Shaosen Zhang, Shaohua Guo, Xinyu Feng, Aneta Afelt, Roger Frutos, Shuisen Zhou, Sylvie Manguin

China is approaching malaria elimination; however, well-documented information on malaria vectors is still missing, which could hinder the development of appropriate surveillance strategies and WHO certification. This review summarizes the nationwide distribution of malaria vectors, their bionomic characteristics, control measures, and related studies. After several years of effort, the area of distribution of the principal malaria vectors was reduced, in particular for Anopheles lesteri (synonym: An.

Qifang Bi, Eva Ferreras, Lorenzo Pezzoli, Dominique Legros, Louise C Ivers, Kashmira Date, Firdausi Qadri, Laura Digilio, David A Sack, Mohammad Ali, Justin Lessler, Francisco J Luquero, Andrew S Azman, Oral Cholera Vaccine Working Group of The Global Task Force on Cholera Control

Two kOCV doses provide protection against cholera for at least 3 years. One kOCV dose provides at least short-term protection, which has important implications for outbreak management. kOCVs are effective tools for cholera control.

Suman Kanungo, Pranab Chatterjee

The development of a cheap and effective oral cholera vaccine (OCV) is a remarkable achievement in the field of cholera prevention. A meta-analysis on the efficacy and effectiveness of OCVs by Qifang Bi and colleagues1 updates the estimates of the 2011 Cochrane review.2 Their analysis includes additional studies published since 2011, yet provides estimates that are almost the same.

Charlier C, Perrodeau É, Leclercq A, et al. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis 2017; 17: 510-19--A member of the MONALISA study group was incorrectly listed in the appendix. Nicolas Vodovar should have read Dominique Vodovar. This correction has been made to the online version as of July 17, 2017.

Fabre V, Cosgrove SE.

antibiotic resistancecarbapenem-resistant enterobacterieacaeantibiotic stewardshipinfection prevention.

There is wide variation in the intensity of treatment for low-risk cancers, and many patients are at risk for overtreatment. Despite 5-year survival rates that approach 100% among patients with low-risk differentiated thyroid cancer, prostate cancer, and ductal carcinoma in situ (DCIS) of the……

To the Editor: Homozygous familial hypercholesterolemia is characterized by profound genetic deficiencies in the low-density lipoprotein (LDL) receptor pathway; patients with the condition who are not receiving lipid-lowering therapy have LDL cholesterol levels in the range of 500 to 1000 mg per……

To the Editor: Lu et al. (March 9 issue) report on an artemisinin-resistant Plasmodium falciparum strain in Africa. We advise caution. Blood levels of dihydroartemisinin were not reported. Parasitemia on day 3 was low (1 parasite per 200 white cells) and could have been caused by pyknotic……

Figure 1.

Rodrigo Dienstmann

Progress is being made in the use of personalized approaches to create both in vitro and in vivo tumour models that could be used to aid cancer drug-treatment decisions and increase our understanding of how tumours respond to therapy.

Presentation of Case. Dr. Nkemdilim Mgbojikwe (Medicine): A 21-year-old woman was admitted to this hospital during the winter because of fever, headache, and myalgias. The patient had been well until 4 days before this admission, when fever, chills, fatigue, malaise, retro-orbital headache, and……

Helina Fikre, Rezika Mohammed, Saba Atinafu, Johan Griensven, Ermias Diro

Objective Cutaneous leishmaniasis (CL) receives far less attention than visceral leishmaniasis. Nevertheless, CL is predominantly caused by a unique species in Ethiopia (L aethiopica), which is known to cause severe forms such as diffuse (DCL) and mucocutaneous leishmaniasis (MCL). We report on the number and type of CL cases diagnosed, the clinical features, the treatments and treatment outcomes in North-West Ethiopia. Methods This is a retrospective chart record analysis of CL patients treated at the Leishmania Research and Treatment Center (LRTC) of the University of Gondar, Ethiopia. Results From 178 CL patients seen between Jan 2014 and Dec 2015, a total of 154 chart records were retrieved. These included 80 localized CL (LCL), 7 DCL and 67 MCL. The median age was 23 years; 71.4% were male. Most (n=121, 78.6%) of the lesions were on the face. The median time since onset was 12 months (6-24 months) and 28.6% presented after a trial of traditional medicine. The treatment of all forms of CL mainly consisted of 30 days of IM antimonial injections. Of these, 51/133 (38.3%) required treatment extension or change due to non-response. Three cases were treated with liposomal amphotericin B or miltefosine (two received the combination), of which two responded well. Conclusion CL was found to be complicated and difficult to treat. MCL was common, and patients presented after long delays. There is an urgent need to look for better treatment options for CL and improve access to care. This article is protected by copyright. All rights reserved.

Stephen V. David

The use of state-of-the-art techniques to study neuronal activity during a navigational task involving sound stimuli broadens our understanding of how neuronal populations produce complex behaviours.

