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Summary: There is a close cross‐talk between complement, Toll‐like receptors (TLRs) and coagulation. The role of the central complement component 5 (C5) in physiological and pathophysiological hemostasis has not, however, been fully elucidated. This study examined the effects of C5 in normal hemostasis and in Escherichia coli‐induced coagulation and tissue factor (TF) up‐regulation. Fresh whole blood obtained from six healthy donors and one C5‐deficient individual (C5D) was anti‐coagulated with the thrombin inhibitor lepirudin. Blood was incubated with or without E. coli in the presence of the C5 inhibitor eculizumab, a blocking anti‐CD14 monoclonal antibody (anti‐CD14) or the TLR‐4 inhibitor eritoran. C5D blood was reconstituted with purified human C5. TF mRNA was measured by quantitative polymerase chain reaction (qPCR) and monocyte TF and CD11b surface expression by flow cytometry. Prothrombin fragment 1+2 (PTF1·2) in plasma and microparticles exposing TF (TF‐MP) was measured by enzyme‐linked immunosorbent assay (ELISA). Coagulation kinetics were analyzed by rotational thromboelastometry and platelet function by PFA‐200. Normal blood with eculizumab as well as C5D blood with or without reconstitution with C5 displayed completely normal biochemical hemostatic patterns. In contrast, E. coli‐induced TF mRNA and TF‐MP were significantly reduced by C5 inhibition. C5 inhibition combined with anti‐CD14 or eritoran completely inhibited the E. coli‐induced monocyte TF, TF‐MP and plasma PTF1·2. Addition of C5a alone did not induce TF expression on monocytes. In conclusion, C5 showed no impact on physiological hemostasis, but substantially contributed to E. coli‐induced procoagulant events, which were abolished by the combined inhibition of C5 and CD14 or TLR‐4. Effect of eculizumab, anti‐CD14 or the TLR‐4 inhibitor eritoran on Escherichia coli (E. coli)‐induced monocyte tissue factor (TF) surface expression (a), tissue factor function in plasma microparticles (TF‐MP) (b) and prothrombin fragment 1+2 (PTF1·2) levels in plasma (c). Inhibition of C5 using eculizumab reduced the E. coli‐induced TF‐MP level. C5 inhibition combined with anti‐CD14 or eritoran completely inhibited the E. coli‐induced monocyte TF, TF‐MP and plasma PTF1·2. [ABSTRACT FROM AUTHOR]

The Cagayan basin of Northern Luzon, an interare basin 250 km long and 80 km wide, contains a 900 m thick sequence of Plio-Pleistocene fluvial and pyroclastic deposits. These deposits are divided into two formations, the Ilagan and Awidon Mesas and three lithofacies associations. The fades, which are interpreted as meandering stream, braided stream, lahar, and pyroclastic flow and fall deposits, occur in coarsening upward sequence. Meandering stream deposits interbedded with tuffs are overlain by braided stream deposits interbedded with coarser pyroclastic deposits. lahars and ignimbrites. The coarsening upward volcaniclastic deposits reflect the tectonic and volcanic evolution of the adjacent Cordillera Central volcanic are. Uplift of the are resulted in the progradation of coarser clastics further into the basin, the development of an alluvial fan, and migration of the basin depocentre away from the arc. The coarsening of the pyroclastic deposits reflects the development of a more proximal calc-alkaline volcanic belt in the maturing volcanic arc. The Cagayan basin sediments serve as an example of the type and sequence of non marine volcaniclastic sediments that may form in other interare basins. This is because the tectonic and volcanic processes which controled sedimentation in the Cagayan basin also affect other are systems and will therefore control or significantly influence volcaniclastic sedimentation in other interare basins. [ABSTRACT FROM AUTHOR]

Abstract Background The term non-specific chest pain (NSCP) is applied to hospitalized patients in order to designate that they neither have an acute coronary syndrome (ACS) nor display evidence of a coronary ischemia. The number of NSCP patients is increasing and comprehensive guidelines specifying their optimal management have not yet been introduced. The objective of this review was to explore the prevalence and prognosis of NSCP versus ACS among patients recruited in consecutive series hospitalized for chest pain suspected to be ACS. Methods This is a systematic literature search where three databases were searched from 1990 to 14 November 2011. In addition, one database was searched for Epub ahead of print per 24 March 2012. Three inclusion criteria were applied: 1. documentation of an unselected consecutive series of patients admitted for chest pain, where this review is based upon two groups of patients defined as follows: a) 'ACS/high-risk' and b) NSCP; 2. at least 100 cases with NSCP; and 3. follow-up of hospital readmissions and mortality for at least six months. Results A total of 2,204 citations were screened after removal of duplicates. Out of 80 full text articles assessed for eligibility 12 studies were included, comprising 24,829 patients (inter-study range 250 to 13,762), with 11,008 (44%) categorized as NSCP and 13,821 (56%) as 'ACS/high-risk'. The mean one-year total mortality rate among patients with NSCP in nine studies was 3.2% (inter-study range 1.4% to 8.1%), with the highest mortality among patients with pre-existing coronary heart disease (CHD). The mean one-year mortality rate among 'ACS/high-risk' patients was 18.0% (inter-study range 14.0% to 19.9%) in four studies with available data. In six studies the mean one-year readmission rate for patients with NSCP was 17.5% (inter-study range 2.5% to 40%). Conclusions Patients with NSCP represent a large, heterogeneous and important group. Due to co-existing CHD in nearly 40% of these patients, their prognosis is not necessarily benign. Although their average one-year mortality rate was almost six times lower than those with 'ACS/high-risk', the subset with concomitant CHD had a relatively poor prognosis when compared with NSCP patients without evidence of CHD.

Abstract Background Smokers have been shown to have lower mortality after acute coronary syndrome than non-smokers. This has been attributed to the younger age, lower co-morbidity, more aggressive treatment and lower risk profile of the smoker. Some studies, however, have used multivariate analyses to show a residual survival benefit for smokers; that is, the "smoker's paradox". The aim of this study was, therefore, to perform a systematic review of the literature and evidence surrounding the existence of the "smoker's paradox". Methods Relevant studies published by September 2010 were identified through literature searches using EMBASE (from 1980), MEDLINE (from 1963) and the Cochrane Central Register of Controlled Trials, with a combination of text words and subject headings used. English-language original articles were included if they presented data on hospitalised patients with defined acute coronary syndrome, reported at least in-hospital mortality, had a clear definition of smoking status (including ex-smokers), presented crude and adjusted mortality data with effect estimates, and had a study sample of > 100 smokers and > 100 non-smokers. Two investigators independently reviewed all titles and abstracts in order to identify potentially relevant articles, with any discrepancies resolved by repeated review and discussion. Results A total of 978 citations were identified, with 18 citations from 17 studies included thereafter. Six studies (one observational study, three registries and two randomised controlled trials on thrombolytic treatment) observed a "smoker's paradox". Between the 1980s and 1990s these studies enrolled patients with acute myocardial infarction (AMI) according to criteria similar to the World Health Organisation criteria from 1979. Among the remaining 11 studies not supporting the existence of the paradox, five studies represented patients undergoing contemporary management. Conclusion The "smoker's paradox" was observed in some studies of AMI patients in the pre-thrombolytic and thrombolytic era, whereas no studies of a contemporary population with acute coronary syndrome have found evidence for such a paradox.

Abstract Background Pneumonia is among the main causes of illness and death in children Methods From July 2004 to June 2007, we examined nasopharyngeal aspirates (NPA) from 2,230 cases of pneumonia (World Health Organization criteria) in children 2 to 35 months old recruited in a randomized trial of zinc supplementation at a field clinic in Bhaktapur, Nepal. The specimens were examined for respiratory syncytial virus (RSV), influenza virus type A (InfA) and B (InfB), parainfluenza virus types 1, 2 and 3 (PIV1, PIV2, and PIV3), and human metapneumovirus (hMPV) using a multiplex reverse transcriptase polymerase chain reaction (PCR) assay. Results We identified 919 virus isolates in 887 (40.0%) of the 2,219 NPA specimens with a valid PCR result, of which 334 (15.1%) yielded RSV, 164 (7.4%) InfA, 129 (5.8%) PIV3, 98 (4.4%) PIV1, 93 (4.2%) hMPV, 84 (3.8%) InfB, and 17 (0.8%) PIV2. CAP occurred in an epidemic pattern with substantial temporal variation during the three years of study. The largest peaks of pneumonia occurrence coincided with peaks of RSV infection, which occurred in epidemics during the rainy season and in winter. The monthly number of RSV infections was positively correlated with relative humidity (rs = 0.40, P = 0.01), but not with temperature or rainfall. An hMPV epidemic occurred during one of the three winter seasons and the monthly number of hMPV cases was also associated with relative humidity (rs = 0.55, P = 0.0005). Conclusion Respiratory RNA viruses were detected from NPA in 40% of CAP cases in our study. The most commonly isolated viruses were RSV, InfA, and PIV3. RSV infections contributed substantially to the observed CAP epidemics. The occurrence of viral CAP in this community seemed to reflect more or less overlapping micro-epidemics with several respiratory viruses, highlighting the challenges of developing and implementing effective public health control measures.

