The Lancet

Since The Lancet published the first Global Burden of Disease Study (GBD) over 10 years ago, every new iteration has brought improvements in data quality and quantity. With the sharpening of these estimates came a reassuring message: year on year, they portrayed an ever-healthier world. Careful reading of the results of GBD 2017 shatter this comforting trend of gradual improvement and instead show plateauing mortality rates on a background of faltering and uneven progress, era-defining epidemics, and dramatic health worker shortages.

GBD 2017 Mortality Collaborators

This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing.

GBD 2017 Causes of Death Collaborators

Improvements in global health have been unevenly distributed among populations. Deaths due to injuries, substance use disorders, armed conflict and terrorism, neoplasms, and cardiovascular disease are expanding threats to global health. For causes of death such as lower respiratory and enteric infections, more rapid progress occurred for children than for the oldest adults, and there is continuing disparity in mortality rates by sex across age groups. Reductions in the death rate of some common diseases are themselves slowing or have ceased, primarily for NCDs, and the death rate for selected causes has increased in the past decade.

GBD 2017 Risk Factor Collaborators

By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity.

GBD 2017 DALYs and HALE Collaborators

With increasing life expectancy in most countries, the question of whether the additional years of life gained are spent in good health or poor health has been increasingly relevant because of the potential policy implications, such as health-care provisions and extending retirement ages. In some locations, a large proportion of those additional years are spent in poor health. Large inequalities in HALE and disease burden exist across countries in different SDI quintiles and between sexes. The burden of disabling conditions has serious implications for health system planning and health-related expenditures.

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators

Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss.

GBD 2017 SDG Collaborators

The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims.

GBD 2017 Population and Fertility Collaborators

Population trends create demographic dividends and headwinds (ie, economic benefits and detriments) that affect national economies and determine national planning needs. Although TFRs are decreasing, the global population continues to grow as mortality declines, with diverse patterns at the national level and across age groups. To our knowledge, this is the first study to provide transparent and replicable estimates of population and fertility, which can be used to inform decision making and to monitor progress.

Meikle, V., Mossberg, A.-K., Mitra, A., Hakansson, A. P., Niederweis, M.

Mycobacterium tuberculosis (Mtb), the causative agent of human tuberculosis (TB), has surpassed HIV/AIDS as the leading cause of death from a single infectious agent. The increasing occurrence of drug resistant strains has become a major challenge for health care systems and, in some cases, rendered TB untreatable. However, developing new TB drugs has been plagued with high failure rates and costs. Alternative strategies to increase the efficacy of current TB treatment regimens include host-directed therapies or agents that make Mtb more susceptible to existing TB drugs. In this study, we show that HAMLET, an alpha-lactalbumin - oleic acid complex derived from human milk, has bactericidal activity against Mtb. HAMLET consists of a micellar oleic acid core surrounded by a shell of partially denatured alpha-lactalbumin molecules and unloads oleic acid into cells upon contact with lipid membranes. At sub-lethal concentrations, HAMLET potentiated a remarkably broad array of TB drugs and antibiotics against Mtb. For example, the minimal inhibitory concentrations of rifampicin, bedaquiline, delamanid and clarithromycin were decreased by 8- to 16-fold. HAMLET also killed Mtb and enhanced the efficacy of TB drugs inside macrophages, a natural habitat of Mtb. Previous studies showed that HAMLET is stable after oral delivery in mice and non-toxic in humans and that it is possible to package hydrophobic compounds in the oleic acid core of HAMLET to increase their solubility and metabolic stability. The potential of HAMLET and other liprotides as drug delivery and sensitization agents in TB chemotherapy is discussed.…

Lisa A. Waddell, Judy Greig, L. Robbin Lindsay, Alison F. Hinckley, Nicholas H. Ogden

by Lisa A. Waddell, Judy Greig, L. Robbin Lindsay, Alison F. Hinckley, Nicholas H. Ogden Lyme disease (LD), caused by bacteria of the Borrelia burgdorferi sensu lato species complex, is the most common vector-borne disease in North America and Europe. A systematic review (SR) was conducted to summarize the global literature on adverse birth outcomes associated with gestational LD in humans. The SR followed an a priori protocol of pretested screening, risk of bias, and data extraction forms. Data were summarized descriptively and random effects meta-analysis (MA) was used where appropriate. The SR identified 45 relevant studies, 29 describing 59 cases reported as gestational LD in the United States, Europe, and Asia (1969–2017). Adverse birth outcomes included spontaneous miscarriage or fetal death (n = 12), newborn death (n = 8), and newborns with an abnormal outcome (e.g. hyperbilirubinemia, respiratory distress and syndactyly) at birth (n = 16). Only one report provided a full case description (clinical manifestations in the mother, negative outcome for the child, and laboratory detection of B. burgdorferi in the child) that provides some evidence for vertical transmission of B. burgdorferi that has negative consequences for the fetus. The results of 17 epidemiological studies are included in this SR. Prevalence of adverse birth outcomes in an exposed population (defined by the authors as: gestational LD, history of LD, tick bites or residence in an endemic area) was compared to that in an unexposed population in eight studies and no difference was reported. A meta-analysis of nine studies showed significantly fewer adverse birth outcomes in women reported to have been treated for gestational LD (11%, 95%CI 7–16) compared to those who were not treated during pregnancy (50%, 95%CI 30–70) providing indirect evidence of an association between gestational LD and adverse birth outcomes. Other risk factors investigated; trimester of exposure, length of LD during pregnancy, acute vs. disseminated LD at diagnosis, and symptomatic LD vs. seropositive women with no LD symptoms during pregnancy were not significantly associated with adverse birth outcomes. This SR summarizes evidence from case studies that provide some limited evidence for transplacental transmission of B. burgdorferi. There was inconsistent evidence for adverse birth outcomes of gestational LD in the epidemiological research, and uncommon adverse outcomes for the fetus may occur as a consequence of gestational LD. The global evidence does not fully characterize the potential impact of gestational LD, and future research that addresses the knowledge gaps may change the findings in this SR. Given the current evidence; prompt diagnosis and treatment of LD during pregnancy is recommended.