Price, Jennifer C.; Dodge, Jennifer L.; Ma, Yifei; Scherzer, Rebecca; Korn, Natalie; Tillinghast, Kyle; Peters, Marion G.; Noworolski, Susan; Tien, Phyllis C.

Objective: Hepatic steatosis (HS) is common in HIV-infected individuals. Magnetic resonance spectroscopy (MRS) is the preferred non-invasive method for HS measurement but is expensive. Controlled attenuation parameter (CAP) also assesses HS and is conveniently performed concomitantly with transient elastography. We aimed to assess the accuracy of CAP in the setting of HIV infection. Design: Cross-sectional study. Methods: CAP and MRS were performed in 82 subjects (39 HIV-monoinfected;7 HCV-monoinfected;21 HIV/HCV-coinfected; 15 with neither infection). We used concordance correlation coefficients to compare log-transformed and standardized CAP and MRS values and linear regression to examine factors associated with CAP and MRS-measured HS. The accuracy of CAP to detect >=mild HS, defined as MRS-liver fat fraction>=0.05, and the factors associated with discordance between CAP and MRS were evaluated. Results: Overall, CAP-HS and MRS-HS correlated moderately well (r = 0.60,p < 0.001), and correlation was strongest in the HIV-monoinfected group (r = 0.67,p < 0.001). Body composition factors (higher BMI, waist circumference, visceral and abdominal subcutaneous adipose tissue) and insulin resistance were significantly associated with both greater CAP-HS and MRS-HS. Using a validated CAP cut-off >=238 decibels/meter, sensitivity and specificity for >=mild HS were 84% and 75% in the entire cohort; 89% and 80% in the HIV-monoinfected group. Higher body composition parameters were more likely to be misclassified as having HS by CAP. Conclusions: Our findings suggest CAP is an acceptable non-invasive surrogate for HS in HIV-infected individuals but may overestimate HS prevalence, especially in individuals with high BMI. Evaluation of factors that improve CAP accuracy and determination of optimal cut-offs are warranted. Copyright (C) 2017 Wolters Kluwer Health, Inc.

Yu Peng

The radiation-induced bystander effect (RIBE) refers to a unique process in which factors released by irradiated cells or tissues exert effects on other parts of the animal not exposed to radiation, causing genomic instability, stress responses and altered apoptosis or cell proliferation. Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge. CPR-4 is secreted from animals irradiated with ultraviolet or ionizing gamma rays, and is the major factor in the conditioned medium that leads to the inhibition of cell death and increased embryonic lethality in unirradiated animals. Moreover, CPR-4 causes these effects and stress responses at unexposed sites distal to the irradiated tissue. The activity of CPR-4 is regulated by the p53 homologue CEP-1 in response to radiation, and CPR-4 seems to exert RIBEs by acting through the insulin-like growth factor receptor DAF-2. Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.

Davey, Dvora L. Joseph; Bekker, Linda-Gail; Gorbach, Pamina; Coates, Thomas; Myer, Landon

: HIV acquisition during pregnancy and postpartum periods remains high despite increased access to and initiation of antiretroviral therapy in sub-Saharan Africa. Moreover, maternal seroconversion during pregnancy and breastfeeding remains a source of significant paediatric HIV infection in the region. In order to curb vertical HIV transmission, HIV acquisition during pregnancy and lactation must significantly decline. Biological and behavioural factors contribute to high HIV incidence, including hormonal changes that alter genital mucosal surfaces, and frequent condomless sex with HIV-infected partners or partners of unknown serostatus. Pregnant and breastfeeding women who are at risk of HIV acquisition during pregnancy and lactation require female controlled interventions such as pre-exposure prophylaxis (PrEP) to prevent HIV acquisition during those particularly vulnerable periods. Before PrEP scale up for pregnant and lactating women, there is an urgent need for operations research to evaluate how best to provide PrEP to pregnant and breastfeeding women in settings of high HIV incidence. This should include how to: (1) integrate PrEP delivery and counselling into antenatal and postnatal care, (2) ensure optimal adherence during at-risk periods, and (3) target PrEP for maximum impact, including reaching pregnant and breastfeeding young women. In light of current knowledge on the safety of PrEP in pregnancy and breastfeeding, next steps are needed to ensure barriers to PrEP effectiveness are addressed. Copyright (C) 2017 Wolters Kluwer Health, Inc.

