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1.  Prognostic nomogram for refining prognostication of the proposed AJCC/UICC 8th edition for nasopharyngeal cancer in the era of intensity-modulated radiotherapy 
Cancer  2016;122(21):3307-3315.
To develop a nomogram for refining prognostication for patients with non-disseminated nasopharyngeal cancer (NPC) staged with the proposed AJCC/UICC 8th edition.
Material and methods
Consecutive patients investigated by magnetic resonance imaging, staged by the proposed AJCC/UICC 8th edition, and irradiated by intensity- modulated radiotherapy (IMRT) from June 2005 to December 2010 were analyzed. The cohort of 1197 patients treated at Fujian Provincial Cancer Hospital was used as the training set and the results were validated by 412 patients from Pamela Youde Nethersole Eastern Hospital. Cox regression analyses were performed to identify significant prognostic factors for developing a nomogram to predict overall survival (OS). The discriminative ability was assessed with concordance index (C-index). Patients were categorized into three risk groups by performing recursive partitioning algorithm (RPA) on the survival scores of the combined set.
Multivariable analysis showed that age, gross primary tumor volume (GTV-P) and lactate dehydrogenase (LDH) were independent prognostic factors for OS in addition to stage-group. The OS nomogram based on all these factors had a statistically higher bias-corrected C-index than prognostication based on stage-group alone (0.712 vs 0.622, p<0.01). These results were consistent for both the training and the validation cohorts. Patients with <135 points were categorized as low-risk, ≥135–<160 points as intermediate-risk and ≥160 points as high-risk, respectively. Their 5-year OS rates were 92%, 84% and 58%, respectively.
The proposed nomogram could improve prognostication when compared with TNM stage-group. This could aid in risk stratification for individual NPC patients.
PMCID: PMC5524130  PMID: 27434142
Nasopharyngeal carcinoma; Nomogram; TNM staging; Prognostication; Intensity modulated radiotherapy
2.  Racial/Ethnic Disparity in NICU Quality of Care Delivery 
Pediatrics  2017;140(3):e20170918.
Differences in neonatal intensive care unit (NICU) quality of care provided to very-low-birth-weight (VLBW; <1500g) infants may contribute to the persistence of racial/ethnic disparity. An examination of such disparities in a population-based sample across multiple dimensions of care and outcomes is lacking.
Prospective observational analysis of 18,616 VLBW infants in 134 California NICUs between January 1, 2010 to December 31, 2014. We assessed quality of care delivery via the Baby-MONITOR, a composite indicator consisting of nine process and outcome measures of quality. For each NICU we calculated a risk adjusted composite and individual component quality score for each race/ethnicity. We standardized each score to the overall population to compare quality of care between and within NICUs.
We found clinically and statistically significant racial/ethnic variation in quality of care delivery between NICUs as well as within NICUs. Composite quality scores ranged by 5.26 standard units (range −2.30 to 2.96). Adjustment of Baby-MONITOR scores by race/ethnicity had only minimal effect on comparative assessments of NICU performance. Among subcomponents of the Baby-MONITOR, non-Hispanic White infants scored higher on measures of process compared with non-Hispanic Blacks and Hispanics. Compared with Whites, non-Hispanic Blacks scored higher on measures of outcome; Hispanics scored lower on seven of the nine Baby-MONITOR subcomponents.
Significant racial/ethnic variation in quality of care delivery exists between and within NICUs. Providing feedback of disparity scores to NICUs could serve as an important starting point for promoting improvement and reducing disparities.
PMCID: PMC5574732  PMID: 28847984
3.  Bacteria-inspired nanorobots with flagellar polymorphic transformations and bundling 
Scientific Reports  2017;7:14098.
Wirelessly controlled nanoscale robots have the potential to be used for both in vitro and in vivo biomedical applications. So far, the vast majority of reported micro- and nanoscale swimmers have taken the approach of mimicking the rotary motion of helical bacterial flagella for propulsion, and are often composed of monolithic inorganic materials or photoactive polymers. However, currently no man-made soft nanohelix has the ability to rapidly reconfigure its geometry in response to multiple forms of environmental stimuli, which has the potential to enhance motility in tortuous heterogeneous biological environments. Here, we report magnetic actuation of self-assembled bacterial flagellar nanorobotic swimmers. Bacterial flagella change their helical form in response to environmental stimuli, leading to a difference in propulsion before and after the change in flagellar form. We experimentally and numerically characterize this response by studying the swimming of three flagellar forms. Also, we demonstrate the ability to steer these devices and induce flagellar bundling in multi-flagellated nanoswimmers.
