Abstract Background In spite of an alarmingly high tuberculosis (TB) burden amongst the Saharia tribe of central India, there is hardly any study to investigate the impact of DOTS implementation on the magnitude of tuberculosis disease and the changes over time. This article present the findings of TB prevalence surveys conducted amongst this indigenous population in two different time periods to know the change in the prevalence of TB. Methods A cross sectional survey was conducted among Saharia population in Shivpuri district, Madhya Pradesh during February 2013 to May 2013 and resurvey during March 2015 to July 2015. All individuals (≥15 years) were examined for chest symptoms suggestive of TB. Sputum samples were collected from all presumptive TB cases and were confirmed by laboratory examination by Ziehl-Neelsen smear microscopy and solid media culture methods. All detected cases were referred to health facility for anti-tuberculosis treatment as per RNTCP guidelines. Results There was significant reduction (trend Chi square 19.97; OR = 1.521; p = 0.000) in the prevalence of TB at the endline (1995 per 100,000) as compared to baseline (3003 per 100,000). The reduction was significant among males as compared to females (OR 1.55; p = 0.000) and in the age group of 25–34 years (OR 2.0; p = 0.007) and 45–54 years (OR 4.39; p = 0.003). There was significant reduction in the prevalence in both smear (OR 1.29; p = 0.02) and culture positive (OR 1.57; p = 0.000) TB at the endline survey. Conclusion The study findings highlight a reduction in the prevalence of TB among Saharia tribal population. Further studies are needed to identify the factors associated with reduction in prevalence among this population and also further surveys to monitor the prevalence trend over a period.…

Salima Gasmi, Nicholas H. Ogden, Marion Ripoche, Patrick A. Leighton, Robbin L. Lindsay, Mark P. Nelder, Erin Rees, Catherine Bouchard, Linda Vrbova, Richard Rusk, Curtis Russell, Yann Pelcat, Samir Mechai, Serge-Olivier Kotchi, Jules K. Koffi

by Salima Gasmi, Nicholas H. Ogden, Marion Ripoche, Patrick A. Leighton, Robbin L. Lindsay, Mark P. Nelder, Erin Rees, Catherine Bouchard, Linda Vrbova, Richard Rusk, Curtis Russell, Yann Pelcat, Samir Mechai, Serge-Olivier Kotchi, Jules K. Koffi Lyme disease, the most commonly reported vector-borne disease in North America, is caused by the spirochete Borrelia burgdorferi sensu stricto, which is transmitted by Ixodes scapularis in eastern Canada and Ixodes pacificus in western Canada. Recently, the northward range expansion of I. scapularis ticks, in south-eastern Canada, has resulted in a dramatic increase in the incidence of human Lyme disease. Detecting emerging areas of Lyme disease risk allows public health to target disease prevention efforts. We analysed passive tick surveillance data from Ontario and Manitoba to i) assess the relationship between the total numbers of I. scapularis submissions in passive surveillance from humans, and the number of human Lyme disease cases, and ii) develop province-specific acarological indicators of risk that can be used to generate surveillance-based risk maps. We also assessed associations between numbers of nymphal I. scapularis tick submissions only and Lyme disease case incidence. Using General Estimating Equation regression, the relationship between I. scapularis submissions (total numbers and numbers of nymphs only) in each census sub-division (CSD) and the number of reported Lyme disease cases was positively correlated and highly significant in the two provinces (P ≤ 0.001). The numbers of I. scapularis submissions over five years discriminated CSDs with ≥ 3 Lyme disease cases from those with < 3 cases with high accuracy when using total numbers of tick submission (Receiver Operating Characteristics area under the curve [AUC] = 0.89) and moderate accuracy (AUC = 0.78) when using nymphal tick submissions only. In Ontario the optimal cut-off point was a total 12 tick submissions from a CSD over five years (Sensitivity = 0.82, Specificity = 0.84), while in Manitoba the cut-off point was five ticks (Sensitivity = 0.71, Specificity = 0.79) suggesting regional variability of the risk of acquiring Lyme disease from an I. scapularis bite. The performances of the acarological indicators developed in this study for Ontario and Manitoba support the ability of passive tick surveillance to provide an early signal of the existence Lyme disease risk areas in regions where ticks and the pathogens they transmit are expanding their range.

Abstract Background A novel method, termed loop-mediated isothermal amplification (LAMP), was developed by Notomi et al. (2000). Individually published results have been reported that this technology has been successfully applied to the detection of a variety of pathogens. However, the overall diagnostic accuracy of LAMP for Mycoplasma pneumoniae (MP) remains unclear. A meta-analysis was therefore performed to review the accuracy of LAMP for Mycoplasma pneumoniae. Methods Cochrane Library and PubMed were systematically searched and checked for studies using LAMP for detecting mycoplasma pneumoniae. We used PCR as a reference standard to evaluate the quality of the studies eligible for inclusion in the meta-analysis. Then, the data from the studies were extracted by two independent assessors. Meta-DiSc 1.4 software was utilized to test the heterogeneity of sensitivity (SEN), specificity (SP), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnosis odds ratio (DOR). The pooled analysis results were plotted, and the summary receiver operating characteristic (SROC) curve was plotted by calculating the area under the curve (AUC). Generated pooled summary estimates (95% CIs) were calculated for the overall accuracy, and a bivariate meta-regression model was used for the meta-analysis. Results Seven studies with nine fourfold tables were included in this meta-analysis. The pooled SEN and SPE for diagnosing Mycoplasma pneumoniae were 0.90 (95% CI: 0.87–0.93) and 0.98 (95% CI: 0.96–0.99), respectively. The PLR was 31.25 (95% CI: 14.83–65.87), NLR 0.10 (95% CI: 0.05–0.22), DOR 399.32 (95% CI: 172.01–927.00), and AUC 0.9892. Conclusions In conclusion, compared with PCR, LAMP is a valuable alternative method for Mycoplasma pneumoniae diagnosis in clinic with high sensitivity and specificity. However, more evidence is required to confirm that LAMP can fully replace other methods in the clinical diagnosis of MP.…

Wentao Wang, Xueqi Zhao, Guiping Li, Lin Wang, Yizhi Chen, Ma Ke, Guang Chen, Tao Chen, Han Meifang, Qin Ning, Xiping Zhao

Abstract Aim We aimed at investigating the effects of age on the predictive performances of non‐invasive fibrosis scores for significant fibrosis in patients with chronic hepatitis B (CHB). Methods A total of 496 CHB patients who underwent liver biopsy were stratified into four age groups: ≤30, 31‐40, 41‐50 and ≥51 years. Receiver operating characteristic curves were used to evaluate the diagnostic performance of aspartate aminotransferase to platelet ratio index (APRI), fibrosis score‐4 (Fib‐4) and gamma‐glutamyl transpeptidase to platelet ratio (GPR) in different age groups. Results The extent of fibrosis significantly increased with age, and the percentage of significant fibrosis (≥F2) was 21.3%, 29.0%, 38.5% and 46.1%, respectively. All three scores displayed the moderate accuracy to diagnose significant fibrosis in overall patients. However, for patients with age≤30 years, APRI, Fib‐4 and GPR performed poorly with the AUROC of 0.567, 0.627 and 0.596, respectively. Furthermore, using the established cut‐off values—1.45 for Fib‐4, the sensitivity for significant fibrosis increased with age, from 14.8%, 38.1%, 74.5% to 97.87% in above age groups, respectively. To improve the diagnostic accuracy for significant fibrosis, the proposed low and high cut‐off points for Fib‐4 were 0.41 and 1.15 in ≤30 years, 0.8 and 1.59 in 31‐40 years, 1.17 and 1.94 in 41‐50 years, 1.76 and 3.10 in ≥51 years, respectively. Conclusions Age may influence the diagnostic thresholds and performance of APRI, Fib‐4 and GPR for significant fibrosis in CHB patients. In particular, these scores performed poorly for identifying significant fibrosis in younger patients (≤30 years). This article is protected by copyright. All rights reserved.