Abstract Background The degree to which insecticide-treated net (ITN) supply accounts for age and gender disparities in ITN use among household members is unknown. This study explores the role of household ITN supply in the variation in ITN use among household members in sub-Saharan Africa. Methods Data was from Malaria Indicator Surveys or Demographic and Health Surveys collected between 2011 and 2016 from 29 countries in sub-Saharan Africa. The main outcome was ITN use the previous night. Other key variables included ITN supply (nets/household members), age and gender of household members. Analytical methods included logistic regressions and meta-regression. Results Across countries, the median (range) of the percentage of households with enough ITNs was 30.7% (8.5–62.0%). Crude analysis showed a sinusoidal pattern in ITN use across age groups of household members, peaking at 0–4 years and again around 30–40 years and dipping among people between 5–14 and 50+ years. This sinusoidal pattern was more pronounced in households with not enough ITNs compared to those with enough ITNs. ITN use tended to be higher in females than males in households with not enough ITNs while use was comparable among females and males in households with enough ITNs. After adjusting for wealth quintile, residence and region, among households with not enough ITNs in all countries, the odds of ITN use were consistently higher among children under 5 years and non-pregnant women 15–49 years. Meta-regressions showed that across all countries, the mean adjusted odds ratio (aOR) of ITN use among children under 5 years, pregnant and non-pregnant women aged 15–49 years and people 50 years and above was significantly higher than among men aged 15–49 years. Among these household members, the relationship was attenuated when there were enough ITNs in the household (dropping 0.26–0.59 points) after adjusting for geographical zone, household ITN supply, population ITN access, and ITN use:access ratio. There was no significant difference in mean aOR of ITN use among school-aged children compared to men aged 15–49 years, regardless of household ITN supply. Conclusions This study demonstrated that having enough ITNs in the household increases level of use and decreases existing disparities between age and gender groups. ITN distribution via mass campaigns and continuous distribution channels should be enhanced as needed to ensure that households have enough ITNs for all members, including men and school-aged children.…

Gokul Raj Kathamuthu, Kadar Moideen, Vaithilingam V. Banurekha, Dina Nair, R. Sridhar, Dhanaraj Baskaran, Subash Babu

by Gokul Raj Kathamuthu, Kadar Moideen, Vaithilingam V. Banurekha, Dina Nair, R. Sridhar, Dhanaraj Baskaran, Subash Babu B cell activating factor/a proliferation-inducing ligand (BAFF/APRIL) are members of the tumor necrosis factor alpha (TNF) α family of ligands, which are essential for B cell survival, development, and modulation of the immune system. To examine the association of circulating levels of BAFF and APRIL with pulmonary tuberculosis (PTB) and tuberculous lymphadenitis (TBL), we measured the systemic levels of APRIL and BAFF in individuals with PTB, TBL, latent tuberculosis (LTB) and healthy controls (HC). Further, we also examined the pre and post-treatment plasma levels of above-mentioned parameters in PTB and TBL individuals upon completion of anti-TB chemotherapy. Next, the association of these cytokines either with extent of disease, disease severity, bacterial burden in PTB and lymph node culture grade or the lymph node size in TBL was also assessed. Finally, ROC analysis was performed to examine the discrimination capacity of APRIL and BAFF between PTB or TBL with LTB. Our study revealed significantly diminished plasma levels of APRIL in PTB and higher plasma levels of BAFF in both PTB and TBL individuals compared to LTB and HC. Furthermore, we observed a significant increase in APRIL levels in TBL and significantly decreased plasma levels of BAFF in both PTB and TBL after the completion of successful anti-TB treatment. There was no statistically positive relationship between BAFF and APRIL levels and the extent of disease, disease severity and bacterial burden in PTB. In TBL, there was a significant correlation between APRIL (but not BAFF) levels with lymph node culture grades. In contrast, APRIL in PTB and BAFF in TBL were able to clearly discriminate from LTB in ROC analysis. In summary, our results showed altered levels of BAFF/APRIL and their modulation upon chemotherapy, suggesting that these cytokines might be involved in the immune-modulation of TB infection.

Kuehn B.

The percentage of US adults with Alzheimer disease and related dementias is projected to grow from 1.6% in 2014 to 3.3% in 2060, according to a study by the CDC in the journal Alzheimer & Dementia.

Stephen Solis-Reyes, Mariano Avino, Art Poon, Lila Kari

by Stephen Solis-Reyes, Mariano Avino, Art Poon, Lila Kari For many disease-causing virus species, global diversity is clustered into a taxonomy of subtypes with clinical significance. In particular, the classification of infections among the subtypes of human immunodeficiency virus type 1 (HIV-1) is a routine component of clinical management, and there are now many classification algorithms available for this purpose. Although several of these algorithms are similar in accuracy and speed, the majority are proprietary and require laboratories to transmit HIV-1 sequence data over the network to remote servers. This potentially exposes sensitive patient data to unauthorized access, and makes it impossible to determine how classifications are made and to maintain the data provenance of clinical bioinformatic workflows. We propose an open-source supervised and alignment-free subtyping method (Kameris) that operates on k-mer frequencies in HIV-1 sequences. We performed a detailed study of the accuracy and performance of subtype classification in comparison to four state-of-the-art programs. Based on our testing data set of manually curated real-world HIV-1 sequences (n = 2, 784), Kameris obtained an overall accuracy of 97%, which matches or exceeds all other tested software, with a processing rate of over 1,500 sequences per second. Furthermore, our fully standalone general-purpose software provides key advantages in terms of data security and privacy, transparency and reproducibility. Finally, we show that our method is readily adaptable to subtype classification of other viruses including dengue, influenza A, and hepatitis B and C virus.

Avi J. Hakim, Kelsey Coy, Padmaja Patnaik, Nouhoum Telly, Tako Ballo, Bouyagui Traore, Seydou Doumbia, Maria Lahuerta

by Avi J. Hakim, Kelsey Coy, Padmaja Patnaik, Nouhoum Telly, Tako Ballo, Bouyagui Traore, Seydou Doumbia, Maria Lahuerta Despite the high HIV prevalence among men who have sex with men (MSM) and transgender women (TGW), there are limited data on progress on their respective HIV antiretroviral treatment (ART) cascades to identify progress and gaps in meeting UNAIDS 90-90-90 targets. We conducted a respondent-driven sampling survey of MSM and TGW in Bamako, Mali from October 2014 to February 2015. We describe the HIV treatment cascade for MSM and TGW, identify correlates of being unaware of HIV-infected status and having unsuppressed viral load levels, and estimate proportion of recent infections. We enrolled 387 MSM and 165 TGW. HIV prevalence was 13.7%. Of those living with HIV, 10.4% were aware of their serostatus, 61.2% of them self-reported being on treatment, and of them, 100% were virally suppressed. In multivariate analysis, factors associated with being unaware of HIV infection included not using free condoms in the last six months (aOR: 5.7, 95% CI: 1.1–29.5) and not having comprehensive knowledge of HIV (aOR: 6.5, 95% CI: 1.4–29.9). Having unsuppressed viral load was associated with identifying as a transgender woman (aOR: 4.8, 95% CI: 1.1–20.7) and not having comprehensive knowledge of HIV (aOR: 6.5, 95% CI: 1.0–40.9). Of the 79 HIV-positive participants, 5.1% had recent infections. While the proportion aware of their HIV status was low despite adjusting for viral load biomarkers, all MSM and TGW on treatment were virally suppressed. Improved testing strategies are urgently needed to achieve the first 90 of the HIV cascade among MSM and TGW in Bamako.