PMCID: PMC5658443  PMID: 29074862
4.  Divergent Reactivity of a Dinuclear (NHC)Nickel(I) Catalyst versus Nickel(0) Enables Chemoselective Trifluoromethylselenolation 
We herein showcase the ability of NHC‐coordinated dinuclear NiI–NiI complexes to override fundamental reactivity limits of mononuclear (NHC)Ni0 catalysts in cross‐couplings. This is demonstrated with the development of a chemoselective trifluoromethylselenolation of aryl iodides catalyzed by a NiI dimer. A novel SeCF3‐bridged NiI dimer was isolated and shown to selectively react with Ar−I bonds. Our computational and experimental reactivity data suggest dinuclear NiI catalysis to be operative. The corresponding Ni0 species, on the other hand, suffers from preferred reaction with the product, ArSeCF3, over productive cross‐coupling and is hence inactive.
PMCID: PMC5656904  PMID: 28795520
catalysis; chemoselectivity; density functional calculations; fluorine; nickel
5.  Proceedings of resources for optimal care of acute care and emergency surgery consensus summit Donegal Ireland 
Opportunities to improve emergency surgery outcomes exist through guided better practice and reduced variability. Few attempts have been made to define optimal care in emergency surgery, and few clinically derived key performance indicators (KPIs) have been published. A summit was therefore convened to look at resources for optimal care of emergency surgery. The aim of the Donegal Summit was to set a platform in place to develop guidelines and KPIs in emergency surgery.
The project had multidisciplinary global involvement in producing consensus statements regarding emergency surgery care in key areas, and to assess feasibility of producing KPIs that could be used to monitor process and outcome of care in the future.
Forty-four key opinion leaders in emergency surgery, across 7 disciplines from 17 countries, composed evidence-based position papers on 14 key areas of emergency surgery and 112 KPIs in 20 acute conditions or emergency systems.
The summit was successful in achieving position papers and KPIs in emergency surgery. While position papers were limited by non-graded evidence and non-validated KPIs, the process set a foundation for the future advancement of emergency surgery.
PMCID: PMC5651635
Emergency surgery; Optimal care; Performance indicators; Surgical outcomes
6.  Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma 
Cancer Cell  2017;32(4):520-537.e5.
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.
Graphical Abstract
•Pediatric HGG and DIPG comprise a diverse set of clinical and biological subgroups•Somatic coding mutations per tumor range from none to among the highest seen in human cancer•Histone mutations co-segregate with distinct alterations and downstream pathways•H3/IDH1 WT tumors may resemble low-grade lesions and have targetable alterations
Mackay et al. perform an integrated analysis of >1,000 cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma. They identify co-segregating mutations in histone-mutant subgroups and show that histone wild-type subgroups are molecularly more similar to lower-grade tumors.
PMCID: PMC5637314  PMID: 28966033
genome; exome; methylation; histone; glioblastoma; DIPG
7.  MicroRNA-433 Dampens Glucocorticoid Receptor Signaling, Impacting Circadian Rhythm and Osteoblastic Gene Expression* 
The Journal of Biological Chemistry  2016;291(41):21717-21728.
Serum glucocorticoids play a critical role in synchronizing circadian rhythm in peripheral tissues, and multiple mechanisms regulate tissue sensitivity to glucocorticoids. In the skeleton, circadian rhythm helps coordinate bone formation and resorption. Circadian rhythm is regulated through transcriptional and post-transcriptional feedback loops that include microRNAs. How microRNAs regulate circadian rhythm in bone is unexplored. We show that in mouse calvaria, miR-433 displays robust circadian rhythm, peaking just after dark. In C3H/10T1/2 cells synchronized with a pulse of dexamethasone, inhibition of miR-433 using a tough decoy altered the period and amplitude of Per2 gene expression, suggesting that miR-433 regulates rhythm. Although miR-433 does not directly target the Per2 3′-UTR, it does target two rhythmically expressed genes in calvaria, Igf1 and Hif1α. miR-433 can target the glucocorticoid receptor; however, glucocorticoid receptor protein abundance was unaffected in miR-433 decoy cells. Rather, miR-433 inhibition dramatically enhanced glucocorticoid signaling due to increased nuclear receptor translocation, activating glucocorticoid receptor transcriptional targets. Last, in calvaria of transgenic mice expressing a miR-433 decoy in osteoblastic cells (Col3.6 promoter), the amplitude of Per2 and Bmal1 mRNA rhythm was increased, confirming that miR-433 regulates circadian rhythm. miR-433 was previously shown to target Runx2, and mRNA for Runx2 and its downstream target, osteocalcin, were also increased in miR-433 decoy mouse calvaria. We hypothesize that miR-433 helps maintain circadian rhythm in osteoblasts by regulating sensitivity to glucocorticoid receptor signaling.