Louis, P., Mercer, B., Cirone, A. M., Johnston, C., Lee, Z. J., Esiobu, N., Li, Z., Wei, J., Dorey, C. K., Shibata, Y., Nan, C.

Chitin is a natural N-acetyl glucosamine polymer and a major structural component of fungal cell walls. Dietary chitin is mucoadhesive; anti-inflammatory effects of chitin microparticles (CMPs, 1 – 10 μm diameters) have been demonstrated in models of inflammatory bowel disease (IBD). The goals in this study were to assess (i) whether CMPs among various chitin preparations are the most effective against colitis in male and female mice, and (ii) whether host chitin-binding TLR2 and CD14 are required for the anti-inflammatory effect of chitin. We found that colitis in male mice was ameliorated by CMPs and large chitin beads (LCB, 40 – 70 μm), but not by chitosan (de-acetylated chitin) microparticles, oligosaccharide chitin or glucosamine. In fact, LCBs were more effective than CMPs. In female colitis, on the other hand, CMPs and LCBs were equally and highly effective. Next, neither sex of TLR2-deficient mice showed anti-inflammatory effects when treated with LCBs. No anti-inflammatory effect of LCBs was seen in either CD14-deficient males or females. Furthermore, an in vitro study indicated that when LCBs and CMPs were digested with stomach acidic mammalian chitinase (AMC), their size-dependent macrophage activations were modified, at least in part, suggesting reduced particle sizes of dietary chitin in the stomach. Interestingly, stomach AMC activity was greater in males than females. Our results indicated that dietary LCBs were the most effective preparation for treating colitis in both sexes; these anti-inflammatory effects of LCBs were dependent on host TLR2 and CD14.…

Lin, J.-N., Lai, C.-H., Yang, C.-H., Huang, Y.-H.

Chryseobacterium infections are uncommon, and previous studies have revealed that C. gleum is frequently misidentified as C. indologenes. We aimed to explore the differences in clinical manifestations and antimicrobial susceptibility patterns between C. gleum and C. indologenes. The database of a clinical microbiology laboratory was searched to identify patients with Chryseobacterium infections between 2005 and 2017. Species were reidentified using 16S rRNA gene sequencing, and patients with C. gleum and C. indologenes infections were included in the study. A total of 42 C. gleum and 84 C. indologenes isolates were collected from consecutive patients. A significant increase in C. indologenes incidence was observed. C. gleum was significantly more associated with bacteremia than was C. indologenes. Patients with C. gleum infections had more comorbidities of malignancy and liver cirrhosis than did those with C. indologenes infections. The overall case fatality rate was 19.8%. Independent risk factors for mortality were female sex and C. indologenes infection. These isolates were most susceptible to minocycline (73%), followed by trimethoprim-sulfamethoxazole (47.6%), tigecycline (34.1%), and levofloxacin (32.5%). Compared with C. indologenes, C. gleum exhibited a significantly higher rate of susceptibility to piperacillin, piperacillin-tazobactam, ceftazidime, tigecycline, and levofloxacin. Alterations in DNA gyrase subunit A were identified to be associated with fluoroquinolone resistance in C. indologenes. No non-synonymous substitutions were observed in the QRDRs of C. gleum. Differences in epidemiology, clinical manifestations, and antimicrobial susceptibility patterns exist between C. gleum and C. indologenes. Additional investigations are needed to explore the significance of these differences.…

Khalilieh, S. G., Yee, K. L., Sanchez, R. I., Fan, L., Anderson, M. S., Sura, M., Laethem, T., Rasmussen, S., van Bortel, L., van Lancker, G., Iwamoto, M.

Identifying and understanding potential drug–drug interactions (DDIs) is vital for treatment of human immunodeficiency virus type 1 (HIV-1) infection. This article discusses DDIs between doravirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI) and cytochrome P450 3A (CYP3A) substrates, and drugs that modulate CYP3A activity. Consistent with previously published in vitro data and DDI trials with CYP3A substrates, midazolam and atorvastatin, doravirine did not have any meaningful impact on the pharmacokinetics of the CYP3A substrates ethinyl estradiol and levonorgestrel. Co-administration of doravirine with CYP3A inhibitors (ritonavir or ketoconazole) increased doravirine exposure approximately 3-fold. However, these increases were not considered clinically meaningful. Conversely, previously published trials showed that co-administered CYP3A inducers (rifampin and rifabutin) decreased doravirine exposure by 88% and 50%, respectively (Yee et al, Clin Drug Investig 2017; 37: 659-667; Khalilieh et al, J Clin Pharmacol 2018; 58: 1044-1052), while doravirine exposure following prior efavirenz administration led to an initial reduction in doravirine exposure of 62%, but became less pronounced with time (Yee et al, Antimicrob Agents Chemother 2017; 61: e01757-16). Overall, the co-administration of doravirine with CYP3A inhibitors and substrates is, therefore, supported by these data together with efficacy and safety data from clinical trials, while co-administration with strong CYP3A inducers, such as rifampin, cannot be recommended. Concomitant dosing with rifabutin (a less potent CYP3A inducer than rifampin) is acceptable if doravirine dosing is adjusted from once to twice daily; however, the effect of other moderate inducers on doravirine pharmacokinetics is unknown.…

Wade DM, Mouncey PR, Richards-Belle A, et al.

This cluster-randomized clinical trial compares the effect of a nurse-led intervention intended to alleviate acute stress and memories of frightening intensive care unit (ICU) experiences vs usual care on patient-reported posttraumatic stress disorder (PTSD) symptom severity 6 months after ICU discharge.

Subramaniam B, Shankar P, Shaefi S, et al.

This randomized clinical trial compares the effects of postoperative intravenous acetaminophen vs placebo, combined with intravenous propofol vs dexmedetomidine, on postoperative in-hospital delirium among older patients undergoing cardiac surgery.

Hernández G, Ospina-Tascón GA, Damiani L, et al.

This randomized trial compares the effects of resuscitation strategies targeting normalization of capillary refill time vs normalization or decrease of serum lactate levels on 28-day mortality among patients with septic shock.