Abstract Background In recent years, outbreaks of varicella have continued to occur, and the coverage rate of varicella vaccine in Jiangsu Province, China, remains unclear. This study aims to analyse the levels of immune antibody against varicella and obtain a comprehensive understanding of the varicella attenuated live vaccine (VarV) coverage rate in children aged 1–9 years in Jiangsu Province. Methods From June to October 2016, a cross-sectional survey was conducted to collect 3631 serum samples from healthy children aged 1–9 years in Jiangsu Province. The immunoglobulin G (IgG) antibody levels of varicella were detected by enzyme-linked immunosorbent assay (ELISA). Results The VarV coverage rate of healthy children was only 43.1% (95% CI: 41.1–44.7%). The seroprevalence after vaccination with a single dose of VarV was only 57.1%, and the overall seropositivity and geometric antibody titre (GMC) were 43.5% and 225.4 mU/ml, respectively. The seropositivity was significantly higher in girls than in boys (χ2 = 18.82, P 

Kuehn B.

The CDC and the US Department of Health and Human Services (HHS) has secured commitments from more than 100 companies, professional societies, and other organizations to participate in a global challenge to reduce antibiotic resistance.

Schiaffino, F., Colston, J. M., Paredes Olortegui, M., Francois, R., Pisanic, N., Burga, R., Penataro Yori, P., Kosek, M. N.

ObjectivesTo determine phenotypic patterns of antibiotic resistance and epidemiology of drug-resistant Campylobacter spp. from a low-resource setting.MethodsA birth cohort of 303 was followed until 5 years of age. Stool from asymptomatic (n= 10,008) and diarrhea samples (n=3175) were cultured for Campylobacter. Disk diffusion to CIP, NAL, ERY, AZM, TET, GM, AMP, AMC, CRO, C and TMS were determined. Antibiotic resistance between C. jejuni and non-C. jejuni isolates, and surveillance and diarrhea samples were compared and the association between personal macrolide exposure and subsequent occurrence of a macrolide resistant Campylobacter spp. was assessed.ResultsOf 917 Campylobacter isolates, 77.4% of C. jejuni isolates and 79.8% non-C. jejuni isolates were resistant to ciprofloxacin while 4.9% of C. jejuni isolates and 24.8% of non-C. jejuni isolates were not susceptible to azithromycin. Of the 303 children, 33.1% were ever diagnosed with a Campylobacter strain non-susceptible to both azithromycin and ciprofloxacin. Personal macrolide exposure did not affect the risk of macrolide resistant Campylobacter. Amoxicillin and clavulanic acid (94.0%) was one of the antibiotics with the highest rates of susceptibility.ConclusionThere is a high incidence of quinolone and macrolide resistant Campylobacter infections in infants under 24 months of age. Given the lack of association between personal exposure to macrolides and a subsequent Campylobacter infection resistant to macrolides, there is a need to evaluate the source of MDR Campylobacter. This study provides compelling evidence to propose amoxicillin/clavulanic acid as a treatment for Campylobacteriosis.…

Sarah L. Buchan, Lang Dou, Marcus Remer, Steven G. Booth, Stuart N. Dunn, Chester Lai, Monika Semmrich, Ingrid Teige, Linda Mårtensson, Christine A. Penfold, H.T. Claude Chan, Jane E. Willoughby, C. Ian Mockridge, Lekh N. Dahal, Kirstie L.S. Cleary, Sonya James, Anne Rogel, Päivi Kannisto, Mats Jernetz, Emily L. Williams, Eugene Healy, J. Sjef Verbeek, Peter W.M. Johnson, Björn Frendéus, Mark S. Cragg, Martin J. Glennie, Juliet C. Gray, Aymen Al-Shamkhani, Stephen A. Beers

Buchan et al. reveal dual anti-tumor activities for antibodies to the co-stimulatory receptor 4-1BB, which depend on antibody isotype and FcγR availability. Sequential scheduling of anti-4-1BB and checkpoint blockade mAbs, and antibodies engineered to harness both Treg cell depleting and effector cell agonism properties show potent anti-tumor activity in preclinical models, laying the groundwork for translation into the clinic.

Abstract Purpose The aim of the study was to assess guideline adherence to combined antiretroviral therapy (ART) in the German ClinSurv HIV Cohort and the real-life impact of the Strategic Timing of Antiretroviral Therapy (START) study, to identify patients not treated as recommended by new guidelines. Methods We used data from the multicenter ClinSurv cohort of the Robert-Koch-Institute (RKI) between 1999 and 2016. Inclusion criteria were people living with HIV/AIDS, ≥ 18 years of age and cART naïve at the first visit (FV). Adherence was defined as starting cART within 6 months of crossing the CD4+ T cell threshold as suggested by the German-Austrian treatment guidelines. Logistic regression was used to identify factors associated with non-adherence. Results 11,817 patients met the inclusion criteria. We observed an overall adherence rate of 60%, in patients with treatment indication who started cART timely between 2002 and 2015. Adherence rate increased constantly, demonstrating a potential increase in patients, with treatment indication, starting cART within 6 months of presentation from 55% in 2008 to 94% in 2015. Patients reporting injection drug use (OR 2.18, 95% CI 1.70–2.95) and patients between 18 years and 39 years of age at the time of their first visit (OR 2.89, 95% CI 1.35–6.18) were identified as risk groups associated with non-adherence. Conclusion The majority of patients below the CD4+ T cell count threshold of applicable guidelines initiated treatment within 6 months. We observed a slowly diminishing proportion of patients not starting cART timely. Delayed treatment was more frequent in patients reporting injection drug use.…

Shiyang Li, John W. Bostick, Jian Ye, Ju Qiu, Bin Zhang, Joseph F. Urban, Dorina Avram, Liang Zhou

The aryl hydrocarbon receptor (Ahr) promotes ILC3 maintenance and function. Li et al. report that Ahr restricts intestinal ILC2 function in a cell-intrinsic manner, suggesting a central role for gut adaptation of Ahr expression in regulating the ILC2-ILC3 balance.