PMCID: PMC5076840  PMID: 27551048
bone; circadian; circadian rhythm; glucocorticoid receptor; microRNA (miRNA); microRNA mechanism; osteoblast; post-transcriptional regulation
8.  Method for single illumination source combined optical coherence tomography and fluorescence imaging of fluorescently labeled ocular structures in transgenic mice 
Experimental eye research  2016;151:68-74.
In vivo imaging permits longitudinal study of ocular disease processes in the same animal over time. Two different in vivo optical imaging modalities – optical coherence tomography (OCT) and fluorescence – provide important structural and cellular data respectively about disease processes. In this Methods in Eye Research article, we describe and demonstrate the combination of these two modalities producing a truly simultaneous OCT and fluorescence imaging system for imaging of fluorescently labeled animal models. This system uses only a single light source to illuminate both modalities, and both share the same field of view. This allows simultaneous acquisition of OCT and fluorescence images, and the benefits of both techniques are realized without incurring increased costs in variability, light exposure, time, and post-processing effort as would occur when the modalities are used separately. We then utilized this system to demonstrate multi-modal imaging in a progression of samples exhibiting both fluorescence and OCT scattering beginning with resolution targets, ex vivo thy1-YFP labeled neurons in mouse eyes, and finally an in vivo longitudinal time course of GFP labelled myeloid cells in a mouse model of ocular allergy.
PMCID: PMC5072542  PMID: 27519152
9.  Colonization Density of the Upper Respiratory Tract as a Predictor of Pneumonia—Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii 
There is limited information on the association between colonization density of upper respiratory tract colonizers and pathogen-specific pneumonia. We assessed this association for Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and Pneumocystis jirovecii.
In 7 low- and middle-income countries, nasopharyngeal/oropharyngeal swabs from children with severe pneumonia and age-frequency matched community controls were tested using quantitative polymerase chain reaction (PCR). Differences in median colonization density were evaluated using the Wilcoxon rank-sum test. Density cutoffs were determined using receiver operating characteristic curves. Cases with a pathogen identified from lung aspirate culture or PCR, pleural fluid culture or PCR, blood culture, and immunofluorescence for P. jirovecii defined microbiologically confirmed cases for the given pathogens.
Higher densities of H. influenzae were observed in both microbiologically confirmed cases and chest radiograph (CXR)-positive cases compared to controls. Staphylococcus aureus and P. jirovecii had higher densities in CXR-positive cases vs controls. A 5.9 log10 copies/mL density cutoff for H. influenzae yielded 86% sensitivity and 77% specificity for detecting microbiologically confirmed cases; however, densities overlapped between cases and controls and positive predictive values were poor (<3%). Informative density cutoffs were not found for S. aureus and M. catarrhalis, and a lack of confirmed case data limited the cutoff identification for P. jirovecii.
There is evidence for an association between H. influenzae colonization density and H. influenzae–confirmed pneumonia in children; the association may be particularly informative in epidemiologic studies. Colonization densities of M. catarrhalis, S. aureus, and P. jirovecii are unlikely to be of diagnostic value in clinical settings.
PMCID: PMC5612712  PMID: 28575367
pneumonia; colonization density; PERCH
10.  Network Analysis: A Novel Method for Mapping Neonatal Acute Transport Patterns in California 
To use network analysis to describe the pattern of neonatal transfers in California, to compare empirical sub-networks with established referral regions, and to determine factors associated with transport outside the originating sub-network.
Study Design
This cross-sectional database study included 6546 infants <28 days old transported within California in 2012. After generating a graph representing acute transfers between hospitals (n=6696), we used community detection techniques to identify more tightly connected sub-networks. These empirically-derived sub-networks were compared to state-defined regional referral networks. Reasons for transfer between empirical sub-networks were assessed using logistic regression.
Empirical sub-networks showed significant overlap with regulatory regions (p <0.001). Transfer outside the empirical sub-network was associated with major congenital anomalies (p<0.001), need for surgery (p=0.01), and insurance as the reason for transfer (p<0.001).
Network analysis accurately reflected empirical neonatal transfer patterns, potentially facilitating quantitative, rather than qualitative, analysis of regionalized health care delivery systems.
PMCID: PMC5446293  PMID: 28333155
11.  An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network *  
The Journal of Biological Chemistry  2016;291(37):19474-19486.
There has been a recent interest in the broader physiological importance of multispecific “drug” transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wet-lab assays, together with re-evaluation of existing transport and knock-out metabolomics data, generated an experimentally validated, confidence ranked set of OAT1-interacting endogenous compounds enabling construction of an “OAT1-centered metabolic interaction network.” Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products, and so-called uremic toxins accumulating in chronic kidney disease. Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication: The Remote Sensing and Signaling Hypothesis (Nigam, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.
