recommendation. Besides body weight considerations, there is no indication that the dosage should be modified in children with malaria compared to adults. Trial registration Pan African Clinical Trials Registry PACTR201202000278282 registration date 2011/02/16…

Abstract Background After antibiotic treatment of Lyme borreliosis, a subset of patients report persistent symptoms, also referred to as post-treatment Lyme disease syndrome. The reported prevalence of persistent symptoms varies considerably, and its pathophysiology is under debate. The LymeProspect study has been designed to investigate the prevalence, severity, and a wide range of hypotheses on the etiology of persistent symptoms among patients treated for Lyme borreliosis in the Netherlands. Methods LymeProspect is a prospective, observational cohort study among adults with proven or probable Lyme borreliosis, either erythema migrans or disseminated manifestations, included at the start of antibiotic treatment. During one year of follow-up, participants are subjected to questionnaires every three months and blood is collected repeatedly during the first three months. The primary outcome is the prevalence of persistent symptoms after treatment, assessed by questionnaires online focusing on fatigue (CIS, subscale fatigue severity), pain (SF-36, subscale pain) and neurocognitive dysfunction (CFQ). Potential microbiological, immunological, genetic, epidemiological and cognitive-behavioral determinants for persistent symptoms are secondary outcome measures. Control cohorts include patients with long-lasting symptoms and unconfirmed Lyme disease, population controls, and subjects having reported a tick bite not followed by Lyme borreliosis. Discussion This article describes the background and design of the LymeProspect study protocol. This study is characterized by a prospective, explorative and multifaceted design. The results of this study will provide insights into the prevalence and determinants of persistent symptoms after treatment for Lyme borreliosis, and may provide a rationale for preventive and treatment recommendations. Trial registration NTR4998 (Netherlands Trial Register). Date of registration: 13 February 2015.…

Abstract Background Group B streptococcus (GBS) is reported as the leading cause of neonatal sepsis and meningitis. Newborns from GBS colonized pregnant women are at high risk of infection. Method A Hospital based cross-sectional study was conducted at Hawassa University Comprehensive Specialized Hospital from November 05, 2014 to March 25, 2015. A total of 280 pregnant women along with their newborns were screened for GBS using standard method recommended by Center of Disease Control and Prevention. GBS strains were serotyped by using serotype specific antisera. A structured questionnaire was used to collect sociodemographic, obstetrics and clinical data of pregnant women and newborns. Data was analyzed by using chi-square and logistic regression to determine factors associated with prevalence of GBS among pregnant women and newborns. Descriptive statistics was used to determine prevalence of GBS among pregnant women and newborns. P value less than 0.05 was considered statistically significant. Result Prevalence of GBS among pregnant women, newborns and vertical transmission rate at Hawassa University Comprehensive Specialized Hospital were 44(15.7%), 26(8.9%) and 59.1% respectively. Among 26 GBS colonized newborns one developed sign and symptoms of early onset disease. Serotype distribution of GBS isolates collected from pregnant women and newborns was Ia 13(18.6%), Ib 9(12.9%), II 24(34.3%), III 8(11.4%), V 14(20%), and NT 2 (2.9%). Conclusion In our study we found relatively high prevalence of GBS among pregnant women and vertical transmission rate. The most prevalent GBS serotypes identified in this study were serotype II followed by V, Ia and Ib. Therefore, appropriate prevention strategies such as intrapartum antibiotic prophylaxis and vaccine development should be considered.…

Alvaro Rojas, Zaira R. Palacios-Baena, Luis Eduardo López-Cortés, Jesús Rodríguez-Baño

Pseudomonas aeruginosa is mostly a nosocomial pathogen affecting predisposed patients. However, community-onset bloodstream infections (CO-BSI) caused by this organism are not exceptional.

Kumar D, Humar A.

Mataseje, L. F., Boyd, D. A., Mulvey, M. R., Longtin, Y.

This report describes two hypervirulent Klebsiella pneumoniae producing KPC identified from a rectal swab and urine culture upon hospital admission. The patient had recent travel to Greece where he was hospitalized. The isolates were sequence type 86, contained an IncHI1B, IncFIB(K) hypervirulent plasmid and an IncFII(K) plasmid harbouring KPC.…

Kelvin K.W. To, Kwok-Hung Chan, Julian Ho, Polly K.P. Pang, Deborah T.Y. Ho, Arthur C.H. Chang, Claudia.W. Seng, Cyril.C.Y. Yip, Vincent C.C. Cheng, Ivan F.N. Hung, Kwok-Yung Yuen

We aimed to determine the viral epidemiology and clinical characteristics of patients with and those without clinically-apparent respiratory tract infection.

Sugiura, D., Maruhashi, T., Okazaki, I.-m., Shimizu, K., Maeda, T. K., Takemoto, T., Okazaki, T.

Targeted blockade of PD-1 using checkpoint inhibitor immunotherapies can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector but not in the activation phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. Using knock-in mice where cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 co-inhibitory signal, while promoting CD28-mediated co-stimulation, and highlights critical components for induction of optimal immune responses.…

Chan L, Hui K, Kuok D, et al.