Mahima Venkateswaran, Binyam Bogale, Khadija Abu Khader, Tamara Awwad, Ingrid K. Friberg, Buthaina Ghanem, Taghreed Hijaz, Kjersti Mørkrid, J. Frederik Frøen

by Mahima Venkateswaran, Binyam Bogale, Khadija Abu Khader, Tamara Awwad, Ingrid K. Friberg, Buthaina Ghanem, Taghreed Hijaz, Kjersti Mørkrid, J. Frederik Frøen Background The proportion of women attending four or more antenatal care (ANC) visits is widely used for monitoring, but provides limited information on quality of care. Effective coverage metrics, assessing if ANC interventions are completely delivered, can identify critical gaps in healthcare service delivery. We aimed to measure coverage of at least one screening and effective coverage of ANC interventions in the public health system in the West Bank, Palestine, and to explore associations between infrastructure-related and maternal sociodemographic variables and effective coverage. Methods We used data from paper-based clinical records of 1369 pregnant women attending ANC in 17 primary healthcare clinics. Infrastructure-related variables were derived from a 2014 national inventory assessment of clinics. Sample size calculations were made to detect effective coverage ranging 40–60% with a 2–3% margin of error, clinics were selected by probability sampling. We calculated inverse probability weighted percentages of: effective coverage of appropriate number and timing of screenings of ANC interventions; and coverage of at least one screening. Results Coverage of one screening and effective coverage of ANC interventions were notably different for screening for: hypertension (98% vs. 10%); fetal growth abnormalities (66% vs. 6%); anemia (93% vs. 14%); gestational diabetes (93% vs. 34%), and antenatal ultrasound (74% vs. 24%). Clinics with a laboratory and ultrasound generally performed better in terms of effective coverage, and maternal sociodemographic factors had no associations with effective coverage estimates. Only 13% of the women attended ANC visits according to the recommended national schedule, driving effective coverage down. Conclusion Indicators for ANC monitoring and their definitions can have important consequences for quantifying health system performance and identifying issues with care provision. To achieve more effective coverage in public primary care clinics in the West Bank, efforts should be made to improve care provision according to prescribed guidelines.…

Verreault, D., Ennis, J., Whaley, K., Killeen, S. Z., Karauzum, H., Aman, M. M. J., Holtsberg, R., Doyle-Meyers, L., Didier, P. J., Zeitlin, L., Roy, C. J.

Staphylococcal enterotoxin B (SEB) is a protein exotoxin found on the cell surface of Staphylococcus aureus that is the source for multiple pathologies in man. When purified and concentrated in aerosol form, SEB can cause an acute and often fatal intoxication, and thus is considered a biological threat agent. There are currently no vaccines or treatments approved for human use. Studies in rodent models of SEB intoxication show that antibody therapy may be a promising treatment strategy, however many have used antibodies only prophylactically or well before any clinical signs of intoxication are apparent. We assessed and compared the protective efficacy of two monoclonal antibodies, Ig121 and c19F1, when administered after aerosol exposure in a uniformly lethal nonhuman primate model of SEB intoxication. Rhesus macaques were challenged using small particle aerosols of SEB, and then were infused intravenously with a single dose of either Ig121 or c19F1 (10 mg/kg) at either 0.5, 2 or 4 hours postexposure. Onset of clinical signs, hematological, and cytokine response in untreated controls confirmed the acute onset and potency of the toxin used in the challenge. All animals administered either Ig121 or c19F1 survived SEB challenge, whereas the untreated controls succumbed to SEB intoxication 30-48 hours postexposure. These results represent the successful therapeutic in vivo protection by two investigational drugs against SEB in a severe nonhuman primate disease model and punctuate the therapeutic value of monoclonal antibodies hold when faced with treatment options for SEB-induced toxicity in a postexposure setting.…

Abstract Background As surveillance is a key strategy for malaria elimination in South Africa, ensuring strong surveillance systems is a National Department of Health priority. Historically, real time tracking of case trends and reporting within 24 h—a requirement in South Africa’s National surveillance guidelines—has not been possible. To enhance surveillance and response efficiency, a mobile surveillance tool, MalariaConnect, was developed using Unstructured Supplementary Service Data (USSD) technology. It was rolled out in health facilities in malaria endemic areas of South Africa to provide 24-h reporting of malaria cases. Methods To evaluate the efficiency of the mobile tool to detect an outbreak data were extracted from the paper based and MalariaConnect reporting systems in Bushbuckridge from 1 January to 18 June 2017. These data were subject to time series analyses to determine if MalariaConnect provided sufficient data reliably to detect increasing case trends reported through the paper system. The Chi squared test was used to determine goodness of fit between the following indicator data generated using MalariaConnect and paper reporting systems: timeliness, completeness, and precision. Results MalariaConnect adequately tracked case trends reported through the paper system. Timeliness of reporting increased significantly using MalariaConnect with 0.63 days to notification compared to 5.65 days using the paper-system (p 

James Samwel Ngocho, Best Magoma, Gaudencia Alois Olomi, Michael Johnson Mahande, Sia Emmanueli Msuya, Marien Isaäk de Jonge, Blandina Theophil Mmbaga

by James Samwel Ngocho, Best Magoma, Gaudencia Alois Olomi, Michael Johnson Mahande, Sia Emmanueli Msuya, Marien Isaäk de Jonge, Blandina Theophil Mmbaga Background Despite the widespread implementation of the pneumococcal conjugate vaccine, Streptococcus pneumoniae remains the leading cause of severe pneumonia associated with mortality among children less than 5 years of age worldwide, with the highest mortality rates recorded in Africa and Asia. However, information on the effectiveness and prevalence of vaccine serotypes post-roll out remains scarce in most African countries. Hence, this systematic review aimed to describe what is known about the decline of childhood invasive pneumococcal disease post-introduction of the pneumococcal conjugate vaccine in Africa. Methods This systematic review included articles published between 2009 and 2018 on the implementation of the pneumococcal conjugate vaccine in Africa. We searched PubMed, Scopus and African Index Medicus for articles in English. Studies on implementation programmes of pneumococcal conjugate vaccine 10/13, with before and after data from different African countries, were considered eligible. The review followed the procedures published in PROSPERO (ID = CRD42016049192). Results In total, 2,280 studies were identified through electronic database research, and only 8 studies were eligible for inclusion in the final analysis. Approximately half (n = 3) of these studies were from South Africa. The overall decline in invasive pneumococcal disease ranged from 31.7 to 80.1%. Invasive pneumococcal diseases caused by vaccine serotypes declined significantly, the decline ranged from 35.0 to 92.0%. A much higher decline (55.0–89.0%) was found in children below 24 months of age. Of all vaccine serotypes, the relative proportions of serotypes 1, 5 and 19A doubled following vaccine roll out. Interpretation Following the introduction of the pneumococcal conjugate vaccine, a significant decline was observed in invasive pneumococcal disease caused by vaccine serotypes. However, data on the effectiveness in this region remain scarce, meriting continued surveillance to assess the effectiveness of pneumococcal vaccination to improve protection against invasive pneumococcal disease.…

Abstract Background Indoor residual spraying (IRS) with Actellic 300 CS was conducted in Lira District between July and August 2016. No formal assessment has been conducted to estimate the effect of spraying with Actellic 300 CS on malaria morbidity in the Ugandan settings. This study assessed malaria morbidity trends before and after IRS with Actellic 300 CS in Lira District in Northern Uganda. Methods The study employed a mixed methods design. Malaria morbidity records from four health facilities were reviewed, focusing on 6 months before and after the IRS intervention. The outcome of interest was malaria morbidity defined as; proportion of outpatient attendance due to total malaria, proportion of outpatient attendance due to confirmed malaria and proportion of malaria case numbers confirmed by microscopy or rapid diagnostic test. Since malaria morbidity was based on count data, an ordinary Poisson regression model was used to obtain percentage point change (pp) in monthly malaria cases before and after IRS. A household survey was also conducted in 159 households to determine IRS coverage and factors associated with spraying. A modified Poisson regression model was fitted to determine factors associated with household spray status. Results The proportion of outpatient attendance due to malaria dropped from 18.7% before spraying to 15.1% after IRS. The proportion of outpatient attendance due to confirmed malaria also dropped from 5.1% before spraying to 4.0% after the IRS intervention. There was a decreasing trend in malaria test positivity rate (TPR) for every unit increase in month after spraying. The decreasing trend in TPR was more prominent 5–6 months after the IRS intervention (Adj. pp = − 0.60, P-value = 0.015; Adj. pp = − 1.19, P-value 