Caroline A. Runyan

The cortex represents information across widely varying timescales. For instance, sensory cortex encodes stimuli that fluctuate over few tens of milliseconds, whereas in association cortex behavioural choices can require the maintenance of information over seconds. However, it remains poorly understood whether diverse timescales result mostly from features intrinsic to individual neurons or from neuronal population activity. This question remains unanswered, because the timescales of coding in populations of neurons have not been studied extensively, and population codes have not been compared systematically across cortical regions. Here we show that population codes can be essential to achieve long coding timescales. Furthermore, we find that the properties of population codes differ between sensory and association cortices. We compared coding for sensory stimuli and behavioural choices in auditory cortex and posterior parietal cortex as mice performed a sound localization task. Auditory stimulus information was stronger in auditory cortex than in posterior parietal cortex, and both regions contained choice information. Although auditory cortex and posterior parietal cortex coded information by tiling in time neurons that were transiently informative for approximately 200 milliseconds, the areas had major differences in functional coupling between neurons, measured as activity correlations that could not be explained by task events. Coupling among posterior parietal cortex neurons was strong and extended over long time lags, whereas coupling among auditory cortex neurons was weak and short-lived. Stronger coupling in posterior parietal cortex led to a population code with long timescales and a representation of choice that remained consistent for approximately 1 second. In contrast, auditory cortex had a code with rapid fluctuations in stimulus and choice information over hundreds of milliseconds. Our results reveal that population codes differ across cortex and that coupling is a variable property of cortical populations that affects the timescale of information coding and the accuracy of behaviour.

Friedrich MJ.

According to a report published in The Lancet Infectious Diseases, multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) are expected to increase by 2040 in India, the Philippines, Russia, and South Africa, countries that already have a high burden of MDR TB. Despite gains against TB in recent years, the disease remains 1 of the top 10 causes of death worldwide. MDR TB is resistant to at least 2 of the most potent drugs used to treat TB, isoniazid and rifampin. XDR TB is defined as MDR TB with additional resistance to fluoroquinolones and second-line injectable drugs for TB.

Although the World Health Organization (WHO) guidelines now recommend universal antiretroviral therapy (ART) regardless of the CD4+ count, 20 to 25% of patients with human immunodeficiency virus (HIV) infection in sub-Saharan Africa present for care with severe immunosuppression (CD4+ count, One……

Tariq R, Pardi DS, Tosh PK, et al.

AbstractBroad-spectrum antibiotics for recurrent multi-drug resistant urinary tract infections (UTIs) disrupt the gut microbiome and promote antibiotic resistance. Fecal microbiota transplantation led to resolution of recurrent Clostridium difficile infection and significantly decreased recurrent UTI frequency and improved antibiotic susceptibility profile of UTI causing organisms in recurrent UTI patients.

Chen-Song Zhang

The major energy source for most cells is glucose, from which ATP is generated via glycolysis and/or oxidative metabolism. Glucose deprivation activates AMP-activated protein kinase (AMPK), but it is unclear whether this activation occurs solely via changes in AMP or ADP, the classical activators of AMPK. Here, we describe an AMP/ADP-independent mechanism that triggers AMPK activation by sensing the absence of fructose-1,6-bisphosphate (FBP), with AMPK being progressively activated as extracellular glucose and intracellular FBP decrease. When unoccupied by FBP, aldolases promote the formation of a lysosomal complex containing at least v-ATPase, ragulator, axin, liver kinase B1 (LKB1) and AMPK, which has previously been shown to be required for AMPK activation. Knockdown of aldolases activates AMPK even in cells with abundant glucose, whereas the catalysis-defective D34S aldolase mutant, which still binds FBP, blocks AMPK activation. Cell-free reconstitution assays show that addition of FBP disrupts the association of axin and LKB1 with v-ATPase and ragulator. Importantly, in some cell types AMP/ATP and ADP/ATP ratios remain unchanged during acute glucose starvation, and intact AMP-binding sites on AMPK are not required for AMPK activation. These results establish that aldolase, as well as being a glycolytic enzyme, is a sensor of glucose availability that regulates AMPK.

To the Editor: Isanaka and colleagues (March 23 issue) tested a heat-stable rotavirus vaccine in Niger and report an efficacy of 66.7% against severe rotavirus gastroenteritis in the per-protocol population. The purpose of rotavirus vaccination is ultimately to reduce the incidence of diarrhea and……

M.S. Joshi, N.N. Ganorkar, S.S. Ranshing, A. Basu, N.A. Chavan, V. Gopalkrishna

Acute gastroenteritis outbreak occurred at Pargaon, Maharashtra, India in 1789 cases with an attack rate of 32.5% between November to December 2015. The stool specimens (n = 32) were investigated for different enteric viral agents using conventional methods. Transmission electron microscopy and RNA polyacrylamide gel electrophoresis respectively identified morphologically distinct rotavirus particles in 28% and RNA migration pattern of Group B Rotavirus (GBR) in 72% of the specimens. Reverse transcription polymerase chain reaction and nucleotide sequencing confirmed presence of GBR in 97% of the samples analyzed. The predominance of GBR infections and absence or insignificant presence of other agents confirmed GBR as an etiological agent of the gastroenteritis outbreak occurred in Maharashtra, India. This article is protected by copyright. All rights reserved …

Powderly WG, Naggie S, Kim AY, et al.