Background: Cancer-related fatigue is a common and distressing late effect of cancer that can persist for decades after treatment completion. Although negatively affecting survivors' quality of life, few, if any, efficacious interventions for persistent, or chronic, fatigue exist., Aims: To inform future interventions, we explored how long-term, young adult cancer survivors (YACSs) with chronic fatigue live with, and manage their fatigue over time, including their experiences with nonpharmacological interventions (NPIs) for chronic fatigue., Methods and Results: We conducted a qualitative focus group study with 15 YACSs (13 women) with chronic fatigue, on average 7.3 years post-diagnosis. The YACS were identified and recruited through a nationwide health survey of cancer survivors (the NOR-CAYACS study). Systematic content analysis was used to identify recurrent themes. Analysis revealed five themes: (1) manifestation of fatigue, detailing chronic fatigue experiences; (2) impact on daily life, highlighting the necessity to balance rest and activity, affecting relationships; (3) NPIs, where walks in nature were notably beneficial; (4) barriers to fatigue management, including energy deficits, treatment-related bodily changes, and self-care prioritization challenges; (5) facilitators to fatigue management, emphasizing the need for regular breaks, self-care practices, and the importance of fatigue management education., Conclusion: This study offers novel insights into the lived experiences of YACSs with chronic fatigue, a subject scarcely examined in prior research. Our findings highlight the significant impact of chronic fatigue and the individualized strategies YACSs use to cope. The research emphasizes the need for personalized interventions to support chronic fatigue management, marking a critical step forward in addressing this often-overlooked issue in survivorship care. Future research should focus on tailored approaches to improve YACSs' quality of life., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Although comprehensive biomarker testing is recommended for all patients with advanced/metastatic non-small cell lung cancer (NSCLC) before initiation of first-line treatment, tissue availability can limit testing. Genomic testing in liquid biopsies can be utilized to overcome the inherent limitations of tissue sampling and identify the most appropriate biomarker-informed treatment option for patients. The Blood First Assay Screening Trial is a global, open-label, multicohort trial that evaluates the efficacy and safety of multiple therapies in patients with advanced/metastatic NSCLC and targetable alterations identified by liquid biopsy. We present data from Cohort D (ROS1-positive). Patients ≥18 years of age with stage IIIB/IV, ROS1-positive NSCLC detected by liquid biopsies received entrectinib 600 mg daily. At data cutoff (November 2021), 55 patients were enrolled and 54 had measurable disease. Cohort D met its primary endpoint: the confirmed objective response rate (ORR) by investigator was 81.5%, which was consistent with the ORR from the integrated analysis of entrectinib (investigator-assessed ORR, 73.4%; data cutoff May 2019, ≥12 months of follow-up). The safety profile of entrectinib was consistent with previous reports. These results demonstrate consistency with those from the integrated analysis of entrectinib in patients with ROS1-positive NSCLC identified by tissue-based testing, and support the clinical value of liquid biopsies to inform clinical decision-making. The integration of liquid biopsies into clinical practice provides patients with a less invasive diagnostic method than tissue-based testing and has faster turnaround times that may expedite the reaching of clinical decisions in the advanced/metastatic NSCLC setting. ClinicalTrials.gov registration: NCT03178552 ., (© 2024. The Author(s).)

Zinc is essential for several biological processes including those critical for the immune system, DNA synthesis, cell division, and growth. Zinc is involved in the pathophysiology of chronic diseases and protects proteins and lipids from oxidative damage. Inadequate zinc intake and low plasma zinc concentration are associated to an increased risk of chronic diseases such as cardiovascular diseases and type 2 diabetes; however, the evidence is limited. Zinc deficiency increases the risk of infections and poor growth and may contribute to the high burden of infectious diseases and stunting in children living in low- and middle-income countries. The risk of zinc deficiency in the populations of the Nordic and Baltic countries is low., Competing Interests: The authors have not received any funding or benefits from industry or elsewhere to conduct this study., (© 2023 Tor A. Strand and Maria Mathisen.)