PMCID: PMC5016685  PMID: 27440044
ABC transporter; diabetes; kidney; microbiome; systems biology; Recon; SLC transporter; chronic kidney disease; genome-scale metabolic reconstruction; pharmacophore
12.  Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study 
Shi, Ting | McAllister, David A | O'Brien, Katherine L | Simoes, Eric A F | Madhi, Shabir A | Gessner, Bradford D | Polack, Fernando P | Balsells, Evelyn | Acacio, Sozinho | Aguayo, Claudia | Alassani, Issifou | Ali, Asad | Antonio, Martin | Awasthi, Shally | Awori, Juliet O | Azziz-Baumgartner, Eduardo | Baggett, Henry C | Baillie, Vicky L | Balmaseda, Angel | Barahona, Alfredo | Basnet, Sudha | Bassat, Quique | Basualdo, Wilma | Bigogo, Godfrey | Bont, Louis | Breiman, Robert F | Brooks, W Abdullah | Broor, Shobha | Bruce, Nigel | Bruden, Dana | Buchy, Philippe | Campbell, Stuart | Carosone-Link, Phyllis | Chadha, Mandeep | Chipeta, James | Chou, Monidarin | Clara, Wilfrido | Cohen, Cheryl | de Cuellar, Elizabeth | Dang, Duc-Anh | Dash-yandag, Budragchaagiin | Deloria-Knoll, Maria | Dherani, Mukesh | Eap, Tekchheng | Ebruke, Bernard E | Echavarria, Marcela | de Freitas Lázaro Emediato, Carla Cecília | Fasce, Rodrigo A | Feikin, Daniel R | Feng, Luzhao | Gentile, Angela | Gordon, Aubree | Goswami, Doli | Goyet, Sophie | Groome, Michelle | Halasa, Natasha | Hirve, Siddhivinayak | Homaira, Nusrat | Howie, Stephen R C | Jara, Jorge | Jroundi, Imane | Kartasasmita, Cissy B | Khuri-Bulos, Najwa | Kotloff, Karen L | Krishnan, Anand | Libster, Romina | Lopez, Olga | Lucero, Marilla G | Lucion, Florencia | Lupisan, Socorro P | Marcone, Debora N | McCracken, John P | Mejia, Mario | Moisi, Jennifer C | Montgomery, Joel M | Moore, David P | Moraleda, Cinta | Moyes, Jocelyn | Munywoki, Patrick | Mutyara, Kuswandewi | Nicol, Mark P | Nokes, D James | Nymadawa, Pagbajabyn | da Costa Oliveira, Maria Tereza | Oshitani, Histoshi | Pandey, Nitin | Paranhos-Baccalà, Gláucia | Phillips, Lia N | Picot, Valentina Sanchez | Rahman, Mustafizur | Rakoto-Andrianarivelo, Mala | Rasmussen, Zeba A | Rath, Barbara A | Robinson, Annick | Romero, Candice | Russomando, Graciela | Salimi, Vahid | Sawatwong, Pongpun | Scheltema, Nienke | Schweiger, Brunhilde | Scott, J Anthony G | Seidenberg, Phil | Shen, Kunling | Singleton, Rosalyn | Sotomayor, Viviana | Strand, Tor A | Sutanto, Agustinus | Sylla, Mariam | Tapia, Milagritos D | Thamthitiwat, Somsak | Thomas, Elizabeth D | Tokarz, Rafal | Turner, Claudia | Venter, Marietjie | Waicharoen, Sunthareeya | Wang, Jianwei | Watthanaworawit, Wanitda | Yoshida, Lay-Myint | Yu, Hongjie | Zar, Heather J | Campbell, Harry | Nair, Harish
Lancet (London, England)  2017;390(10098):946-958.
We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015.
We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity.
We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6–50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7–3·8) hospital admissions, and 59 600 (48 000–74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2–1·7) hospital admissions, and 27 300 (UR 20 700–36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600–149 400). Incidence and mortality varied substantially from year to year in any given population.
Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group.
The Bill & Melinda Gates Foundation.
PMCID: PMC5592248  PMID: 28689664
13.  Dynamics affecting the risk of silent circulation when oral polio vaccination is stopped 
Epidemics  2017;20:21-36.
•Silent circulation (SC) of wild polio viruses (WPV) when oral polio vaccine (OPV) use is stopped, could threaten eradication.•We analyzed a model designed to develop theory about mechanisms and factors that lead to SC and how SC risks can be assessed using surveillance data.•Prolonged low-level SC emerges as a threshold phenomenon through a mechanism related to balancing contributions of different populations to the effective reproduction number.•Factors that promote this mechanism are many years of inadequate vaccination efforts, ongoing waning of immunity against transmission years after last OPV or WPV infection, low transmissibility of OPV, and high transmission conditions.•Analyzing acute flaccid paralysis surveillance or environmental surveillance data by themselves cannot assess the risk that an SC threshold has been passed, but new methods to analyze them jointly could do so.