Robert T. Manguso

Immunotherapy with PD-1 checkpoint blockade is effective in only a minority of patients with cancer, suggesting that additional treatment strategies are needed. Here we use a pooled in vivo genetic screening approach using CRISPR-Cas9 genome editing in transplantable tumours in mice treated with immunotherapy to discover previously undescribed immunotherapy targets. We tested 2,368 genes expressed by melanoma cells to identify those that synergize with or cause resistance to checkpoint blockade. We recovered the known immune evasion molecules PD-L1 and CD47, and confirmed that defects in interferon-? signalling caused resistance to immunotherapy. Tumours were sensitized to immunotherapy by deletion of genes involved in several diverse pathways, including NF-?B signalling, antigen presentation and the unfolded protein response. In addition, deletion of the protein tyrosine phosphatase PTPN2 in tumour cells increased the efficacy of immunotherapy by enhancing interferon-?-mediated effects on antigen presentation and growth suppression. In vivo genetic screens in tumour models can identify new immunotherapy targets in unanticipated pathways.

To the Editor: In the SEARCH for Diabetes in Youth study, Mayer-Davis and colleagues (April 13 issue) found a significant annual increase of 8.9% in the incidence of type 2 diabetes in the 2003-2012 period among Native American youths 10 to 19 years of age -- the largest increase in any racial or……

Azusa Inoue

Mammalian sperm and oocytes have different epigenetic landscapes and are organized in different fashions. After fertilization, the initially distinct parental epigenomes become largely equalized with the exception of certain loci, including imprinting control regions. How parental chromatin becomes equalized and how imprinting control regions escape from this reprogramming is largely unknown. Here we profile parental allele-specific DNase I hypersensitive sites in mouse zygotes and morula embryos, and investigate the epigenetic mechanisms underlying these allelic sites. Integrated analyses of DNA methylome and tri-methylation at lysine 27 of histone H3 (H3K27me3) chromatin immunoprecipitation followed by sequencing identify 76 genes with paternal allele-specific DNase I hypersensitive sites that are devoid of DNA methylation but harbour maternal allele-specific H3K27me3. Interestingly, these genes are paternally expressed in preimplantation embryos, and ectopic removal of H3K27me3 induces maternal allele expression. H3K27me3-dependent imprinting is largely lost in the embryonic cell lineage, but at least five genes maintain their imprinted expression in the extra-embryonic cell lineage. The five genes include all paternally expressed autosomal imprinted genes previously demonstrated to be independent of oocyte DNA methylation. Thus, our study identifies maternal H3K27me3 as a DNA methylation-independent imprinting mechanism.

Bruce E. Kemp

The molecule fructose-1,6-bisphosphate, which is produced during glucose metabolism, has been shown to mediate cellular sensing of glucose deprivation through an unexpected mechanism.

To the Editor: The decline in mortality and incidence of cardiovascular complications among patients with diabetes that is reported by Rawshani et al. (April 13 issue) is much smaller among patients with type 2 diabetes than among those with type 1 diabetes. This finding is probably due to the……

Suzanne Filteau, G. PrayGod, S. L. Woodd, Henrik Friis, D. C. Heimburger, J. R. Koethe, P. Kelly, L. Kasonka, Andrea M. Rehman

Objectives Low grip strength is a marker of frailty and a risk factor for mortality among HIV patients and other populations. We investigated factors associated with grip strength in malnourished HIV patients at referral to ART, and at 12 weeks and 2-3 years after starting ART. Methods The study involved HIV-infected Zambian and Tanzanian participants recruited to the NUSTART trial when malnourished (body mass index …

Lely Solari, Alonso Soto, Patrick Van der Stuyft

Objectives Diagnosis of pleural tuberculosis (PT) is still a challenge, particularly in resource- constrained settings. Alternative diagnostic tools are needed. We aimed at evaluating the utility of Clinical Prediction Rules (CPRs) for diagnosis of Pleural Tuberculosis (PT) in Peru. Methods We identified CPRs for diagnosis of PT through a structured literature search. CPRs using high-complexity tests, as defined by the FDA, were excluded. We applied the identified CPRs to patients with pleural exudates attending two third-level hospitals in Lima, Peru, a setting with high incidence of tuberculosis. Besides pleural fluid analysis, patients underwent closed pleural biopsy for reaching a final diagnosis through combining microbiological and histopathological criteria. We evaluated the performance of the CPRs against this composite reference standard using classic indicators of diagnostic test validity. Results We found 15 eligible CPRs, of which 12 could be validated. Most included ADA, age, lymphocyte proportion and protein in pleural fluid as predictive findings. 259 patients were included for their validation. 176 (67%) had PT and 50 (19%) malignant pleural effusion. The overall accuracy of the CPRs varied from 41% to 86%. Two had a positive likelihood ratio (LR) above 10, but none a negative LR below 0.1. ADA alone at a cutoff of >=40 IU attained 87% diagnostic accuracy and had a positive LR of 6.6 and a negative LR of 0.2. Conclusion Many CPRs for PT are available. In addition to ADA alone, none of them contributes significantly to diagnosis of PT. This article is protected by copyright. All rights reserved.