J. E. Sealy et al.

Abstract Background Toll-like receptor (TLR) single nucleotide polymorphisms (SNPs) have been associated with regulation of TLR expression and development of active tuberculosis (TB). The objectives of this study were to determine whether TLR8 and TLR9 SNPs were associated with the development of latent TB infection (LTBI) and the subsequent pulmonary TB (PTB) in a Chinese Han population. Methods Two independent samples were enrolled. The first sample contained 584 TB cases and 608 controls; the second sample included 204 healthy controls, 201 LTBI subjects and 209 bacteria-confirmed active PTB patients. Three SNPs (rs3764880, rs187084 and rs5743836) were genotyped. The associations between the SNPs and risk of LTBI or PTB were investigated using unconditional logistic regression analysis. Results The A-allele of TLR8 rs3764880 SNP was protective against the development of TB in males (A vs G, OR = 0.58, 95%CI = 0.37–0.91). The AA genotype of rs3764880 SNP was found to increase the risk of PTB among females with an OR of 4.81 (1.11–20.85). The G allele of TLR9 SNP rs187084 was found to increase the risk of PTB (G vs A, P = 0.01, OR = 1.48, 95% CI = 1.10–2.00), the significance was also observed under dominant genetic models. The GA-genotype of TLR9 rs187084 SNP was found to increase the risk of PTB with an OR of 1.68 (1.07–2.65), but was found to decrease the risk of MTB infection with an OR = 0.64 (0.41–0.98). TLR9_rs5743836 SNP was excluded from the data analyses, because the minimum allele frequency was

A. E. James et al.

Patrick Ebner, Friedrich Götz

The excretion of cytoplasmic and signal-peptide-less proteins (ECP) by microorganisms and eukaryotes remains a fascinating topic. In principle, it appears to be a waste of energy. However, it turns out that – extracellularly – some cytoplasmic proteins (CPs) exert a completely different function such as contributing to pathogenicity or evasion of the immune system. Such CPs have been referred to as ‘moonlighting’ proteins. ECP is boosted by many endogenous or external factors that impair the membrane or cell wall structure.

Meilleur C, Wardell C, Mele T, et al.

AbstractSuperantigens (SAgs) released by common Gram-positive bacterial pathogens have been reported to delete, anergize or activate mouse T cells. However, little is known about their effects on preexisting memory CD8 + T cell (TCD8) pools. Furthermore, whether SAgs manipulate human memory TCD8 responses to cognate antigens is unknown. We employed a human peripheral blood mononuclear cell culture system and a non-transgenic mouse model in which the impact of stimulation by two fundamentally distinct SAgs, staphylococcal enterotoxin B and Mycoplasma arthritidis mitogen, on influenza- and/or cytomegalovirus-specific memory TCD8 could be monitored. Bacterial SAgs surprisingly expanded antiviral memory TCD8 generated naturally through infection or artificially through vaccination. Mechanistically, this was a T cell-intrinsic and TCR Vβ-dependent phenomenon. Importantly, SAg-expanded TCD8 displayed an effector memory phenotype and were capable of producing interferon-γ and destroying target cells ex vivo or in vivo. These findings have clear implications for antimicrobial defense and rational vaccine design.

Stephen P. Carter, Andrew Robertson, Kate L. Palphramand, Mark A. Chambers, Robbie A. McDonald, Richard J. Delahay

by Stephen P. Carter, Andrew Robertson, Kate L. Palphramand, Mark A. Chambers, Robbie A. McDonald, Richard J. Delahay The deployment of baits containing vaccines or toxins has been used successfully in the management of wildlife populations, including for disease control. Optimisation of deployment strategies seeks to maximise uptake by the targeted population whilst ensuring cost-effectiveness. Tuberculosis (TB) caused by infection with Mycobacterium bovis affects a broad range of mammalian hosts across the globe, including cattle, wildlife and humans. The control of TB in cattle in the UK and Republic of Ireland is hampered by persistent infection in European badgers (Meles meles). The present study aimed to determine the best strategy for maximising uptake of an oral vaccine by wild badgers, using a surrogate novel bait deployed at 40 badger social groups. Baits contained a blood-borne biomarker (Iophenoxic Acid, IPA) in order to measure consumption in badgers subsequently cage trapped at targeted setts. Evidence for the consumption of bait was found in 83% (199/240) of captured badgers. The probability that badgers had consumed at least one bait (IPA >10 μg ml-1) was significantly higher following deployment in spring than in summer. Lower uptake amongst social groups where more badgers were captured, suggested competition for baits. The probability of bait consumption was significantly higher at groups where main and outlier setts were provided with baits than at those where outliers were present but not baited. Badgers captured 10–14 days post bait feeding had significantly higher levels of bait uptake compared to those caught 24–28 days later. Uptake rates did not vary significantly in relation to badger age and whether bait was placed above ground or down setts. This study suggests that high levels of bait uptake can be achieved in wild badger populations and identifies factors influencing the potential success of different deployment strategies. The implications for the development of an oral badger vaccine are discussed.

Arpadi, Stephen; Lamb, Matthew; Isaie Nzeyimana, N.; Vandebriel, Greet; Anyalechi, Gloria; Wong, Marcia; Smith, Rebecca; Rivadeneira, Emilia D.; Kayirangwa, Eugenie; Malamba, Samuel S.; Musoni, Canisious; Koumans, Emilia H.; Braaten, Mollie; Nsanzimana, Sabin

Abstract: Background: In 2012, Rwanda introduced a Treat All approach for HIV-infected children under age 5. We compared antiretroviral therapy (ART) initiation, outcomes, and retention, before and after this change. Methods: We conducted a retrospective study of children enrolled into care between June 2009-December 2011 (Before Treat All cohort [BTA]) and between July 2012-April 2015 (Treat All cohort [TA]). Setting: Medical records of a nationally representative sample were abstracted for all eligible aged 18-60 months from 100 Rwandan public health facilities. Results: We abstracted 374 medical records: 227 in the BTA and 147 in the TA cohorts. Mean (SD) age at enrollment was (3 years [1.1]). Among BTA, 59% initiated ART within one year, vs. 89% in the TA cohort. Median time to ART initiation was 68 days (IQR 14-494) for BTA and 9 days (IQR 0-28) for TA (p

Jumare, Jibreel; El-Kamary, Samer S.; Magder, Laurence; Hungerford, Laura; Umlauf, Anya; Franklin, Donald; Ghate, Manisha; Abimiku, Alash’le; Charurat, Man; Letendre, Scott; Ellis, Ronald J.; Mehendale, Sanjay; Blattner, William A.; Royal, Walter III; Marcotte, Thomas D.; Heaton, Robert K.; Grant, Igor; McCutchan, J. Allen