Abstract Background The levels of insecticide-treated net use among pregnant women and uptake of intermittent preventive treatment in pregnancy, have been sub-optimal in Nigeria. Previous studies have reported positive correlations between knowledge, attitude and practice of malaria preventive measures. It has also been reported that information and motivation, act through a mediator (behavioural skills), to cause a health behaviour change. The aim of this study was as such to develop, implement, and assess the effects of a health educational intervention based on the information–motivation–behavioural skills (IMB) model on the levels of knowledge, motivation, and behavioural skills for ITN use and IPTp uptake among pregnant women in a hospital in north-eastern Nigeria. Methods This was a randomized controlled parallel-group trial in which 372 antenatal care attendees were randomly assigned to either an intervention or control group after collecting baseline data using a structured questionnaire. The intervention group received a 4-h health education on malaria, guided by a module developed based on the IMB theory, while the control group received health education on breastfeeding for a similar duration and by the same facilitator. Follow-up data were subsequently collected at 2 months and at 4 months post-intervention using the same questionnaire. The generalized linear mixed models analysis was used to determine the between-group and within-group effects of the intervention. The intention-to-treat analysis was used after missing data had been replaced. This was followed by a sensitivity analysis, where the analyses were repeated without replacing the missing values. Results The intervention was significant in achieving a 12.75% (p 

Valeria Savasi, Francesca Parisi, Monica Oneta, Arianna Laoreti, Bina Parrilla, Piergiorgio Duca, Irene Cetin

by Valeria Savasi, Francesca Parisi, Monica Oneta, Arianna Laoreti, Bina Parrilla, Piergiorgio Duca, Irene Cetin Background HIV-1 infected patients show impaired semen parameters. Currently, it is not clear whether HIV-1 infection itself or antiretroviral therapy have an effect on semen parameters. We aim evaluate semen quality in a large cohort of fertile HIV-1 infected men under stable highly active antiretroviral therapy (HAART) and to assess the effect of HAART type and duration on semen parameters. Materials and methods Between January 2010 and June 2014, we enrolled in a retrospective case-control study 770 HIV-1 patients under stable HAART asking a reproductive counselling with their HIV negative partner. Co-infections with HBV or HCV, genital tract infections and known causes of infertility represented exclusion criteria. Semen samples were analysed and compared with the WHO reference values. A multivariate analysis including HAART type and duration, age, viral load and CD4 count, was performed on 600 patients out of 770. Results The median values of all semen parameters were significantly lower among HIV-1 infected patients compared to the WHO reference group, with a significant proportion of patients having values below the 5th percentile of the WHO reference value. In a multivariate analysis, only age and viral load negatively impacted progressive motility (β -0.3 (95% CI: -0.5; -0.0) %, p

Abstract Background The direct effectiveness of infant rotavirus vaccination implemented in 2006 in the United States has been evaluated extensively, however, understanding of population-level vaccine effectiveness (VE) is still incomplete. Methods We analyzed time series data on rotavirus gastroenteritis (RVGE) and all-cause acute gastroenteritis (AGE) hospitalization rates in the United States from the MarketScan® Research Databases for July 2001–June 2016. Individuals were grouped into ages 0–4, 5–9, 10–14, 15–24, 25–44, and 45–64 years. Negative binomial regression models were fitted to monthly RVGE and AGE data to estimate the direct, indirect, overall, and total VE. Results A total of 9211 RVGE and 726,528 AGE hospitalizations were analyzed. Children 0–4 years of age had the largest declines in RVGE hospitalizations with direct VE of 87% (95% CI: 83, 90%). Substantial indirect effects were observed across age groups and generally declined in each older group. Overall VE against RVGE hospitalizations for all ages combined was 69% (95% CI: 62, 76%). Total VE was highest among young children; a vaccinated child in the post-vaccine era has a 95% reduced risk of RVGE hospitalization compared to a child in the pre-vaccine era. We observed higher direct VE in odd post-vaccine years and an opposite pattern for indirect VE. Conclusions Vaccine benefits extended to unvaccinated individuals in all age groups, suggesting infants are important drivers of disease transmission across the population. Imperfect disease classification and changing disease incidence may lead to bias in observed direct VE. Trial registration Not applicable.…

Milanes, J. E., Suryadi, J., Abendroth, J., Van Voorhis, W. C., Barrett, K. F., Dranow, D. M., Phan, I. Q., Patrick, S. L., Rozema, S. D., Khalifa, M. M., Golden, J. E., Morris, J. C.

Infection with the free-living amoeba Naegleria fowleri leads to life-threatening primary amoebic meningoencephalitis. Efficacious treatment options for these infections are limited and the mortality rate is very high (~98%). Parasite metabolism may provide suitable targets for therapeutic design. Like most other organisms, glucose metabolism is critical for parasite viability, being required for growth in culture. The first enzyme required for glucose metabolism is typically a hexokinase (HK), which transfers a phosphate from ATP to glucose. The products of this enzyme are required for both glycolysis and the pentose phosphate pathway. However, the N. fowleri genome lacks an obvious HK homolog and instead harbors a glucokinase (Glck). The N. fowleri Glck (NfGlck) shares limited (25%) amino acid identity with the mammalian host enzyme (HsGlck), suggesting that parasite-specific inhibitors with anti-amoeba activity could be generated. Following heterologous expression, NfGlck was found to have a limited hexose substrate range, with greatest activity observed with glucose. The enzyme had apparent Km values of 42.5 ± 7.3 μM and 141.6 ± 9.9 μM for glucose and ATP, respectively. The NfGlck structure was determined and refined to 2.2 Å resolution, revealing that the enzyme shares greatest structural similarity with the Trypanosoma cruzi Glck. These similarities include binding modes and binding environments for substrates. To identify inhibitors of NfGlck, we screened a small collection of inhibitors of glucose phosphorylating enzymes and identified several small molecules with IC50 values < 1 μM that may prove useful as hit chemotypes for further lead and therapeutic development against N. fowleri.…

Yong-chao Qiao, Yan Xu, Dong-xiang Jiang, Xiao Wang, Feng Wang, Jun Yang, Ye-sheng Wei