Killpack, T. L., Ballesteros, M., Bunnell, S. C., Bedugnis, A., Kobzik, L., Hu, L. T., Petnicki-Ocwieja, T.

Phagocytosis of the Lyme disease causing pathogen Borrelia burgdorferi has been shown to be important in generating an inflammatory response to the pathogen. As a result, understanding the mechanisms of phagocytosis has been an area of great interest in the field of Lyme disease. Several cell surface receptors that participate in B. burgdorferi phagocytosis have been reported, including scavenger receptor MARCO and integrin α3β1. We sought to define the mechanisms by which these receptors mediated phagocytosis and to identify signaling pathways activated downstream of these receptors upon contact with B. burgdorferi. We identified both Syk and Src signaling pathways as ones that participate in B. burgdorferi phagocytosis and resulting cytokine activation. In our studies we found that MARCO and integrin β1 both play a role in the activation of the Src kinase pathway. However, only integrin β1 participates in the activation of Syk. Interestingly, the integrin activates Syk without the help of signaling adaptors Dap12 or FcR. Thus, we report that multiple pathways participate in B. burgdorferi internalization and different cell surface receptors act simultaneously in cooperation and independently to mediate phagocytosis.

The sustainable growth rate (SGR), a formula used by the Centers for Medicare and Medicaid Services (CMS), frequently specified large cuts in Medicare rates of payment for physician services, which led Congress to step in to defer the cuts. Now that the SGR has been repealed, the dominant policy……

Manchala Nageswar Reddy, Ranjeet Dungdung, Rajendra Pilankatta

Objectives Human serum protein profiling of the individual infected with multiple dengue virus serotypes for identifying the potential biomarkers and to investigate the cause for the severity of dengue virus infection. Methods Dengue virus NS1 positive serum samples were pooled into two groups (S2 and S3) based on the molecular serotyping and number of heterotypic infections. The pooled serum samples were subjected to two dimensional gel electrophoresis (2DGE) to identify the differentially expressed proteins. The peptide masses of up regulated protein were detected by matrix-assisted laser desorption ionization time-of-flight MALDI-TOF mass spectrometry and analyzed by MASCOT search engine. The results were compared with the control group (S1). The commonly upregulated protein was validated by quantitative ELISA and compared with control as well as single serotypic infected samples. Results Based on 2DGE, total thirteen proteins were differentially upregulated in S2 and S3 groups as compared to control. Some of the upregulated proteins were involved in mediating the complement activation of immune response. The Apolipoprotein A-1 (APO A-1) was upregulated in S2 and S3 groups. Upon validation, APO A-1 levels were increased in line with the number of heterotypic infection of dengue viruses. Conclusion Heterotypic infection of dengue viruses upregulate the serum proteins involved in the complement pathway in the early phase of infection. There was a significant increase in the level of APO A-1 in three different serotypic infections of dengue virus as compared to control. Further, the role of APO-A1 can be explored in elucidating the mechanism of dengue pathogenesis. This article is protected by copyright. All rights reserved.

Devin Sok

No immunogen to date has reliably elicited broadly neutralizing antibodies to HIV in humans or animal models. Advances in the design of immunogens (BG505 SOSIP) that antigenically mimic the HIV envelope glycoprotein (Env)1 have improved the elicitation of potent isolate-specific antibody responses in rabbits2 and macaques3, but so far failed to induce broadly neutralizing antibodies. One possible contributor to this failure is that the relevant antibody repertoires are poorly suited to target somewhat occluded conserved epitope regions on Env relative to exposed variable epitopes. To test this hypothesis, we immunized four cows with BG505 SOSIP. The antibody repertoire of cows contains long third heavy chain complementarity determining regions (HCDR3) with an ultralong subset that can reach over 70 amino acids in length4-9. Remarkably, BG505 SOSIP immunization resulted in rapid elicitation of broad and potent serum antibody responses in all four cows. Longitudinal serum analysis for one cow showed the development of neutralization breadth (20%, n = 117 cross-clade isolates) in 42 days and 96% breadth (n = 117) at 381 days. A monoclonal antibody isolated from this cow harboured an ultralong HCDR3 of 60 amino acids and neutralized 72% of cross-clade isolates (n = 117) with a potent median IC50 value of 0.028 ?g ml-1. We note that breadth was elicited with a single trimer immunogen and did not require additional envelope diversity. Immunization of cows may provide an avenue to rapidly generate antibody prophylactics and therapeutics to address disease agents that have evolved to avoid human antibody responses.

Joynt Maddox KE.