Respiratory viruses cause a substantial proportion of respiratory tract infections in children but are underrecognized as a cause of severe pneumonia hospitalization in low-income settings. We employed 22 real-time PCR assays and retrospectively reanalyzed 610 nasopharyngeal aspirate specimens from children aged 2 to 35 months with severe pneumonia (WHO definition) admitted to Kanti Childrens' Hospital in Kathmandu, Nepal, from January 2006 through June 2008. Previously, ≥1 of 7 viruses had been detected by multiplex reverse transcription-PCR in 30% (188/627) of cases. Reanalyzing the stored specimens, we detected ≥1 pathogens, including 18 respiratory viruses and 3 atypical bacteria, in 98.7% (602/610) of cases. Rhinovirus (RV) and respiratory syncytial virus (RSV) were the most common, detected in 318 (52.1%) and 299 (49%) cases, respectively, followed by adenovirus (AdV) (10.6%), human metapneumovirus (hMPV) (9.7%), parainfluenza virus type 3 (8.4%), and enterovirus (7.7%). The remaining pathogens were each detected in less than 5%. Mycoplasma pneumoniae was most common among the atypical bacteria (3.7%). Codetections were observed in 53.3% of cases. Single-virus detection was more common for hMPV (46%) and RSV (41%) than for RV (22%) and AdV (6%). The mean cycle threshold value for detection of each pathogen tended to be lower in single-pathogen detections than in codetections. This finding was significant for RSV, RV, and AdV. RSV outbreaks occurred at the end of the monsoon or during winter. An expanded diagnostic PCR panel substantially increased the detection of respiratory viruses in young Nepalese children hospitalized with severe pneumonia. IMPORTANCE Respiratory viruses are an important cause of respiratory tract infections in children but are underrecognized as a cause of pneumonia hospitalization in low-income settings. Previously, we detected at least one of seven respiratory viruses by PCR in 30% of young Nepalese children hospitalized with severe pneumonia over a period of 36 months. Using updated PCR assays detecting 21 different viruses and atypical bacteria, we reanalyzed 610 stored upper-respiratory specimens from these children. Respiratory viruses were detected in nearly all children hospitalized for pneumonia. RSV and rhinovirus were the predominant pathogens detected. Detection of two or more pathogens was observed in more than 50% of the pneumonia cases. Single-virus detection was more common for human metapneumovirus and RSV than for rhinovirus and adenovirus. The concentration of virus was higher (low cycle threshold [ C T ] value) for single detected pathogens, hinting at a high viral load as a marker of clinical significance.

Background: Human parainfluenza virus (hPIV) is a common virus in childhood acute lower respiratory infections (ALRI). However, no estimates have been made to quantify the global burden of hPIV in childhood ALRI. We aimed to estimate the global and regional hPIV-associated and hPIV-attributable ALRI incidence, hospital admissions, and mortality for children younger than 5 years and stratified by 0-5 months, 6-11 months, and 12-59 months of age., Methods: We did a systematic review of hPIV-associated ALRI burden studies published between Jan 1, 1995, and Dec 31, 2020, found in MEDLINE, Embase, Global Health, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Global Health Library, three Chinese databases, and Google search, and also identified a further 41 high-quality unpublished studies through an international research network. We included studies reporting community incidence of ALRI with laboratory-confirmed hPIV; hospital admission rates of ALRI or ALRI with hypoxaemia in children with laboratory-confirmed hPIV; proportions of patients with ALRI admitted to hospital with laboratory-confirmed hPIV; or in-hospital case-fatality ratios (hCFRs) of ALRI with laboratory-confirmed hPIV. We used a modified Newcastle-Ottawa Scale to assess risk of bias. We analysed incidence, hospital admission rates, and hCFRs of hPIV-associated ALRI using a generalised linear mixed model. Adjustment was made to account for the non-detection of hPIV-4. We estimated hPIV-associated ALRI cases, hospital admissions, and in-hospital deaths using adjusted incidence, hospital admission rates, and hCFRs. We estimated the overall hPIV-associated ALRI mortality (both in-hospital and out-hospital mortality) on the basis of the number of in-hospital deaths and care-seeking for child pneumonia. We estimated hPIV-attributable ALRI burden by accounting for attributable fractions for hPIV in laboratory-confirmed hPIV cases and deaths. Sensitivity analyses were done to validate the estimates of overall hPIV-associated ALRI mortality and hPIV-attributable ALRI mortality. The systematic