Reiko Shimbashi, Bin Chang, Yoshinari Tanabe, Hiroaki Takeda, Hiroshi Watanabe, Tetsuya Kubota, Kei Kasahara, Kengo Oshima, Junichiro Nishi, Takaya Maruyama, Koji Kuronuma, Jiro Fujita, Tatsuki Ikuse, Yuki Kinjo, Motoi Suzuki, Anusak Kerdsin, Tomoe Shimada, Munehisa Fukusumi, Keiko Tanaka-Taya, Tamano Matsui, Tomimasa Sunagawa, Makoto Ohnishi, Kazunori Oishi, and the Adult IPD Study Group

by Reiko Shimbashi, Bin Chang, Yoshinari Tanabe, Hiroaki Takeda, Hiroshi Watanabe, Tetsuya Kubota, Kei Kasahara, Kengo Oshima, Junichiro Nishi, Takaya Maruyama, Koji Kuronuma, Jiro Fujita, Tatsuki Ikuse, Yuki Kinjo, Motoi Suzuki, Anusak Kerdsin, Tomoe Shimada, Munehisa Fukusumi, Keiko Tanaka-Taya, Tamano Matsui, Tomimasa Sunagawa, Makoto Ohnishi, Kazunori Oishi, and the Adult IPD Study Group Enhanced surveillance of invasive pneumococcal disease (IPD) in adults was conducted during April 2013–March 2018 in 10 of 47 prefectures in Japan, and a total of 1277 IPD patients were enrolled. An emergence of IPD caused by serotype 12F was identified during May 2015–March 2018 through this surveillance. 12F isolates were composed of four related sequence types. In total, 120 patients with 12F IPD were reported during this period. To characterize the clinical features of 12F IPD, the disease characteristics of these patients were compared with those of 1157 patients with non-12F IPD. Compared with the non-12F IPD patients, a significantly lower proportion of 12F IPD patients was aged 65 years or older (55% vs. 70%), vaccinated with 23-valent pneumococcal polysaccharide (4% vs. 14%), had comorbid illness (65% vs. 77%), or were immunocompromised (19% vs. 30%; all P < 0.05). No significant difference in the proportion of case fatalities was found between the two groups. The proportions of those aged 65 years or older (53% vs. 69%) and with bacteremic pneumonia (35% vs. 69%) were significantly lower in 17 patients who died from 12F IPD than in 205 patients who died from non-12F IPD (all P < 0.05). Differences in clinical features were similarly found between 12F IPD patients and patients in low- or intermediate-level invasive potential serogroups. Our data demonstrated that serotype 12F was associated with IPD in younger adults and a lower proportion of comorbid illness, including immunocompromised conditions, in adult IPD, suggesting the high invasive potential of the serotype 12F. In addition, patients who died from 12F IPD were younger and had proportionately more bacteremia without focus. These findings may provide new insight into the pathogenesis of IPD in adults caused by 12F serotype with a high invasive potential.

The Research Letter titled “Trends in First Gabapentin and Pregabalin Prescriptions in Primary Care in the United Kingdom, 1993-2017,” published in the November 27, 2018, issue includes errors in the Introduction. This included indicating that gabapentin is approved for epilepsy, neuropathic pain, and migraines and that pregabalin is approved for generalized anxiety disorder. It was also indicated that in 2017, the UK government reclassified gabapentinoids as class C controlled substances. The Introduction has been corrected and now indicates that pregabalin is approved for epilepsy, neuropathic pain, and migraines, that gabapentin is approved for generalized anxiety disorder, and that in April 2019, the UK government will reclassify gabapentinoids as class C controlled substances. (All other information in the Introduction was correct and is unchanged.) This article was corrected online.

Abstract Background Using serum markers of hepatitis B virus (HBV) infection, we aimed to develop a quantitative model that explains the complicated immune response to this infection. Methods Serum samples from HBV-infected patients were randomly selected and divided into groups based on HBV-DNA positivity or negativity. Quantitative markers of HBV were measured. Formulae for Antibody index (IAb) [(anti-HBs * 1/anti-HBe + anti-HBs * 1/anti-HBc + 1/anti-HBc * 1/anti-HBe)0.5] and Antigen index (IAg) [(HBsAg * HBeAg)0.5] were introduced. Results IAg values were statistically higher (p  50, IAg values were mostly  250, IAb values were mostly

Jens Nielsen, Lasse S. Vestergaard, Lukas Richter, Daniela Schmid, Natalia Bustos, Tommi Asikainen, Ramona Trebbien, Gleb Denissov, Kaire Innos, Mikko J. Virtanen, Anne Fouillet, Theodore Lytras, Kassiani Gkolfinopoulou, Matthias an der Heiden, Linus Grabenhenrich, Helmut Uphoff, Anna Paldy, Janos Bobvos, Lisa Domegan, Joan O’Donnell, Matteo Scortichini, Annamaria de Martino, Joël Mossong, Kathleen England, Jackie Melillo, Liselotte van Asten, Marit MA de Lange, Ragnhild Tønnessen, Richard A. White, Susana

Weekly monitoring of European all-cause excess mortality, the EuroMOMO network, observed high excess mortality during the influenza B/Yamagata dominated 2017/18 winter season, especially among elderly. We describe all-cause excess and influenza-attributable mortality during the season 2017/18 in Europe.

Ghimire, S., Maharjan, B., Jongedijk, E. M., Kosterink, J. G. W., Ghimire, G. R., Touw, D. J., van der Werf, T. S., Shrestha, B., Alffenaar, J.-W. C.

Saliva may be a useful alternative matrix for monitoring levofloxacin concentrations in multi-drug resistant TB patients. The objectives of this study were: a) to evaluate the correlation between plasma and salivary Lfx concentrations in MDR-TB patients; and b) to gauge the possibility of using saliva as an alternative sampling matrix for therapeutic drug monitoring of Lfx in TB endemic areas. This was a prospective pharmacokinetic study that enrolled MDR-TB patients receiving levofloxacin (Lfx; 750-1000mg once daily dosing) under standardized treatment regimen in Nepal. Paired blood and saliva samples were collected at steady state. Lfx concentrations were quantified using liquid chromatography- tandem mass spectrometry. Pharmacokinetic parameters were calculated using non-compartmental kinetics. Lfx drug exposure was evaluated in 23 MDR-TB patients. During the first month, the median (IQR) area under the concentration-time curve (AUC0-24) was 67.09 (53.93-98.37) mg*h/L in saliva and 99.91 (76.80-129.70) mg*h/L in plasma, and the saliva plasma (S/P) ratio was 0.69 (0.53-0.99). Similarly, during the second month, the median (IQR) AUC0-24 was 75.63 (61.45-125.5) mg*h/L in saliva and 102.7 (84.46-131.9) mg*h/L in plasma with a S/P ratio of 0.73 (0.66-1.18). Furthermore, large inter-and intra-individual variabilities in Lfx concentrations were observed. This study could not demonstrate a strong correlation between plasma and saliva Lfx levels. Despite a good Lfx penetration in saliva, the variability in individual saliva-to-plasma ratios limits the use of saliva as a valid substitute for plasma. Nevertheless, saliva could be useful in semi-quantitatively predicting Lfx plasma levels.…

Abstract Background In the event of a shigellosis outbreak in a childcare setting, exclusion policies are typically applied to afflicted children to limit shigellosis transmission. However, there is scarce evidence of their impact. Methods We evaluated five exclusion policies: Children return to childcare after: i) two consecutive laboratory tests (either PCR or culture) do not detect Shigella, ii) a single negative laboratory test (PCR or culture) does not detect Shigella, iii) seven days after beginning antimicrobial treatment, iv) after being symptom-free for 24 h, or v) 14 days after symptom onset. We also included four treatments to assess the policy options: i) immediate, effective treatment; ii) effective treatment after laboratory diagnosis; iii) no treatment; iv) ineffective treatment. Relying on published data, we calculated the likelihood that a child reentering childcare would be infectious, and the number of childcare-days lost per policy. Results Requiring two consecutive negative PCR tests yielded a probability of onward transmission of