In this issue of JAMA, Dharmarajan and colleagues evaluated whether the Hospital Readmissions Reduction Program (HRRP), which focuses on reducing 30-day hospital readmission rates, has been accompanied by changes in mortality rates. The HRRP is a mandatory national program that penalizes hospitals with higher-than-expected readmission rates based on the clinical risk of their patient population; in 2017, 79% of eligible hospitals were penalized, and the average penalty among penalized hospitals was 0.74% of Medicare inpatient payments. Congress created the HRRP to focus attention on the previously overlooked issue of readmission, a clinical outcome considered to represent unacceptable lapses in care and preventable spending.

Malte H. Wehmeyer, Patrick Ingiliz, Stefan Christensen, Dietrich Hueppe, Thomas Lutz, Karl Georg Simon, Knud Schewe, Christoph Boesecke, Axel Baumgarten, Heiner Busch, Juergen Rockstroh, Guenther Schmutz, Torben Kimhofer, Florian Berger, Stefan Mauss, Julian Schulze zur Wiesch

There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. 342 chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co-infected patients [11.1%]). SVR12 rates in the "intention-to-treat" analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir ± ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir ± ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir ± ribavirin for 12 weeks 71.4% (10/14) and sofosbuvir/ledipasvir ± ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow-up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir ± ribavirin for 12 weeks and sofosbuvir/ledipasvir ± ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment-experienced or HIV/HCV co-infected patients. This article is protected by copyright. All rights reserved …

To the Editor: In 2012, the results of the Crystalloid versus Hydroxyethyl Starch Trial (CHEST) were published. CHEST was an investigator-initiated, randomized, controlled trial in which 6% hydroxyethyl starch with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4,……

Figure 1.

Lockie, Christopher J. A.; Gillon, Stuart A.; Barrett, Nicholas A.; Taylor, Daniel; Mazumder, Asif; Paramesh, Kaggere; Rowland, Katie; Daly, Kathleen; Camporota, Luigi; Meadows, Christopher I. S.; Glover, Guy W.; Ioannou, Nicholas; Langrish, Christopher J.; Tricklebank, Stephen; Retter, Andrew; Wyncoll, Duncan L. A.

Objectives: For patients supported with veno-venous extracorporeal membrane oxygenation, the occurrence of intracranial hemorrhage is associated with a high mortality. It is unclear whether intracranial hemorrhage is a consequence of the extracorporeal intervention or of the underlying severe respiratory pathology. In a cohort of patients transferred to a regional severe respiratory failure center that routinely employs admission brain imaging, we sought 1) the prevalence of intracranial hemorrhage; 2) survival and neurologic outcomes; and 3) factors associated with intracranial hemorrhage. Design: A single-center, retrospective, observational cohort study. Setting: Tertiary referral severe respiratory failure center, university teaching hospital. Patients: Patients admitted between December 2011 and February 2016. Intervention: None. Measurements and Main Results: Three hundred forty-two patients were identified: 250 managed with extracorporeal support and 92 managed using conventional ventilation. The prevalence of intracranial hemorrhage was 16.4% in extracorporeal membrane oxygenation patients and 7.6% in conventionally managed patients (p = 0.04). Multivariate analysis revealed factors independently associated with intracranial hemorrhage to be duration of ventilation (d) (odds ratio, 1.13 [95% CI, 1.03-1.23]; p = 0.011) and admission fibrinogen (g/L) (odds ratio, 0.73 [0.57-0.91]; p = 0.009); extracorporeal membrane oxygenation was not an independent risk factor (odds ratio, 3.29 [0.96-15.99]; p = 0.088). In patients who received veno-venous extracorporeal membrane oxygenation, there was no significant difference in 6-month survival between patients with and without intracranial hemorrhage (68.3% vs 76.0%; p = 0.350). Good neurologic function was observed in 92%. Conclusions: We report a higher prevalence of intracranial hemorrhage than has previously been described with high level of neurologically intact survival. Duration of mechanical ventilation and admission fibrinogen, but not exposure to extracorporeal support, are independently associated with intracranial hemorrhage. Copyright (C) by 2017 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

To the Editor: The review of sickle cell disease by Piel et al. (April 20 issue) is timely and highlights the need to address the lack of research about this disease in sub-Saharan Africa. The authors rightly state that in the past two decades, childhood mortality has been reduced in sub-Saharan……

Agudelo-Hernandez, Arcadio; Chen, Yue; Bullotta, Arlene; Buchanan, William G; Klamar-Blain, Cynthia R; Borowski, Luann; Riddler, Sharon A; Rinaldo, Charles R; Macatangay, Bernard JC