Background: Risk of cognitive impairment is increased among persons with high or low body mass index (BMI) in HIV- and HIV+ populations in resource-rich settings. We examined this association among HIV+ patients in three resource-limited settings. Methods: This secondary analysis included data of 761 HIV+ volunteers pooled from 3 prospective cohort studies conducted in China (n=404; 53%), India (n=200; 26%) and Nigeria (n=157; 21%). World Health Organization (WHO) weight classifications were based on BMI. T scores, adjusted for demographics and practice effects, were derived from a 7-domain neuropsychological battery. Neurocognitive impairment (NCI) was defined as global deficit score (GDS) of ≥ 0.5. Results: Overall prevalence of NCI at baseline was 27.7% (similar across all cohorts). The overweight/obese and underweight constituted 37.3% and 15.5% of the total participants respectively. In a multivariable logistic regression of pooled longitudinal data, adjusting for clinical and demographic variables, the odds of global neurocognitive impairment were 38% higher among the overweight/obese as compared to normal weight participants (OR: 1.38 [95% CI: 1.1, 1.72]; P=0.005). Similarly, the odds of global neurocognitive impairment were 39% higher among the underweight as compared to normal weight participants (OR: 1.39 [95% CI: 1.03, 1.87]; P=0.029). Conclusion: Neurocognitive impairment among HIV-1 infected patients was more prevalent in both overweight/obese and underweight than normal weight individuals in three resource-limited settings, confirming observations in resource rich settings. Mechanisms underlying these associations are unclear, but likely differ for underweight and overweight persons. Corresponding author: E-mail: jibreel.jumare@som.umaryland.edu, Tel: (410) 706-7192, Fax: (410) 706-1944 Conflicts of Interest and Source of Funding: WAB is an editor for JAIDS. Other authors have no conflicts to report. This work was supported by National Institutes of Health grant #R01 P30 MH62512-14 (to Igor Grant), National Institute of Mental Health (NIMH) grant #R01 MH78748 (to Thomas D. Marcotte), National Institutes of Health grant #R01 MH086356 (to William A. Blattner and Walter Royal, III) and by National Institutes of Health Fogarty/AIDS International Training and Research Program grant #2D43TW001041-14 (training support to Jibreel Jumare). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Puzantian T, Gasper JJ.

This study assesses the availability of pharmacist-furnished naloxone 2 years after implementation of legislation in California allowing provision of the drug without a physician’s prescription.

Abstract Background Hepatitis B virus (HBV) genotype E is a poorly studied genotype that almost exclusively occurs in African people. It seems to harbour intrinsic potential oncogenic activity and virological characteristics of immune scape but a paucity of information is available on clinical and virological characteristic of HBV genotype E-infected patients as well as on the efficacy of anti-HBV drugs for such patients. The increasing flow of migrants from high endemic HBV sub-Saharan Africa, where genotype E is the predominant one, to Western countries makes improving such knowledge critical in order to deliver proper medical care. Methods Prospective observational study of naïve patients of sub-Saharan origin treated for chronic HBV genotype E infection at a Tropical Medicine clinic sited in Spain from February 2004 to January 2018. The aim of the study was to describe the response of chronic HBV genotype E infection to nucleos(t)ide analogues (NA), entecavir or tenofovir, in real clinical practice. Results During the study period, 2209 sub-Saharan patients were assisted at our Tropical Medicine Unit and 609 (27.6%) had chronic HBV (CHB) infection. Genotype information was available for 55 naïve patients initiating treatment with NA (entecavir or tenofovir), 43 (84.3%) of them being genotype E, although 15 were excluded because they did not meet study inclusion criteria. Thus, a total of 28 CHB genotype E patients were included and followed for 24 months at least. Twenty-one patients were in HBeAg-negative chronic hepatitis phase and 7 patients in HBeAg-positive chronic hepatitis phase. After one year of treatment, among those with good adherence, 89.4% (17/19) of the HBeAg-negative patients and 80% of the HBeAg-positive ones had undetectable viral loads. Response rates reached 100% in both groups after 15–18 months of follow-up. Out of the 7 HBeAg-positive patients, 6 (85.7%) presented HBeAg loss in a median time of 31.8 months. Neither serious adverse effects nor hepatocarcinoma cases happened during the study period. Conclusions HBV genotype may influence disease progression and antiviral response. Our study provides precious information on the efficacy and safety of NA treatment for CHB genotype E infection, a fairly unknown genotype with and increasing epidemiological impact.…

Abstract Background Nevirapine has been used as antiretroviral agent since early ‘90. Although nevirapine is not currently recommended in initial anti-HIV regimens, its use remains consistent in a certain number of HIV-1-positive subjects. Thus, our aim was to determine clinical and genetic factors involved in the development of severe nevirapine induced liver toxicity. Methods We retrospectively analyzed all HIV positive patients who were followed at the Infectious Diseases Unit, DIBIC Luigi Sacco, University of Milan from May 2011 to December 2015. All patients treated with nevirapine who underwent a genotyping for the functional variants mapping into ABCB1, CYP2B6, CYP3A4 and CYP3A5 genes were included in the analysis. Severe hepatotoxicity was defined as ACTG grade 3–4 AST/ALT increase during the first three months of nevirapine treatment. The causality assessment between NVP exposure and drug-induced liver injury was performed by using the updated Roussel Uclaf Causality Assessment Methods. Hardy Weinberg equilibrium was tested by χ2 test. A multivariable logistic regression model was constructed using a backward elimination method. Results Three hundred and sixty-two patients were included in the analysis, of which 8 (2.2%) experienced a severe liver toxicity. We observed no differences between patients with and without liver toxicity as regards gender, ethnicity, age and immune-virological status. A higher prevalence of HCV coinfection (75.0% vs 30.2%; p = .0013) and higher baseline AST (58 IU/L vs 26 IU/L; p = 0.041) and ALT (82 IU/L vs 27 IU/L; p = 0.047) median levels were observed in patients with liver toxicity vs those without toxicity. The genotypes CT/TT at ABCB1 rs1045642 single nucleotide polymorphism (SNP), showed a protective effect for liver toxicity when compared with genotype CC (OR = 0.18, 95%CI 0.04–0.76; p = 0.020) in univariate analysis. In the multivariate model, HCV coinfection was independently associated with higher risk of developing liver toxicity (aOR = 8.00, 95%CI 1.27–50.29; p = 0.027), whereas ABCB1 rs1045642 CT/TT genotypes (aOR = 0.10, 95%CI 0.02–0.47; p = 0.004) was associated with a lower risk. Conclusions According to our findings HCV coinfection and ABCB1 rs1045642 SNP represent independent determinants of severe liver toxicity related to nevirapine. This genetic evaluation could be included as toxicity assessment in HIV-1-positive subjects treated with nevirapine.…

H. Koo et al.

Tortelli, Brett A.; Char, Douglas M.; Crane, John S.; Powderly, William G.; Salter, Amber; Chan, Philip A.; Patel, Rupa R.