Abstract Background Insecticide-based interventions play an integral role in malaria vector control. However, the continued spread of insecticide resistance threatens to undermine progress made thus far and may ultimately lead to operational failure of current control measures. Clothianidin and chlorfenapyr both have unique modes of action and have expanded the number of insecticide classes available to vector control programmes. Prior to field use, it is imperative to establish their toxicity against local mosquito populations and evaluate potential cross-resistance with other chemicals used contemporarily or historically. The aim of this study was to determine the diagnostic doses of clothianidin and chlorfenapyr and their efficacies against Anopheles arabiensis, the predominant Ethiopian malaria vector species. Methods A range of doses of clothianidin and chlorfenapyr were tested, using modified WHO susceptibility tests and CDC bottle bioassays, respectively, against an Ethiopian susceptible laboratory strain and a wild population of An. arabiensis collected from Oromia Region, Ethiopia. Cross-resistance to other public health insecticides: carbamates (bendiocarb and propoxur), organophosphate (malathion) and pyrethroids (deltamethrin and permethrin), was assessed in the same mosquito populations using CDC bottle bioassays. Results Complete mosquito mortality was observed with the laboratory strain using the recommended diagnostic doses for clothianidin (2%/filter paper) and chlorfenapyr (100 µg/bottle). The field population was resistant to malathion (83% mortality), capable of surviving 2×, 5× and 10× the diagnostic dose of both deltamethrin and permethrin, but susceptible to bendiocarb and propoxur. The field population of An. arabiensis was significantly more susceptible to clothianidin, reaching 100% mortality by day 2 compared to the laboratory strain (100% mortality by day 3). In contrast, the wild population was less susceptible to chlorfenapyr, with the highest mortality of 99% at 72 h using 200 µg/bottle compared to the laboratory colony, which reached complete mortality at 50 µg/bottle by 24 h. Conclusions The putative diagnostic doses of clothianidin and chlorfenapyr are appropriate for monitoring resistance in An. arabiensis from Ethiopia. The unique modes of action and an absence of cross-resistance render clothianidin and chlorfenapyr potential candidates for inclusion in the National Malaria Control Programme vector control efforts, particularly in areas with high pre-existing or emergent resistance to other insecticide classes.…

Liese, J., Schüle, L., Oberhettinger, P., Tschörner, L., Nguyen, T., Dörfel, D., Vogel, W., Marschal, M., Autenrieth, I., Willmann, M., Peter, S.

Background: Vancomycin-resistant Enterococcus faecium (VREfm) is a frequent cause of nosocomial outbreaks. In the second half of 2015 a sharp increase in the incidence of VREfm was observed at our university medical center. Next-generation sequencing (NGS) was used to analyze the first isolates of VREfm recovered from patients between 2010 and 2016 (n=773) in order to decipher epidemiological change, outbreak dynamics, and possible transmission routes.Materials and methods: VREfm isolates were analyzed using whole genome sequencing followed by sequence type extraction, and phylogenetic analysis. We examined epidemiological data, room occupancy data, and patient transferals and calculated an intensity score for patient-to-patient contact.Results: Phylogenetic analysis revealed the presence of 38 NGS clusters and 110 single clones. The increase of VREfm was mainly caused by the expansion of two newly introduced NGS clusters, comprising VanB-type strains of the MLST sequence type (ST)80 and ST117. Combining phylogenetic information with epidemiological data, intra-hospital transmission could be demonstrated, however to a lesser extent than initially expected based solely on epidemiological data. The outbreak clones were continuously imported from other hospitals, suggesting a change of the epidemiological situation at a regional scale. Tracking intra-hospital patient transferals, two major axes could be identified that contributed to the spread of VREfm within the hospital.Conclusions: NGS-based outbreak analysis revealed a dramatic change in the local and regional epidemiology of VREfm, emphasizing the role of healthcare networks in the spread of VREfm.…

Voelker R.

A noninvasive test that doesn’t require comparison with a baseline assessment before an injury occurred has received FDA approval to help diagnose concussion in children and adults.

Abstract Background To control and eventually eliminate vivax malaria, radical treatment with primaquine (PQ) is essential after completion of blood-stage treatment. Although in many malaria-endemic countries, village health volunteers (VHVs) are engaged in diagnostic treatment of malaria in remote communities, they principally provide blood-stage treatment. In such a situation, access to PQ following blood-stage treatment can be a barrier to complete treatment. However, studies on access to PQ treatment have been scarce and limited in health facility-based settings. This study aimed to identify factors associated with access to PQ treatment in rural Papua New Guinea (PNG) from the community case management perspective. Methods A community-based, cross-sectional survey was conducted to collect sociodemographic information on children under 15 years of age, their households, and their caretakers in East Sepik Province, PNG. Data collection lasted from February to March, 2015. Information on the diagnoses of potential non-falciparum malaria and prescription of PQ in preceding year (January to December 2014) were obtained from child health-record books. Then, multilevel logistic regression model was used to determine the factors associated with formal health facility visits for PQ treatment among children with potential non-falciparum malaria. Results Of 420 episodes diagnosed as potential non-falciparum malaria, 46 (11%) were immediately given PQ. The rest were instructed to visit formal health facilities (HFs) for PQ, and the patients obtained PQ during the second visit to HFs was 44%. Consequently, the overall proportion of PQ prescription was 50%. Logistic regression analysis suggested that among the patients who were instructed to visit HFs for PQ treatment, the initial visit to VHV and higher transportation costs to HF were inversely associated with PQ prescription during the second visit to an HF. Conclusions Few children received PQ treatment during the second visit to HFs following diagnosis of potential non-falciparum malaria. These findings suggest a need to establish a policy to reduce structural and economic barriers and improve rural inhabitant access to PQ treatment.…

Jousset, A. B., Oueslati, S., Bernabeu, S., Takissian, J., Creton, E., Vogel, A., Sauvadet, A., Cotellon, G., Gauthier, L., Bonnin, R. A., Dortet, L., Naas, T.

In Enterobacter cloacae complex (ECC), the over-production of the chromosome-encoded cephalosporinase (cAmpC) associated with decreased outer membrane permeability may result in carbapenem resistance. Here, we have characterized ACT-28, a cAmpC with weak carbapenemase activity, from a single Enterobacter kobei lineage. ECC clinical isolates were characterized by whole genome sequencing (WGS), susceptibility testing, minimal inhibitory concentration and carbapenemase activity was monitored using diverse carbapenem hydrolysis methods. ACT-28 steady state kinetic parameters were determined.Among 1039 non carbapenemase-producing ECC isolates with decreased susceptibility to carbapenems received in 2016-2017 at the French National Reference Center for antibiotic resistance, only eight displayed a positive carbapenemase detection test (Carba NP). These eight ECC isolates were resistant to broad-spectrum cephalosporins due to AmpC derepression, showed decreased susceptibility to carbapenems and were categorized as a carbapenemase-producing Enterobacteriaceae (CPE) according to several carbapenemase detection assays. WGS identified a single clone of E. kobei ST125 expressing only its cAmpC, ACT-28. BlaACT-28 gene was expressed in a wild type and in a porin-deficient E. coli background and compared to blaACT-1 gene. Detection of carbapenemase activity was positive only for E. coli expressing blaACT-28 gene. Kinetic parameters of purified ACT-28 revealed a slightly increased imipenem hydrolysis as compared to ACT-1. In silico porin analysis revealed the presence of a peculiar OmpC-like protein specific to E. kobei ST125 that could impair carbapenem influx into the periplasm and thus enhance carbapenem-resistance caused by ACT-28.We described a widespread lineage of E. kobei ST125 producing ACT-28, with weak carbapenemase activity that can lead to false-positive detection by several biochemical and phenotypic diagnostic tests. …

Diamond R.