AbstractHighly pathogenic avian influenza (HPAI)-H7N9 virus arising from low pathogenic avian influenza (LPAI)-H7N9 virus with polybasic amino acid substitutions in the haemagglutinin was detected in 2017. We compared the tropism, replication competence and cytokine induction of HPAI-H7N9, LPAI-H7N9 and HPAI-H5N1 in ex vivo human respiratory tract explants and in vitro culture of human alveolar epithelial cells (AECs) and pulmonary microvascular endothelial cells (HMVEC-L).Replication competence of HPAI- and LPAI-H7N9 were comparable in ex vivo cultures of bronchus and lung. HPAI-H7N9 predominantly infected AECs, while limited infection was observed in bronchus. The reduced tropism of HPAI-H7N9 in bronchial epithelium may explain the lack of human-to-human transmission despite a number of mammalian adaptation markers. Apical and basolateral release of virus was observed only in HPAI-H7N9 and H5N1 infected AECs regardless of infection route. HPAI-H7N9, but not LPAI-H7N9 efficiently replicated in HMVEC-L implying that endothelial tropism may involve in pathogenesis of HPAI-H7N9 disease.

Abstract Background Despite major improvements in child survival rates, the number of deaths due to diarrhea remains unacceptably high. We aimed to describe diarrhea-associated mortality and evaluate risk factors for death among Mozambican children with moderate-to-severe diarrhea (MSD). Methods Between December 2007 and November 2012, children under-five with MSD were enrolled in Manhiça district, as part of the Global Enteric Multicenter study (GEMS). Clinical, epidemiological, and socio-demographic characteristics were collected. Anthropometric measurements were performed and stool samples collected upon recruitment. A follow-up visit ~ 60 days post-enrolment was conducted and verbal autopsies performed in all death cases. Results Of the 916 MSD-cases analyzed; 90% (821/916) completed 60 days follow-up and 69 patients died. The case fatality rate at follow-up was 8% (69/821), and the mortality rate 10.2 (95%CI: 7.75–13.59) deaths per 1000 persons-week at risk. Nearly half of the deaths 48% (33/69) among study participants clustered within 2 weeks of the onset of diarrhea. Typical enteropathogenic Escherichia coli (typical EPEC) and Cryptosporidium were the two pathogens associated to an increased risk of death in the univariate analysis with (HR = 4.16, p = 0.0461) and (H = 2.84, p = 0.0001) respectively. Conversely, Rotavirus infection was associated to a decreased risk of death (HR = 0.52, p = 0.0198). According to the multivariate analysis, risk factors for death included co-morbidities such as malnutrition (HR = 4.13, p 

Sancar F.

The FDA has warned that robotically assisted surgical devices haven’t been established as safe and effective to treat or prevent breast or cervical cancers.

Quintana-Hayashi, M. P., Venkatakrishnan, V., Haesebrouck, F., Linden, S.

Infection with Brachyspira hyodysenteriae results in mucoid hemorrhagic diarrhea. This pathogen is associated with the colonic mucus layer, mainly composed of mucins. Infection regulates mucin O-glycosylation in the colon and increases mucin secretion as well as B. hyodysenteriae binding sites on mucins. Here, we analyzed potential mucin epitopes for B. hyodysenteriae adhesion in the colon, as well as the effect of colonic mucins on bacterial growth. Associations between B. hyodysenteriae binding to pig colon mucins and mucin glycan data showed that B. hyodysenteriae binding was associated with the presence of N-glycolylneuraminic acid (NeuGc) on mucins. The role of sialic acid in B. hyodysenteriae adhesion was analyzed after the removal of sialic acid residues on the mucins by enzymatic treatment with sialidase A, which decreased bacterial binding to the mucins. The effect of pig colon mucins on B. hyodysenteriae growth was determined in carbohydrate free media. B. hyodysenteriae growth increased in the presence of mucins from two out of five infected pigs, suggesting utilization of mucins as a carbon source for growth. Additionally, bacterial growth was enhanced by free sialic acid and N-acetylglucosamine. The results highlight a role of sialic acid as an adhesion epitope for B. hyodysenteriae interaction with colonic mucins. Furthermore, the mucin response and glycosylation changes exerted in the colon during B. hyodysenteriae infection results in a potentially favorable environment for pathogen growth in the intestinal mucus layer.…

Spanier AJ, McLaine P, Gilden RC.

In this issue of JAMA, the US Preventive Services Task Force (USPSTF) presents its recommendation on screening for elevated blood lead levels in children and pregnant women, along with the evidence summary supporting this recommendation—a reevaluation of the 2006 recommendations. Lead exposure in children is associated with significant neurologic effects, including deficits in IQ and increased risk of hyperactivity. Elevated lead levels in pregnant women are associated with gestational hypertension and spontaneous abortion. While changes in public policy have led to substantial declines in prevalence of lead poisoning and elevated lead levels in children, prevention of lead exposure and its consequences remains of paramount importance.