No abstract available…

Abstract Background There are randomized trials assessing a variety of antiviral drugs for hepatitis B virus (HBV), but the relative effectiveness of these drugs in the treatment of patients co-infected with human immunodeficiency virus (HIV) remains unclear. The objectives of the current study were to estimate and rank the relative effectiveness of antiviral drugs for treating HBV and HIV co-infected patients. Methods Randomized trials, assessing the efficacy of antiviral drugs for HBV and HIV co-infected patients were searched in health-related databases. The methodological quality of the included trials was evaluated using the Cochrane risk of bias tool. Main outcome in this meta-analysis study was the success of treatment by antivirals as determined by virologic response. We performed pairwise and network meta-analysis of these trials and assessed the quality of evidence using the GRADE approach. Results Seven randomized trials (329 participants) were included in this network meta-analysis study. A network geometry was formed with six treatment options including four antiviral drugs, adefovir (ADV), emtricitabine (FTC), lamivudine (LMV) and tenofovir disoproxil fumarate (TDF), combination treatment of TDF plus LMV, and placebo. The weighted percentage contributions of each comparison distributed fairly equally in the entire network of evidence. An assumption of consistency required for network meta-analysis was not violated (the global Wald test for inconsistency: Chi2(4) = 3.63, p = 0.46). The results of estimates showed no differences between the treatment regimens in terms of viral response for treating HBV and HIV co-infected patients, which spanned both benefit and harm (e.g. LMV vs TDF plus LMV: OR: 0.37, 95%CI: 0.06–2.41). Overall, the certainty of evidence was very low in all comparisons (e.g. LMV vs TDF plus LMV: 218 fewer per 1000,121 more to 602 fewer, very low certainty). Therefore, we remained uncertain to the true ranking of the antiviral treatments in HBV/ HIV co-infected patients. Conclusions The findings suggest that the evidence is insufficient to provide guidance to the relative effectiveness of currently available antiviral drugs with dual activity in treating co-infection of HBV/HIV. Well-designed, large clinical trials in this field to address other important outcomes from different epidemiological settings are recommended.…

Yeka A, Wallender E, Mulebeke R, et al.

AbstractBackgroundIn Uganda, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ) showed excellent treatment efficacy for uncomplicated malaria in prior trials. As resistance to artemisinins and piperaquine is increasing in southeast Asia, and as prevalence of Plasmodium falciparum polymorphisms associated with resistance has changed, we reassessed treatment efficacies at 3 sites in Uganda.MethodsFor this randomized, single blinded clinical trial, children aged 6–59 months with uncomplicated falciparum malaria were assigned treatment with AL or DHA-PQ and followed for 42 days. Primary endpoints were risks of recurrent parasitemia, either unadjusted or adjusted to distinguish recrudescence from new infection. We assessed selection by study regimens of relevant P. falciparum genetic polymorphisms associated with drug resistance.ResultsOf 599 patients enrolled, 578 completed follow-up. There were no early treatment failures. The risk of recurrent parasitemia was lower with DHA-PQ compared to AL at all 3 sites at 42 days (26.0% vs 47.0%, p

Abstract Background Methicillin resistant Staphylococcus aureus (MRSA) is recognized worldwide as a leading cause of hospital and community infections. Biofilm formation by MRSA is an extremely important virulence factor to be understood. Our aim was to establish phenotypic and genotypic characterization of virulence factors among 43 MRSA clinical isolates in a Tunisian hospital. Methods We investigated enzymatic profiles, biofilm production and prevalences of genes encoding intracellular adhesion molecules (icaA and icaD), Microbial Surface Components Recognizing Adhesive Matrix Molecules genes (fnbA, fnbB and cna) and exoenzymes genes (geh, sspA and sspB). Results Our findings revealed that caseinase, gelatinase, lipase and lecithinase activities were detected in 100%, 100%, 76.6% and 93.3% of cases respectively. This study showed that 23 strains (76.7%) were slime producers on Congo red medium. Furthermore, 46.5% and 53.5% of isolates were respectively highly and moderately biofilm-forming on polystyrene. Significant association was found between both biofilm tests. PCR detection showed that 74.4%, 18.6%, 69.8%, 65.1% and 74.4% of isolates harbored fnbA, fnbB, icaA, icaD and cna genes respectively. In addition, 34.9%, 18.6% and 30.2% of MRSA strains were found positive for sspA, sspB and geh genes respectively. Further, statistical data showed that the presence of the fnbA and fnbB genes was significantly associated with a high biofilm production on polystyrene. However, no statistical association was observed for the icaA, icaD and cna genes. Conclusions This study indicates that the detection of fnbA and fnbB contributing to the first step of biofilm formation has been predictable of high biofilm production. As studied factors contribute to MRSA virulence, this research could be of value in orienting towards the development of new preventive and therapeutic measures.…

Rania Abu Seir, Kifaya Azmi, Ayob Hamdan, Hanan Namouz, Fuad Jaar, Hanaa Jaber, Carmit Rubin, Dafna Doron, Galia Rahav, Ziad Abdeen, Gili Regev-Yochay

by Rania Abu Seir, Kifaya Azmi, Ayob Hamdan, Hanan Namouz, Fuad Jaar, Hanaa Jaber, Carmit Rubin, Dafna Doron, Galia Rahav, Ziad Abdeen, Gili Regev-Yochay Background Pneumococcal conjugate vaccines (PCVs), PCV10 and PCV13, are currently used in different countries. We have previously reported the effectiveness of PCV7, following its introduction in Israel and before PCVs were introduced in Palestine. Here, we extended the study and compared the initial impact of PCV10 to that of PCV7/13. Methods Four cross-sectional surveys of S. pneumoniae carriage among children…

Abstract Background Even though malaria is generally on the decline due extensive control and elimination efforts, it still remains a public health problem for over 40% of the world’s population. During the course of malaria infection, parasites and red blood cells come under oxidative stress and there is host immune response in an attempt to protect the red blood cells. The frequency of monocytes and lymphocytes in peripheral blood might, therefore, be expected to reflect the state of an individual’s immune response to the infection. Circulating monocytes and lymphocytes could therefore serve as an index in relation to malaria parasitaemia. The purpose of this study was to determine whether the relative count of monocytes to lymphocytes in peripheral blood (M:L ratio) can predict parasitaemia and, therefore, the severity of malaria infection. Methods Two millilitre of venous blood sample were taken from participants by venisection into anticoagulant tubes. Thick and thin blood films were made and stained with Giemsa and examined for malaria parasites. Whole blood specimen were analysed for full blood count using ABX Pentra 60 C+ automated haematological analyzer. Data was entered into Microsoft Word and analysed using Statistical Package for Social Sciences (SPSS, Version 20.0) and Graphpad prism. Spearman’s correlation was used to determine correlation between occurrences of clinical malaria and the monocytes and lymphocytes ratio. Statistical significance was taken as p ≤ 0.05 with 95% confidence interval. Results The study comprised of 1629 (m = 896; f = 733) children up to 5 years presenting with clinical malaria as cases and 445 (m = 257; f = 188) apparently healthy children as controls. The results indicated that there was a significant positive correlation between the monocytes to lymphocytes ratio and the presence of parasites (p = 0.04) and the level of parasitaemia within the age group of 0–3 years (p = 0.02) and 4–5 years (p = 0.03). Conclusions The monocyte to lymphocyte ratio obtained correlated positively with the presence of malaria as well as the level of parasitaemia. The outcome of this work implies that monocyte to lymphocyte ratio can be used to predict the level of parasitaemia and together with other factors, the development of severe malaria.…