Design: : We evaluated the subclinical shedding of 6 different herpesviruses in antiretroviral drug-treated HIV(+) men who have sex with men (MSM), and determined how this is associated with markers of inflammation and immune activation. Methods: We obtained blood, semen, throat washing, urine, and stool from 15 antiretroviral-treated HIV-1-infected MSM with CD4+ T cell reconstitution, and 12 age-matched HIV(-) MSM from the Multicenter AIDS Cohort Study at 4 timepoints over 24 weeks to measure DNA levels of cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1 and 2, human herpesvirus 6 (HHV6), and HHV8. T cell activation and plasma levels of soluble markers of inflammation and activation were also measured at the corresponding timepoints. Results: HIV(+) participants had a trend for higher total herpesvirus shedding rate. HIV(+) participants also had a significantly higher rate of shedding EBV and CMV compared to the HIV(-) group. Herpesvirus shedding was mostly seen in throat washings. In the HIV(+) group, herpesvirus shedding rate inversely correlated with plasma levels of interferon gamma-induced protein 10 (IP-10) and soluble CD163 (sCD163). CMV DNA levels negatively correlated with levels of T cell activation. There was a trend for a positive correlation between EBV shedding rate and plasma soluble CD14. HHV6 shedding rate negatively correlated with plasma levels of interleukin-6, sCD163, and IP-10.Correlations were not observed among HIV(-) individuals. Conclusions: Among treated HIV-infected MSM, there are higher subclinical shedding rates of some herpesviruses that occurs in different body compartments and negatively correlates with levels of inflammation and immune activation. Copyright (C) 2017 Wolters Kluwer Health, Inc.

Kuipers, K., Jong, W. S. P., van der Gaast-de Jongh, C. E., Houben, D., van Opzeeland, F., Simonetti, E., van Selm, S., de Groot, R., Koenders, M. I., Azarian, T., Pupo, E., van der Ley, P., Langereis, J. D., Zomer, A., Luirink, J., de Jonge, M. I.

Serotype-specific protection against a Streptococcus pneumoniae is an important limitation of the current polysaccharide-based vaccines. To prevent serotype replacement, reduce transmission and limit emergence of new variants, it is essential to induce broad protection and restrict pneumococcal colonization. In this study, we used a prototype vaccine formulation consisting of LPS-detoxified outer membrane vesicles (OMVs) from Salmonella Typhimurium displaying the variable N-terminus of PspA (α1α2) for intranasal vaccination, which induced strong Th17 immunity associated with substantial reduction of pneumococcal colonization. Despite the variable nature of this protein a common MHCII epitope was identified, based on in silico prediction combined with ex vivo screening, and was essential for the IL17A-mediated cross-reactivity and associated with cross-protection. Based on 1352 PspA sequences derived from a pneumococcal carriage cohort, this OMV-based vaccine formulation containing a single α1α2 type was estimated to cover 19.1% strains, illustrating the potential of Th17-mediated cross protection.

John J, Giri S, Karthikeyan A, et al.

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>In 2014, 2 studies showed that inactivated poliovirus vaccine (IPV) boosts intestinal immunity in children previously immunized with oral poliovirus vaccine (OPV). As a result, IPV was introduced in mass campaigns to help achieve polio eradication.<div class="boxTitle">Methods.</div>We conducted an open-label, randomized, controlled trial to assess the duration of the boost in intestinal immunity following a dose of IPV given to OPV-immunized children. Nine hundred healthy children in Vellore, India, aged 1-4 years were randomized (1:1:1) to receive IPV at 5 months (arm A), at enrollment (arm B), or no vaccine (arm C). The primary outcome was poliovirus shedding in stool 7 days after bivalent OPV challenge at 11 months. <div class="boxTitle">Results.</div>For children in arms A, B, and C, 284 (94.7%), 297 (99.0%), and 296 (98.7%), respectively, were eligible for primary per-protocol analysis. Poliovirus shedding 7 days after challenge was less prevalent in arms A and B compared with C (24.6%, 25.6%, and 36.4%, respectively; risk ratio 0.68 [95% confidence interval: 0.53-0.87] for A versus C, and 0.70 [0.55-0.90] for B versus C).<div class="boxTitle">Conclusions.</div>Protection against poliovirus remained elevated 6 and 11 months after an IPV boost, although at a lower level than reported at 1 month.<div class="boxTitle">Clinical Trials Registration.</div>CTRI/2014/09/004979.</span>…

Until recently, progress in the fight against human immunodeficiency virus (HIV) infection was primarily measured in terms of the number of patients who were started on antiretroviral therapy (ART). Major efforts to increase access to ART in the low- and middle-income countries that are most……

Schwaber MJ, Carmeli Y.

AbstractIn 2006 the Israeli healthcare system faced an unprecedented outbreak of carbapenem-resistant Enterobacteriaceae (CRE), primarily involving KPC-producing Klebsiella pneumoniae clonal complex CC258. This public health crisis exposed major gaps in infection control. In response, Israel established a national infection control infrastructure. The steps taken in building this infrastructure and benefits realized from its creation are described.