Waning immunity could allow transmission of polioviruses without causing poliomyelitis by promoting silent circulation (SC). Undetected SC when oral polio vaccine (OPV) use is stopped could cause difficult to control epidemics. Little is known about waning. To develop theory about what generates SC, we modeled a range of waning patterns. We varied both OPV and wild polio virus (WPV) transmissibility, the time from beginning vaccination to reaching low polio levels, and the infection to paralysis ratio (IPR). There was longer SC when waning continued over time rather than stopping after a few years, when WPV transmissibility was higher or OPV transmissibility was lower, and when the IPR was higher. These interacted in a way that makes recent emergence of prolonged SC a possibility. As the time to reach low infection levels increased, vaccine rates needed to eliminate polio increased and a threshold was passed where prolonged low-level SC emerged. These phenomena were caused by increased contributions to the force of infection from reinfections. The resulting SC occurs at low levels that would be difficult to detect using environmental surveillance. For all waning patterns, modest levels of vaccination of adults shortened SC. Previous modeling studies may have missed these phenomena because (1) they used models with no or very short duration waning and (2) they fit models to paralytic polio case counts. Our analyses show that polio case counts cannot predict SC because nearly identical polio case count patterns can be generated by a range of waning patterns that generate different patterns of SC. We conclude that the possibility of prolonged SC is real but unquantified, that vaccinating modest fractions of adults could reduce SC risk, and that joint analysis of acute flaccid paralysis and environmental surveillance data can help assess SC risks and ensure low risks before stopping OPV.
PMCID: PMC5608688  PMID: 28283373
Polio; Transmission; Modeling; Eradication; Waning
14.  Phage therapy: An alternative to antibiotics in the age of multi-drug resistance 
The practice of phage therapy, which uses bacterial viruses (phages) to treat bacterial infections, has been around for almost a century. The universal decline in the effectiveness of antibiotics has generated renewed interest in revisiting this practice. Conventionally, phage therapy relies on the use of naturally-occurring phages to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins. Current research on the use of phages and their lytic proteins, specifically against multidrug-resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments. Antibacterial therapies, whether phage- or antibiotic-based, each have relative advantages and disadvantages; accordingly, many considerations must be taken into account when designing novel therapeutic approaches for preventing and treating bacterial infections. Although much is still unknown about the interactions between phage, bacteria, and human host, the time to take phage therapy seriously seems to be rapidly approaching.
PMCID: PMC5547374
Bacteriophage; Bacteriophage therapy; Phage; Phage therapy; Endolysin; Lysin; Multidrug resistance; Antibiotic resistance; Phage safety; Methicillin-resistant Staphylococcus aureus
15.  Loss of Humoral and Cellular Immunity to Invasive Nontyphoidal Salmonella during Current or Convalescent Plasmodium falciparum Infection in Malawian Children 
Invasive nontyphoidal Salmonella (iNTS) infections are commonly associated with Plasmodium falciparum infections, but the immunologic basis for this linkage is poorly understood. We hypothesized that P. falciparum infection compromises the humoral and cellular immunity of the host to NTS, which increases the susceptibility of the host to iNTS infection. We prospectively recruited children aged between 6 and 60 months at a Community Health Centre in Blantyre, Malawi, and allocated them to the following groups; febrile with uncomplicated malaria, febrile malaria negative, and nonfebrile malaria negative. Levels of Salmonella enterica serovar Typhimurium-specific serum bactericidal activity (SBA) and whole-blood bactericidal activity (WBBA), complement C3 deposition, and neutrophil respiratory burst activity (NRBA) were measured. Levels of SBA with respect to S. Typhimurium were reduced in febrile P. falciparum-infected children (median, −0.20 log10 [interquartile range {IQR}, −1.85, 0.32]) compared to nonfebrile malaria-negative children (median, −1.42 log10 [IQR, −2.0, −0.47], P = 0.052). In relation to SBA, C3 deposition on S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 7.5% [IQR, 4.1, 15.0]) compared to nonfebrile malaria-negative children (median, 29% [IQR, 11.8, 48.0], P = 0.048). WBBA with respect to S. Typhimurium was significantly reduced in febrile P. falciparum-infected children (median, 0.25 log10 [IQR, −0.73, 1.13], P = 0.0001) compared to nonfebrile malaria-negative children (median, −1.0 log10 [IQR, −1.68, −0.16]). In relation to WBBA, S. Typhimurium-specific NRBA was reduced in febrile P. falciparum-infected children (median, 8.8% [IQR, 3.7, 20], P = 0.0001) compared to nonfebrile malaria-negative children (median, 40.5% [IQR, 33, 65.8]). P. falciparum infection impairs humoral and cellular immunity to S. Typhimurium in children during malaria episodes, which may explain the increased risk of iNTS observed in children from settings of malaria endemicity. The mechanisms underlying humoral immunity impairment are incompletely understood and should be explored further.