Anita W. M. Suijkerbuijk, Albert Jan van Hoek, Jelle Koopsen, Robert A. de Man, Marie-Josee J. Mangen, Hester E. de Melker, Johan J. Polder, G. Ardine de Wit, Irene K. Veldhuijzen

by Anita W. M. Suijkerbuijk, Albert Jan van Hoek, Jelle Koopsen, Robert A. de Man, Marie-Josee J. Mangen, Hester E. de Melker, Johan J. Polder, G. Ardine de Wit, Irene K. Veldhuijzen Background Chronic infection with hepatitis B or C virus (HBV/HCV) can progress to cirrhosis, liver cancer, and even death. In a low endemic country as the Netherlands, migrants are a key risk group and could benefit from early diagnosis and antiviral treatment. We assessed the cost-effectiveness of screening foreign-born migrants for chronic HBV and/or HCV using a societal perspective. Methods The cost-effectiveness was evaluated using a Markov model. Estimates on prevalence, screening programme costs, participation and treatment uptake, transition probabilities, healthcare costs, productivity losses and utilities were derived from the literature. The cost per Quality Adjusted Life Year (QALY) gained was estimated and sensitivity analyses were performed. Results For most migrant groups with an expected high number of chronically infected cases in the Netherlands combined screening is cost-effective, with incremental cost-effectiveness ratios (ICERs) ranging from €4,962/QALY gained for migrants originating from the Former Soviet Union and Vietnam to €9,375/QALY gained for Polish migrants. HBV and HCV screening proved to be cost-effective for migrants from countries with chronic HBV or HCV prevalence of ≥0.41% and ≥0.22%, with ICERs below the Dutch cost-effectiveness reference value of €20,000/QALY gained. Sensitivity analysis showed that treatment costs influenced the ICER for both infections. Conclusions For most migrant populations in a low-endemic country offering combined HBV and HCV screening is cost-effective. Implementation of targeted HBV and HCV screening programmes to increase early diagnosis and treatment is important to reduce the burden of chronic hepatitis B and C among migrants.…

A. C. Brown et al.

Phillips, Tamsin K; Wilson, Ira B; Brittain, Kirsty; Zerbe, Allison; Mellins, Claude A; Remien, Robert H; Orrell, Catherine; Abrams, Elaine J; Myer, Landon

Introduction: Routine HIV viral load (VL) monitoring is recommended for patients on antiretroviral therapy (ART) but frequent VL testing, required in pregnant and postpartum women, is often not feasible. Self-reported adherence can be valuable, but little is known about its longitudinal characteristics. Methods: We followed women living with HIV from ART initiation in pregnancy through 18 months postpartum in Cape Town, South Africa, with repeated measurement of VL and self-reported adherence using a three-item scale. We used generalized estimating equations (with results presented as odds ratios [OR] with 95% confidence intervals [CI]) to investigate the association between viremia and change in adherence over pairs of consecutive visits. Results: Among 2085 visit pairs from 433 women, a decrease in self-reported adherence relative to the previous visit on any of three self-report items, or the combined scale, was associated with VL >50 and >1000 copies/mL. The best performing thresholds to predict VL >50 copies/mL were a single level decrease on the Likert response item “how good a job did you do at taking your HIV medicines in the way that you were supposed to?” (OR 2.08 95% CI 1.48-2.91), and a decrease equivalent to ≥5 missed doses or a one level decrease in score on either of two Likert items (OR 1.34 95% CI 1.06-1.69). Conclusion: Longitudinal changes in self-reported adherence can help identify patients with viremia. This approach warrants consideration in settings where frequent viral load monitoring or other objective adherence measures are not possible. Corresponding author: Tamsin K Phillips, Level 5 Falmouth Building, School of Public Health & Family Medicine, University of Cape Town, Cape Town, South Africa, Tel: +27 21 650 1646, Email: tk.phillips@uct.ac.za Conflicts of interest and sources of funding: This research was supported by the President’s Emergency Plan for AIDS Relief (PEPFAR) through the National Institute of Child Health and Human Development (NICHD), grant number 1R01HD074558. Additional funding comes from the Elizabeth Glaser Pediatric AIDS Foundation. Dr. Wilson is partially supported by the Providence/Boston Center for AIDS Research (P30AI042853) and by Institutional Development Award Number U54GM115677 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds Advance Clinical and Translational Research (Advance-CTR) from the Rhode Island IDeA-CTR award (U54GM115677). Dr Orrell is partially supported through DAIDS grants (1R01AI122300 – 01, 1R34MH108393-01 and 2UM1AI0695-08). Drs. Mellins and Remien are partially supported by NIMH Center Grant (P30-MH43520). For the remaining authors none were declared. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

G. Anil Kumar, Rakhi Dandona, Bharat B. Rewari, S. G. Prem Kumar, Sukarma Tanwar, Marielle C. Gagnier, Venkata S. Vishnumolakala, Lalit Dandona

by G. Anil Kumar, Rakhi Dandona, Bharat B. Rewari, S. G. Prem Kumar, Sukarma Tanwar, Marielle C. Gagnier, Venkata S. Vishnumolakala, Lalit Dandona Introduction India has scaled-up antiretroviral treatment (ART) in public sector facilities, but data to understand time trends of average cost of ART are limited. Materials and methods Cost and output data were collected at all public sector ART centres in undivided Andhra Pradesh (high-HIV burden state) and Rajasthan (low-HIV burden state) in India from fiscal year 2007–2008 to 2012–2013. Average cost per patient for first-line ART, and its relation with scale of services, were assessed. Using data on scale of services, the average cost was estimated up to 2015–2016. Break-even point was estimated from average and marginal cost functions. Costs were adjusted to 2015 constant price. Results The average cost per patient alive and on ART in 2015–2016 was US$162 in undivided Andhra Pradesh and US$186 in Rajasthan, which was 51.4% and 35.8% lower than in 2007–2008, respectively. Average ART drug cost declined by 27.2% during this period, and was 70.9% and 61.5% of the total ART cost in the two states in 2015–2016. The average cost other than ART drugs declined by 73.1% and 45.7%, with the number of patients served increasing 7 and 14.2 times, respectively. Average cost other than ART drugs had a significant negative relation with scale (R2 = 86.4%-82.8%, p