In this narrative medicine essay, a pediatrician recalls how her residency program and peers helped her through a challenging pregnancy and postpartum period, compares herself to women who are not so lucky, and calls on the physician community to advocate for a change in US policy to provide 12-week paid family leave.

Voelker R.

The first US clinical trial of intravenously administered bacteriophage therapy has received FDA approval. Physician researchers at the University of California San Diego (UCSD) School of Medicine will conduct the trial in collaboration with AmpliPhi Biosciences Corporation, a San Diego–based biotechnology company.

Nicolas Dauby, Patrice Jissendi-Tchofo, Camilo Garcia

Gingras, H., Patron, K., Bhattacharya, A., Leprohon, P., Ouellette, M.

Two whole genome screening approaches are described for studying the mode of action and the mechanisms of resistance to trimethoprim (TMP) in the Gram positive Streptococcus pneumoniae. The gain of function approach (Int-Seq) relies on a genomic library of DNA fragments integrated into a fucose-inducible cassette. The second approach leading to both gain and loss of function mutations is based on chemical mutagenesis coupled to next-generation sequencing (Mut-Seq). Both approaches pointed at the drug target dihydrofolate reductase (DHFR) as a major resistance mechanism to TMP. Resistance was achieved by dhfr overexpression either through the addition of fucose (Int-Seq) or by mutations upstream of the gene (Mut-Seq). Three type of mutations increased expression by disrupting a predicted Rho-independent terminator upstream of dhfr. Known and novel DHFR mutations were also detected by Mut-Seq and these were functionally validated for TMP resistance. The two approaches also suggested that an increase in the metabolic flux from purine synthesis to GTP and then to folate can modulate the susceptibility to TMP. We finally provide evidence for a novel role of the ABC transporter PatAB in TMP susceptibility. Our genomic screens highlighted novel aspects on the mode of action and resistance mechanisms to antibiotics.…

Hezekiah K. Adesokan, Elizabeth M. Streicher, Paul D. van Helden, Rob M. Warren, Simeon I. B. Cadmus

by Hezekiah K. Adesokan, Elizabeth M. Streicher, Paul D. van Helden, Rob M. Warren, Simeon I. B. Cadmus Molecular typing techniques are useful in understanding tuberculosis epidemiology; yet, they have been under-utilised at the human-animal interface in Nigeria. Sixty-four Mycobacterium tuberculosis complex (MTBC) isolates including 42 M. tuberculosis, 13 M. bovis and nine M. africanum obtained from livestock workers (LW, n = 47) and their cattle (n = 17) in three geographical zones of Nigeria were genotyped to identify and evaluate the genetic diversity of the circulating MTBC using spoligotyping. Distribution into clades of M. tuberculosis revealed; 45.3% Uganda I- [SIT46- cattle: 1; LW: 28], 14.1% Latin American Mediterranean- [SIT61, cattle: 1; LW: 8], and 1.6% T- [SIT53—LW: 1]. The M. bovis strains were 6.3% SB0944 [cattle: 4] and 1.6% each of SB0300, SB1026, SB1027 and SB1439 [cattle: 4]. Seventeen MTBC isolates [cattle: 7; LW: 10] yielded 14 new spoligotype patterns including three M. tuberculosis strains (three isolates), five M. bovis strains (five isolates) and six M. africanum strains (nine isolates), two of which belonged to MAF1. Only few families namely, the not previously described Uganda I-, LAM and SB0944 are predominant among the LW and cattle, with other types in lower prevalences. The strain population structure indicates an intriguing diversity and possible zoonotic linkage with consequences for TB control in the country. The need to employ newer molecular techniques such as Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats and whole genome sequence to decipher circulating MTBC strains in Nigeria is advocated.

Abstract Purpose Individuals with methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI) can be simultaneously colonized with MRSA on multiple body sites. Using whole genome sequencing (WGS), the intrahost relatedness of MRSA colonization and infection isolates was investigated. Methods In the context of a prospective case–control study of SSTI, we analyzed colonization and infection isolates from US Army Infantry trainees with purulent infection due to MRSA. At the time of clinical presentation for SSTI, culture swabs were obtained from the infection site, as well as from the patient’s nasal, oral, inguinal, and perianal regions. S. aureus culture and susceptibility was performed by standard methods. DNA from MRSA isolates was extracted and libraries were produced. Sequences were generated on an Illumina MiSeq, sequence reads were assembled, and single nucleotide variant (SNV) data were analyzed. Results Of 74 trainees with MRSA SSTI, 19 (25.7%) were colonized with MRSA. Ten (52.6%) were colonized on more than one body site. Colonization frequency by anatomic site was as follows: inguinal region (33%), nasal region (30%), perianal region (22%), and oral region (14%). A total of 36 MRSA colonization isolates were characterized. The intrahost median number of SNVs between infection and colonization isolates was 17. Among trainees with recurrent MRSA SSTI, limited intrahost diversity suggests that persistent colonization is a major contributor to recurrence risk. Conclusions Among military trainees with MRSA SSTI, genomic characterization of infection and colonization isolates revealed a high degree of strain relatedness. Single acquisition events may account for MRSA colonization and infection in this population.…

Abstract Background Community- associated methicillin resistant Staphylococcus aureus (CA-MRSA) cause serious infections and rates continue to rise worldwide. Use of geocoded electronic health record (EHR) data to prevent spread of disease is limited in health service research. We demonstrate how geocoded EHR and spatial analyses can be used to identify risks for CA-MRSA in children, which are tied to place-based determinants and would not be uncovered using traditional EHR data analyses. Methods An epidemiology study was conducted on children from January 1, 2002 through December 31, 2010 who were treated for Staphylococcus aureus infections. A generalized estimated equations (GEE) model was developed and crude and adjusted odds ratios were based on S. aureus risks. We measured the risk of S. aureus as standardized incidence ratios (SIR) calculated within aggregated US 2010 Census tracts called spatially adaptive filters, and then created maps that differentiate the geographic patterns of antibiotic resistant and non-resistant forms of S. aureus. Results CA-MRSA rates increased at higher rates compared to non-resistant forms, p = 0.01. Children with no or public health insurance had higher odds of CA-MRSA infection. Black children were almost 1.5 times as likely as white children to have CA-MRSA infections (aOR 95% CI 1.44,1.75, p 

Bradshaw JM, Ensor SA, Lorenz HL.

To the Editor In the cohort study by Dr Lowe and colleagues, the association of gestational diabetes with later maternal diabetes and childhood adiposity was explored. The authors reported that gestational diabetes was associated with the development of maternal diabetic disorders (type 2 diabetes and prediabetes) but was not significantly associated with the development of childhood overweight or obesity.