PMCID: PMC5498726  PMID: 28515136
Salmonella; malaria; children; immunity; susceptibility
16.  A retrospective study of emergency department potassium disturbances: severity, treatment, and outcomes 
Disturbances in potassium (K) levels are relatively common and may be associated with significant morbidity and mortality; however, treatments vary. Our purpose was to determine the incidence, treatments, and outcomes associated with hyperkalemia and hypokalemia in emergency department (ED) patients.
We performed a structured, retrospective review of electronic medical records of consecutive adult ED patients with K measured while in the ED. Demographic, clinical, and laboratory data as well as treatments, disposition, and in-hospital complications were collected. Univariate and multivariate analyses, presented as adjusted odds ratios, were used to compare outcomes by K levels.
Of 100,260 visits in 2014, an ED K level was ordered in 48,827 (49%). A total of 1,738 patients (3.6%) were excluded because of sample hemolysis. The K was low (<3.5 mEq/L) in 5.5%, normal (3.5 to 5.0 mEq/L) in 90.9%, and elevated (>5.0 mEq/L) in 3.6% of patients. Patients with hyperkalemia were older (64 vs. 49 years, P<0.001) and more likely male (58% vs. 40%, P<0.001). Treatment for hyperkalemia varied greatly. After adjusting for confounders, both hyperkalemia and hypokalemia were associated with inpatient hospitalization and death. At least one medication was used to manage hyperkalemia in 11.5% of patients with a K of 5.1 to 5.4 mEq/L, 36.4% of those with a K 5.5 to 6 mEq/L and 77.0% of the cohort with K >6 mEq/L.
Hyperkalemia or hypokalemia occur in 1 of 11 ED patients and are associated with inpatient admission and mortality. Treatment of hyperkalemia varies greatly suggesting the need for evidence-based treatment guidelines.
PMCID: PMC5511959
Hyperkalemia; Hypokalemia; Mortality; Admission; Emergency service, hospital
17.  Protein Phosphorylation and Mineral Binding Affect the Secondary Structure of the Leucine-Rich Amelogenin Peptide 
Previously, we have shown that serine-16 phosphorylation in native full-length porcine amelogenin (P173) and the Leucine-Rich Amelogenin Peptide (LRAP(+P)), an alternative amelogenin splice product, affects protein assembly and mineralization in vitro. Notably, P173 and LRAP(+P) stabilize amorphous calcium phosphate (ACP) and inhibit hydroxyapatite (HA) formation, while non-phosphorylated counterparts (rP172, LRAP(−P)) guide the growth of ordered bundles of HA crystals. Based on these findings, we hypothesize that the phosphorylation of full-length amelogenin and LRAP induces conformational changes that critically affect its capacity to interact with forming calcium phosphate mineral phases. To test this hypothesis, we have utilized Fourier transform infrared spectroscopy (FTIR) to determine the secondary structure of LRAP(−P) and LRAP(+P) in the absence/presence of calcium and selected mineral phases relevant to amelogenesis; i.e., hydroxyapatite (HA: an enamel crystal prototype) and (ACP: an enamel crystal precursor phase). Aqueous solutions of LRAP(−P) or LRAP(+P) were prepared with or without 7.5 mM of CaCl2 at pH 7.4. FTIR spectra of each solution were obtained using attenuated total reflectance, and amide-I peaks were analyzed to provide secondary structure information. Secondary structures of LRAP(+P) and LRAP(−P) were similarly assessed following incubation with suspensions of HA and pyrophosphate-stabilized ACP. Amide I spectra of LRAP(−P) and LRAP(+P) were found to be distinct from each other in all cases. Spectra analyses showed that LRAP(−P) is comprised mostly of random coil and β-sheet, while LRAP(+P) exhibits more β-sheet and α-helix with little random coil. With added Ca, the random coil content increased in LRAP(−P), while LRAP(+P) exhibited a decrease in α-helix components. Incubation of LRAP(−P) with HA or ACP resulted in comparable increases in β-sheet structure. Notably, however, LRAP(+P) secondary structure was more affected by ACP, primarily showing an increase in β-sheet structure, compared to that observed with added HA. These collective findings indicate that phosphorylation induces unique secondary structural changes that may enhance the functional capacity of native phosphorylated amelogenins like LRAP to stabilize an ACP precursor phase during early stages of enamel mineral formation.