Kayana Suryadi, Nancy Shine

by Kayana Suryadi, Nancy Shine Bacillus anthracis is a major biological warfare threat. The inhalation form of infection can kill quickly. While antibiotic treatment is effective, if diagnosis is delayed, the rapidly produced toxin may already be present in lethal amounts. This report describes a fast, sensitive, specific and accurate method for detection of active infection by Bacillus anthracis in plasma. One of the virulence factors, anthrax lethal factor, is an endopeptidase present in blood early in the infection. However, the use of peptidic substrates to detect endopetidases is problematic in plasma due to the presence of other proteases and the likelihood of nonspecific cleavage of the substrate. The fluorescently labeled peptide substrate MAPKKide Plus designed in this study is not cleaved by plasma proteases and thus is specific for lethal factor. Three detection strategies are described. Two include enrichment by capture from plasma using lethal factor antibody-coated microtiter plates or similarly coated immuno-tubes. The captured lethal factor is exposed to the MAPKKide Plus, and the amount of cleavage is determined either by HPLC or microplate reader. Concentration of lethal factor using the antibody-coated plates aplnd HPLC allows for detection of less than 5 pg lethal factor/ml of neat plasma after 2 hours of incubation. Using antibody-coated immuno-tubes, 20 pg lethal factor/ml plasma can be detected in 5 hours by a simple end point read of fluorescence in a microplate reader. For a third strategy, the substrate is added directly to diluted plasma, and cleavage is monitored by the increase in fluorescence as a function of time. The limit of detection by this simple method is 25 ng lethal factor/ml of plasma in 15 minutes, 5 ng/ml after 45 minutes, and…

Chojnacki, M., Philbrick, A., Wucher, B., Reed, J. N., Tomaras, A., Dunman, P. M., Wozniak, R. A. F.

Staphylococcus aureus and Pseudomonas aeruginosa are two of the most common causes of bacterial keratitis and corresponding corneal blindness. Accordingly, such infections are predominantly treated with broad spectrum fourth generation fluoroquinolones, such as moxifloxacin. Yet rising fluoroquinolone resistance has necessitated the development of alternative therapeutic options. Herein we describe development of a polymyxin B/trimethoprim (PT) ophthalmic formulation containing the antibiotic rifampicin, which exhibits synergistic antimicrobial activity toward a panel of contemporary ocular clinical S. aureus and P. aeruginosa isolates, low spontaneous resistance frequency, and displays in vitro bactericidal kinetics and antibiofilm activities equaling or exceeding the antimicrobial properties of moxifloxacin. The PT + rifampicin combination also demonstrated increased efficacy in comparison to either commercial PT or moxifloxacin in a murine keratitis model of infection, resulting in bacterial clearance of 70% in animals treated. These results suggest that the combination PT and rifampicin may represent a novel antimicrobial agent in the treatment of bacterial keratitis.…

Abbasi J.

Patients with heart failure may develop secondary mitral regurgitation, in which a dysfunctional heart valve allows blood to leak back into the organ’s left atrium and the lungs, further worsening the condition. Some patients remain symptomatic despite receiving maximal heart failure therapies.

Bertrand, Pierre-Marie; Pereira, Bruno; Adda, Mireille; Timsit, Jean-François; Wolff, Michel; Hilbert, Gilles; Gruson, Didier; Garrouste-Orgeas, Maïté; Argaud, Laurent; Constantin, Jean-Michel; Chabanne, Russel; Quenot, Jean-Pierre; Bohe, Julien; Guerin, Claude; Papazian, Laurent; Jonquet, Olivier; Klouche, Kada; Delahaye, Arnaud; Riu, Beatrice; Zieleskiewicz, Laurent; Darmon, Michaël; Azoulay, Elie; Souweine, Bertrand; Lautrette, Alexandre

Objectives: To compare the assessment of decision-making capacity of ICU patients by attending clinicians (physicians, nurses, and residents) with a capacity score measured by the Mini-Mental Status Examination, completed by Aid to Capacity Evaluation if necessary. The primary outcome was agreement between physicians’ assessments and the score. Secondary outcomes were agreement between nurses’ or residents’ assessments and the score and identification of factors associated with disagreement. Design: A 1-day prevalence study. Setting: Nineteen ICUs in France. Subjects: All patients hospitalized in the ICU on the study day and the attending clinicians. Interventions: The decision-making capacity of patients was assessed by the attending clinicians and independently by an observer using the score. Measurements and Main Results: A total of 206 patients were assessed by 213 attending clinicians (57 physicians, 97 nurses, and 59 residents). Physicians designated more patients as having decision-making capacity (n = 92/206 [45%]) than score (n = 34/206 [17%]; absolute difference 28% [95% CI, 20–37%]; p = 0.001). There was a high disagreement between assessments of all clinicians and score (Kappa coefficient 0.39 [95% CI, 0.29–0.50] for physicians; 0.39 [95% CI, 0.27–0.52] for nurses; and 0.46 [95% CI, 0.35–0.58] for residents). The main factor associated with disagreement was a Glasgow Coma Scale score between 10 and 15 (odds ratio, 2.92 [1.18–7.19], p = 0.02 for physicians; 4.97 [1.50–16.45], p = 0.01 for nurses; and 3.39 [1.12–10.29], p = 0.03 for residents) without differentiating between the Glasgow Coma Scale scores from 10 to 15. Conclusions: The decision-making capacity of ICU patients was largely overestimated by all attending clinicians as compared with a score. The main factor associated with disagreement was a Glasgow Coma Scale score between 10 and 15, suggesting that clinicians confused consciousness with decision-making capacity. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal). Supported, in part, by the Gabriel Montpied Teaching Hospital. Dr. Wolff’s institution received funding from Pfizer. Dr. Azoulay’s institution received funding from Fisher & Paykel, Pfizer, Alexion, Gilead, and Jazz Pharma, and he received funding from lecturing for Baxter, Gilead, Astellas, and Alexion. Dr. Lautrette received support for article research from Gabriel Montpied Teaching Hospital (France). The remaining authors have disclosed that they do not have any potential conflicts of interest. For information regarding this article, E-mail: alautrette@chu-clermontferrand.fr Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

Tamara Girbl, Tchern Lenn, Lorena Perez, Loïc Rolas, Anna Barkaway, Aude Thiriot, Carlos del Fresno, Eleanor Lynam, Elin Hub, Marcus Thelen, Gerard Graham, Ronen Alon, David Sancho, Ulrich H. von Andrian, Mathieu-Benoit Voisin, Antal Rot, Sussan Nourshargh

Girbl et al. find that sequential interactions with the chemokines CXCL1 and CXCL2 guide neutrophil crawling and subsequent migration through venular walls during inflammation. Transmigrating neutrophils promoted unidirectional luminal-to-abluminal migration by depositing CXCL2 on the chemokine receptor ACKR1 at endothelial junctions, providing a paradigm of self-guided migration.

Biesecker LG, Nussbaum RL, Rehm HL.

This Genomics and Precision Health article explains the use of genomic testing in clinical settings when a genetic basis for disease is suspected, but the evaluation has not provided enough specificity to guide selection of a single gene test or a gene panel test.