Lowe WL, Jr, Scholtens DM, Metzger BE.

In Reply Mr Bradshaw and colleagues raised 3 primary concerns related to the findings of our recent study: (1) oral glucose tolerance test results may vary within individuals, leading to identification of women with gestational diabetes who may not meet criteria in a subsequent oral glucose tolerance test; (2) the IADPSG criteria as accepted by WHO may be too sensitive and not associated with long-term child outcomes; and (3) the HAPO Follow-up Study failed to meet its recruitment target, which reduced power and contributed to the failure to find an association between gestational diabetes and childhood overweight and obesity.

Angel N. Desai, John W. Ramatowski, Britta Lassmann, Alison Holmes, Shaheen Mehtar, Gonzalo Bearman

Yohannes Ejigu, Jeanette H. Magnus, Johanne Sundby, Maria Magnus

Angus DC.

What is the best approach for resuscitation of a patient with septic shock? Despite considerable investigation over several decades, this important question still has no clear answer. There is agreement that resuscitation should proceed quickly, for the longer the delay, the greater the physiologic stress and end-organ injury. However, treatment options are principally intravenous fluids and vasoactive agents, which have the capacity to both help or harm the patient. Thus, these therapies must be titrated in response to markers of the adequacy of resuscitation. The 2016 Surviving Sepsis Guidelines advocate that the principal marker of the adequacy of resuscitation is serum lactate. Serum lactate level is elevated when the body relies on anaerobic metabolism. As such, an elevated serum lactate level is a reflection of tissue hypoperfusion and thus considered axiomatic of shock. However, serum lactate level can be elevated in conditions other than shock and yet may not always be elevated in some shock states. Furthermore, lactate clearance is often considered too slow to provide timely feedback to clinicians regarding the consequences of their treatment decisions. Moreover, not all patients with shock can be cared for in settings with access to rapid-turnaround serum lactate assays.

Megan B. Fitzpatrick, Racheal S. Dube Mandishora, David A. Katzenstein, Kathy McCarty, Jenna Weber, Malaya K. Sahoo, Justen Manasa, Zvavahera Mike Chirenje, Benjamin A. Pinsky

Friedrich MJ.

Daily administration of hydroxyurea is feasible and safe for children with sickle cell anemia in sub-Saharan Africa, according to new research.

Mira-Martinez, S., Pickford, A. K., Rovira-Graells, N., Guetens, P., Tinto-Font, E., Cortes, A., Rosanas-Urgell, A.

During the intraerythrocytic asexual cycle malaria parasites acquire nutrients and other solutes through a broad selectivity channel localized at the membrane of the infected erythrocyte termed Plasmodial Surface Anion Channel (PSAC). The protein product of the Plasmodium falciparum clonally variant clag3.1 and clag3.2 genes determines PSAC activity. Switches in the expression of clag3 genes, which are regulated by epigenetic mechanisms, are associated with changes in PSAC-dependent permeability that can result in resistance to compounds toxic for the parasite such as blasticidin S. Here we investigated whether other antimalarial drugs require CLAG3 to reach their intracellular target and consequently are prone to parasite resistance by epigenetic mechanisms. We found that the bis-thiazolium salts T3 (also known as albitiazolium) and T16 require the product of clag3 genes to enter infected erythrocytes. P. falciparum populations can develop resistance to these compounds via selection of parasites with dramatically reduced expression of both genes. However, other compounds previously demonstrated or predicted to enter infected erythrocytes through transport pathways absent from non-infected erythrocytes, such as fosmidomycin, doxycycline, azithromycin, lumefantrine or pentamidine, do not require expression of clag3 genes for their anti-malarial activity. This suggests that they use alternative CLAG3-independent routes to access parasites. Our results demonstrate that P. falciparum can develop resistance to diverse antimalarial compounds by epigenetic changes in the expression of clag3 genes. This is of concern for drug development efforts because drug resistance by epigenetic mechanisms can arise quickly, even during the course of a single infection.…

Xu, J., Wang, B., Fu, L., Zhu, H., Guo, S., Huang, H., Yin, D., Zhang, Y., Lu, Y.

The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog TBI-166 was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against Mycobacterium tuberculosis and its potential to accumulate and discolor skin. In vitro activity of TBI-166 against both drug-sensitive and drug-resistant M. tuberculosis is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3x10-7 in wild strains of M. tuberculosis. TBI-166 demonstrates at least equivalent activity compared to CFZ against intracellular M. tuberculosis and in low-dose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.…

Moya, B., Barcelo, I. M., Cabot, G., Torrens, G., Palwe, S., Joshi, P., Umarkar, K., Takalkar, S., Periasamy, H., Bhagwat, S., Patel, M., Bou, G., Oliver, A.

Zidebactam and WCK 5153 are novel Bicyclo-acyl Hydrazides (BCH) agents that have previously been shown to act as β-lactam enhancer (BLE) antibiotics in Pseudomonas aeruginosa and Acinetobacter baumannii. The objectives of this work were to identify the molecular targets of these BCHs in Klebsiella pneumoniae and to investigate their potential BLE activity on cefepime and aztreonam against metallo-β-lactamase (MBL) -producing strains in vitro and in vivo. PBP-binding profiles were determined by BOCILLIN FL assay, and 50% inhibitory concentrations (IC50) were determined using the ImageQuant TL Software. MICs and kill kinetics for zidebactam, WCK 5153 and cefepime or aztreonam, alone and in combination were determined against clinical K. pneumoniae isolates producing MBLs- blaVIM-1 or blaNDM-1 (+ ESBLs and class C) to assess the in vitro enhancer effect of BCH compounds in conjunction with β-lactams. Additionally, murine systemic and thigh infection studies were conducted to evaluate BLE effect in vivo. Zidebactam and WCK 5153 showed specific, high PBP2 affinity in K. pneumoniae. MICs of BLEs were >64 μg/ml for all MBL-producing strains. Time-kill studies showed that a combination of these BLEs with either cefepime or aztreonam provided 1->3 log10-kill against MBL-producing K. pneumoniae strains. Furthermore, the bactericidal synergy observed for these BLE-BL combinations translated well into in vivo efficacy even in the absence of MBL inhibition by BLEs, a characteristic feature of β-lactam enhancer mechanism of action. Zidebactam and WCK 5153 are potent PBP2 inhibitors, and display in vitro and in vivo BLE effect against MDR K. pneumoniae clinical isolates producing MBLs.…

Blevins, A. M., Lashinsky, J. N., McCammon, C., Kollef, M., Micek, S., Juang, P.

Critically ill patients are frequently treated with empiric antibiotic therapy including vancomycin and β-Lactams. Recent evidence suggests an increased risk of acute kidney injury (AKI) in patients who received the combination of vancomycin and piperacillin/tazobactam (VPT) compared with patients who received vancomycin alone or vancomycin in combination with cefepime (VC) or meropenem (VM), but most studies have been conducted predominately in the non-critically ill population. A retrospective cohort study including 2492 patients was conducted in the intensive care units of a large university hospital with the primary outcome being the development of any AKI. The rate of any AKI, as defined by the KDIGO guidelines, was 39.3% for VPT patients, 24.2% for VC, and 23.5% for VM patients (p