PMCID: PMC5489624  PMID: 28706493
amelogenesis; amelogenin; leucine-rich amelogenin peptide; secondary structure; FTIR; tooth enamel
18.  Genetic Determinants of the Pharmacokinetic Variability of Rifampin in Malawian Adults with Pulmonary Tuberculosis 
Variable exposure to antituberculosis (TB) drugs, partially driven by genetic factors, may be associated with poor clinical outcomes. Previous studies have suggested an influence of the SLCO1B1 locus on the plasma area under the concentration-time curve (AUC) of rifampin. We evaluated the contribution of single nucleotide polymorphisms (SNPs) in SLCO1B1 and other candidate genes (AADAC and CES-1) to interindividual pharmacokinetic variability in Malawi. A total of 174 adults with pulmonary TB underwent sampling of plasma rifampin concentrations at 2 and 6 h postdose. Data from a prior cohort of 47 intensively sampled, similar patients from the same setting were available to support population pharmacokinetic model development in NONMEM v7.2, using a two-stage strategy to improve information during the absorption phase. In contrast to recent studies in South Africa and Uganda, SNPs in SLCO1B1 did not explain variability in AUC0–∞ of rifampin. No pharmacokinetic associations were identified with AADAC or CES-1 SNPs, which were rare in the Malawian population. Pharmacogenetic determinants of rifampin exposure may vary between African populations. SLCO1B1 and other novel candidate genes, as well as nongenetic sources of interindividual variability, should be further explored in geographically diverse, adequately powered cohorts.
PMCID: PMC5487625  PMID: 28461315
tuberculosis; pharmacokinetics; single nucleotide polymorphism; SLCO1B1; AADAC; CES-1
19.  Local Failure in Parameningeal Rhabdomyosarcoma Correlates With Poor Response to Induction Chemotherapy 
Local control remains a challenge in pediatric parameningeal rhabdomyosarcoma (PM-RMS), and survival after local failure (LF) is poor. Identifying patients with a high risk of LF is of great interest to clinicians. In this study, we examined whether tumor response to induction chemotherapy (CT) could predict LF in embryonal PM-RMS.
We identified 24 patients with embryonal PM-RMS, age 2 to 18 years, with complete magnetic resonance imaging and gross residual disease after surgical resection. All patients received proton radiation therapy (RT), median dose 50.4 GyRBE (50.4-55.8 GyRBE). Tumor size was measured before initial CT and before RT.
With a median follow-up time of 4.1 years for survivors, LF was seen in 9 patients (37.5%). The median time from the initiation of CT to the start of RT was 4.8 weeks. Patients with LF had a similar initial (pre-CT) tumor volume compared with patients with local controlled (LC) (54 cm3 vs 43 cm3, P=.9) but a greater median volume before RT (pre-RT) (40 cm3 vs 7 cm3, P=.009) and a smaller median relative percent volume reduction (RPVR) in tumor size (0.4% vs 78%, P<.001). Older age (P=.05), larger pre-RT tumor volume (P=.03), and smaller RPVR (P=.003) were significantly associated with actuarial LF on univariate Cox analysis.
Poor response to induction CT appears to be associated with an increased risk of LF in pediatric embryonal PM-RMS.
PMCID: PMC5479480  PMID: 25864172
22.  Thematic analysis of barriers and facilitators to implementation of neonatal resuscitation guideline changes 
To evaluate experiences regarding implementation of Neonatal Resuscitation Program (NRP) guideline changes in the context of a collaborative quality improvement (QI) project.
Focus groups were conducted with local QI leaders and providers from 9 sites that participated in a QI collaborative. Thematic analysis identified facilitators and barriers to implementation of NRP guideline changes and quality improvement in general.
Facilitators for QI included comparative process measurement and data tracking. Barriers to QI were shifting priorities and aspects of the project that seemed inefficient. Specific to NRP, implementation strategies that worked involved rapid feedback, and education on rationale for change. Changes that interrupted traditional workflow proved challenging to implement. Limited resources and perceptions of increased workload were also barriers to implementation.
Collaborative QI methods are generally well accepted, particularly data tracking, sharing experience, and education. Strategies to increase efficiency and manage workload may facilitate improved staff attitudes toward change.
PMCID: PMC5334207  PMID: 27906192
quality improvement; Neonatal Resuscitation Program; implementation science; barriers and facilitators
23.  Challenges of stroke management in resource-limited settings: A case-based reflection 
Malawi Medical Journal  2017;29(2):189-193.