J Tiraboschi, S Ray, K Patel, A Teague, M Pace, P Phalora, N Robinson, E Hopkins, J Meyerowitz, Y Wang, J Cason, S Kaye, J Sanderson, P Klenerman, S Fidler, J Frater, J Fox

Objectives Antiretroviral therapy (ART) during acute HIV infection (AHI) restricts the HIV reservoir, but additional interventions are necessary to induce a cure. Intravenous immunoglobulin (IVIG) is not HIV-specific but is safe and temporarily reduces the HIV reservoir in chronic HIV infection. We present a randomized controlled trial to investigate whether IVIG plus ART in AHI reduces the HIV reservoir and immune activation compared with ART alone. Methods Ten men with AHI (Fiebig II-IV) initiated ART (tenofovir, entricitabine, ritonavir boosted darunavir and raltegravir) at HIV-1 diagnosis and were randomized to ART alone or ART plus 5 days of IVIG, once virally suppressed (week 19). Blood samples were evaluated for viral reservoir, immune activation, immune exhaustion and microbial translocation. Flexible sigmoidoscopy was performed at weeks 19, 24 and 48, and gut proviral DNA and cell numbers determined. Results IVIG was well tolerated and no viral blips (> 50 HIV-1 RNA copies/mL) occurred during IVIG therapy. From baseline to week 48, total HIV DNA in peripheral blood mononuclear cells (PBMCs) (cases: -3.7 log10 copies/106 CD4 cells; controls: -3.87 log10 copies/106 CD4 cells) declined with no differences observed between the groups (P = 0.49). Declines were observed in both groups from week 19 to week 48 in total HIV DNA in PBMCs (P = 0.38), serum low copy RNA (P = 0.57) and gut total HIV DNA (P = 0.55), but again there were no significant differences between arms. Biomarkers of immune activation, immune exhaustion and microbial translocation and the CD4:CD8 ratio were similar between arms for all comparisons. Conclusions Although safe, IVIG in AHI did not impact total HIV DNA, immune function or microbial translocation in peripheral blood or gut tissue.

Changkeun Lee

TMEM175 is a lysosomal K+ channel that is important for maintaining the membrane potential and pH stability in lysosomes. It contains two homologous copies of a six-transmembrane-helix (6-TM) domain, which has no sequence homology to the canonical tetrameric K+ channels and lacks the TVGYG selectivity filter motif found in these channels. The prokaryotic TMEM175 channel, which is present in a subset of bacteria and archaea, contains only a single 6-TM domain and functions as a tetramer. Here, we present the crystal structure of a prokaryotic TMEM175 channel from Chamaesiphon minutus, CmTMEM175, the architecture of which represents a completely different fold from that of canonical K+ channels. All six transmembrane helices of CmTMEM175 are tightly packed within each subunit without undergoing domain swapping. The highly conserved TM1 helix acts as the pore-lining inner helix, creating an hourglass-shaped ion permeation pathway in the channel tetramer. Three layers of hydrophobic residues on the carboxy-terminal half of the TM1 helices form a bottleneck along the ion conduction pathway and serve as the selectivity filter of the channel. Mutagenesis analysis suggests that the first layer of the highly conserved isoleucine residues in the filter is primarily responsible for channel selectivity. Thus, the structure of CmTMEM175 represents a novel architecture of a tetrameric cation channel whose ion selectivity mechanism appears to be distinct from that of the classical K+ channel family.

Walker M, Pion S, Fang H, et al.

AbstractBackgroundMass drug administration (MDA) with ivermectin is the cornerstone of efforts to eliminate human onchocerciasis by 2020/2025. The feasibility of elimination crucially depends on the effects of multiple ivermectin doses on Onchocerca volvulus. A single ivermectin (standard) dose clears the skin-dwelling microfilarial progeny of adult worms (macrofilariae) and temporarily impedes the release of such progeny by female macrofilariae, but a macrofilaricidal effect has been deemed minimal. Multiple doses of ivermectin may cumulatively and permanently reduce the fertility and shorten the lifespan of adult females, but rigorous quantification of these effects necessitates interrogating longitudinal data on macrofilariae with suitably powerful analytical techniques.MethodsUsing a novel mathematical modelling approach, we analysed-at an individual participant level-longitudinal data on viability and fertility of female worms from the single most comprehensive multiple-dose clinical trial of ivermectin, comparing three-monthly with annual treatments administered for three years, in Cameroon.ResultsMultiple doses of ivermectin have a partial macrofilaricidal and a modest permanent sterilising effect after 4 or more consecutive treatments, even at routine MDA doses (150 ?g/kg) and (annual) frequencies. The life expectancy of adult O. volvulus is reduced by approximately 50% and 70% after three years of annual or three-monthly (quarterly) exposures to ivermectin.ConclusionsOur quantification of macrofilaricidal and sterilising effects of ivermectin should be incorporated into transmission models informing onchocerciasis elimination efforts in Africa and residual foci in Latin America. It also provides a framework to assess macrofilaricidal candidate drugs currently under development.