A 19-year-old man presented with a 1-year history of headache, generalised body weakness, progressive memory loss, and disorientation. One month prior to admission, there was aggravation of the weakness of the right upper limb, with new-onset difficulty with mastication, speech impairment, apathy, and urinary incontinence. On clinical examination, the patient had a motor aphasia and a right-sided hemiparesis with increased muscle tone and hyperreflexia. A noncontrast computed tomography (CT) scan of the brain revealed large ischaemic strokes extending beyond the classical vascular territories. Cerebrospinal fluid analysis showed a mildly increased protein level. The electrocardiogram revealed an irregular sinus bradycardia. The remainder of the cardiovascular and laboratory workup was unremarkable. Considering a working diagnosis of central nervous system vasculitis, the patient was treated with aspirin, prednisolone, and physiotherapy. However, he died suddenly a few weeks later. Based on this case, we discuss the challenges of stroke management in resource-limited settings, provide practical tips for general practitioners, reflect on the potential avenues for short- and long-term action, and introduce the budding collaboration platform between the University College London, the University of Liverpool, the Queen Elizabeth Central Hospital, and the Malawi-Liverpool-Wellcome Trust Clinical Research Programme.
PMCID: PMC5610294
24.  Chest Radiograph Findings in Childhood Pneumonia Cases From the Multisite PERCH Study 
In the Pneumonia Etiology Research for Child Health study, abnormal chest radiographs (CXRs) in cases were associated with hypoxemia, crackles, tachypnea, and fever. Overall, 54% of CXRs were abnormal (site range, 35%–64%). Consolidation on CXR was associated with an increased risk of mortality.
Chest radiographs (CXRs) are frequently used to assess pneumonia cases. Variations in CXR appearances between epidemiological settings and their correlation with clinical signs are not well documented.
The Pneumonia Etiology Research for Child Health project enrolled 4232 cases of hospitalized World Health Organization (WHO)–defined severe and very severe pneumonia from 9 sites in 7 countries (Bangladesh, the Gambia, Kenya, Mali, South Africa, Thailand, and Zambia). At admission, each case underwent a standardized assessment of clinical signs and pneumonia risk factors by trained health personnel, and a CXR was taken that was interpreted using the standardized WHO methodology. CXRs were categorized as abnormal (consolidation and/or other infiltrate), normal, or uninterpretable.
CXRs were interpretable in 3587 (85%) cases, of which 1935 (54%) were abnormal (site range, 35%–64%). Cases with abnormal CXRs were more likely than those with normal CXRs to have hypoxemia (45% vs 26%), crackles (69% vs 62%), tachypnea (85% vs 80%), or fever (20% vs 16%) and less likely to have wheeze (30% vs 38%; all P < .05). CXR consolidation was associated with a higher case fatality ratio at 30-day follow-up (13.5%) compared to other infiltrate (4.7%) or normal (4.9%) CXRs.
Clinically diagnosed pneumonia cases with abnormal CXRs were more likely to have signs typically associated with pneumonia. However, CXR-normal cases were common, and clinical signs considered indicative of pneumonia were present in substantial proportions of these cases. CXR-consolidation cases represent a group with an increased likelihood of death at 30 days post-discharge.
PMCID: PMC5447837
chest radiograph; pneumonia; pediatrics; signs and symptoms; mortality; .
25.  Detection of Pneumococcal DNA in Blood by Polymerase Chain Reaction for Diagnosing Pneumococcal Pneumonia in Young Children From Low- and Middle-Income Countries 
We investigated the performance of polymerase chain reaction (PCR) on blood in the diagnosis of pneumococcal pneumonia among children from 7 low- and middle-income countries.
We tested blood by PCR for the pneumococcal autolysin gene in children aged 1–59 months in the Pneumonia Etiology Research for Child Health (PERCH) study. Children had World Health Organization–defined severe or very severe pneumonia or were age-frequency–matched community controls. Additionally, we tested blood from general pediatric admissions in Kilifi, Kenya, a PERCH site. The proportion PCR-positive was compared among cases with microbiologically confirmed pneumococcal pneumonia (MCPP), cases without a confirmed bacterial infection (nonconfirmed), cases confirmed for nonpneumococcal bacteria, and controls.
In PERCH, 7.3% (n = 291/3995) of cases and 5.5% (n = 273/4987) of controls were blood pneumococcal PCR-positive (P < .001), compared with 64.3% (n = 36/56) of MCPP cases and 6.3% (n = 243/3832) of nonconfirmed cases (P < .001). Blood pneumococcal PCR positivity was higher in children from the 5 African countries (5.5%–11.5% among cases and 5.3%–10.2% among controls) than from the 2 Asian countries (1.3% and 1.0% among cases and 0.8% and 0.8% among controls). Among Kilifi general pediatric admissions, 3.9% (n = 274/6968) were PCR-positive, including 61.7% (n = 37/60) of those with positive blood cultures for pneumococcus.
The utility of pneumococcal PCR on blood for diagnosing childhood pneumococcal pneumonia in the 7 low- and middle-income countries studied is limited by poor specificity and by poor sensitivity among MCPP cases.
PMCID: PMC5447841
pneumonia; pneumococcus; PCR; blood; diagnosis.

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