review protocol was registered on PROSPERO (CRD42019148570)., Findings: 203 studies were identified, including 162 hPIV-associated ALRI burden studies and a further 41 high-quality unpublished studies. Globally in 2018, an estimated 18·8 million (uncertainty range 12·8-28·9) ALRI cases, 725 000 (433 000-1 260 000) ALRI hospital admissions, and 34 400 (16 400-73 800) ALRI deaths were attributable to hPIVs among children younger than 5 years. The age-stratified and region-stratified analyses suggested that about 61% (35% for infants aged 0-5 months and 26% for 6-11 months) of the hospital admissions and 66% (42% for infants aged 0-5 months and 24% for 6-11 months) of the in-hospital deaths were in infants, and 70% of the in-hospital deaths were in low-income and lower-middle-income countries. Between 73% and 100% (varying by outcome) of the data had a low risk in study design; the proportion was 46-65% for the adjustment for health-care use, 59-77% for patient groups excluded, 54-93% for case definition, 42-93% for sampling strategy, and 67-77% for test methods. Heterogeneity in estimates was found between studies for each outcome., Interpretation: We report the first global burden estimates of hPIV-associated and hPIV-attributable ALRI in young children. Globally, approximately 13% of ALRI cases, 4-14% of ALRI hospital admissions, and 4% of childhood ALRI mortality were attributable to hPIV. These numbers indicate a potentially notable burden of hPIV in ALRI morbidity and mortality in young children. These estimates should encourage and inform investment to accelerate the development of targeted interventions., Funding: Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests YL reports grants from WHO outside the submitted work. MD-K reports grants from Merck and Pfizer, and personal fees from Merck outside the submitted work. SAM reports grants from the Bill & Melinda Gates Foundation, GlaxoSmithKline, Minervax, and Pfizer; and personal fees from the Bill & Melinda Gates Foundation outside the submitted work. CC reports grants from PATH, Sanofi Pasteur, and the US Centers for Disease Control and Prevention; and non-financial support (funds to travel to meeting) from Parexel during the conduct of the study. SRCH reports grants from Bill & Melinda Gates Foundation during the conduct of the study. HO reports grants from the Japan Agency for Medical Research and Development during the conduct of the study. EAFS reports grants, personal fees, and non-financial support (travel to Investigator meetings and to consultation meetings) from AstraZeneca, Merck, Pfizer, Regeneron, and Roche; personal fees from AbbVie, Alere, and Cidara; non-financial support (travel to meetings) from AbbVie and Novavax; other support fees for being on data and safety monitoring board from AbbVie and GlaxoSmithKline; and grants from Johnson and Johnson and Novavax, outside the submitted work. JAGS reports grants from the Bill & Melinda Gates Foundation, Gavi, The Vaccine Alliance, the UK Medical Research Council, the UK National Institute for Health Research, and the Wellcome Trust, outside the submitted work. L-MY reports grants from Japan Initiative for Global Research Network on Infectious Diseases and Agency for Medical Research and Development during the conduct of the study. HJZ reports grants from the Bill & Melinda Gates Foundation, the South Africa Medical Research Council, and the South Africa National Research Foundation, outside the submitted work. HC reports grants from the Bill & Melinda Gates Foundation, Johns Hopkins University, Sanofi, and WHO; and personal fees from the Bill & Melinda Gates Foundation, Johns Hopkins University, Sanofi, and WHO, during the conduct of the study. HN reports grants from the Bill & Melinda Gates Foundation and personal fees from the Bill & Melinda Gates Foundation during the conduct of the study; and grants from the Foundation for Influenza Epidemiology, Innovative Medicines Initiative, Sanofi, UK National Institute for Health Research, and WHO, and personal fees from AbbVie, Foundation for Influenza Epidemiology, Janssen, Reviral, and Sanofi, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady-state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open-label, fixed-sequence study. Patients with BRAF V600 mutation-positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed-effects analysis of variance model was used to compare log-transformed area under the concentration-time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady-state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121-161) for both maximum plasma concentration and area under the concentration-time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated., (© 2020, The American College of Clinical Pharmacology.)

Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are last therapeutic resorts in patients with familial hypercholesterolemia (FH). We explored changes in lipoprotein subclasses and high-density lipoprotein (HDL) function when changing treatment from lipoprotein apheresis to PCSK9 inhibition. We measured the levels of low-density lipoprotein (LDL) and HDL particle subclasses, serum amyloid A1 (SAA1), paraoxonase-1 (PON1) activity and cholesterol efflux capacity (CEC) in three heterozygous FH patients. Concentrations of all LDL particle subclasses were reduced during apheresis (large 68.0 ± 17.5 to 16.3 ± 2.1 mg/dL, (p = 0.03), intermediate 38.3 ± 0.6 to 5.0 ± 3.5 mg/dL (p = 0.004) and small 5.0 ± 2.6 to 0.2 ± 0.1 mg/dL (p = 0.08)). There were non-significant reductions in the LDL subclasses during evolocumab treatment. There were non-significant reductions in subclasses of HDL particles during apheresis, and no changes during evolocumab treatment. CEC was unchanged throughout the study, while the SAA1/PON1 ratio was unchanged during apheresis but decreased during evolocumab treatment. In conclusion, there were significant reductions in large and intermediate size LDL particles during apheresis, and a non-significant reduction in small LDL particles. There were only non-significant reductions in the LDL subclasses during evolocumab treatment., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Globally, solid fuels are used by about 3 billion people for cooking and a smaller number use kerosene. These fuels have been associated with acute lower respiratory infection (ALRI) in children. Previous work in Bhaktapur, Nepal, showed comparable relationships of biomass and kerosene cooking fuels with ALRI in young children, compared to those using electricity for cooking. We examine the relationship of kitchen PM 2.5 concentrations to ALRI in those households., Methods: ALRI cases and age-matched controls were enrolled from a cohort of children 2-35 months old. 24-h PM 2.5 was measured once in each participant's kitchen. The main analysis was carried out with conditional logistic regression, with PM 2.5 measures specified both continuously and as quartiles., Results: In the kitchens of 393 cases and 431 controls, quartiles of increasing PM 2.5 concentration were associated with a monotonic increase in odds ratios (OR): 1.51 (95% CI: 1.00, 2.27), 2.22 (1.47, 3.34), 2.48 (1.63, 3.77), for the 3 highest exposure quartiles. The general kitchen concentration-response shape across all stoves was supralinear. There was evidence for increased risk with biomass stoves, but the slope for kerosene stoves was steeper, the highest quartile OR being 5.36 (1.35, 21.3). Evidence for increased risk was also found for gas stoves., Conclusion: Results support previous reports that biomass and kerosene cooking fuels are both ALRI risk factors, but suggests that PM 2.5 from kerosene is more potent on a unit mass basis. Further studies with larger sample sizes and preferably using electricity as the baseline fuel are needed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Bariatric surgery has been shown to reduce cardiovascular events and cause-specific mortality for coronary artery disease in obese patients. Lipoprotein biomarkers relating to low-density lipoprotein (LDL), high-density lipoprotein (HDL), their subfractions, and macrophage cholesterol efflux have all been hypothesized to be of value in cardiovascular risk assessment., Objectives: The objective of this study was to examine the effect of a lifestyle intervention followed by bariatric surgery on the lipid profile of morbidly obese patients., Methods: Thirty-four morbidly obese patients were evaluated before and after lifestyle changes and then 1 year after bariatric surgery. They were compared with 17 lean subjects. Several lipoprotein metrics, serum amyloid A (SAA), serum paraoxonase-1 (PON1), and macrophage cholesterol efflux capacity (CEC) were assessed., Results: Average weight loss after the lifestyle intervention was 10.5% and 1 year after bariatric surgery was 33.9%. The lifestyle intervention significantly decreased triglycerides (TGs; -28.7 mg/dL, P < .05), LDL cholesterol (LDL-C; -32.3 mg/dL, P < .0001), and apolipoprotein B (apoB; -62.9 μg/mL, P < .001). Bariatric surgery further reduced TGs (-36.7 mg/dL, P < .05), increased HDL cholesterol (+12 mg/dL, P < .0001), and reductions in LDL-C and apoB were sustained. Bariatric surgery reduced large, buoyant LDL (P < .0001), but had no effect on the small, dense LDL. The large HDL subfractions increased (P < .0001), but there was no effect on the smaller HDL subfractions. The ratio for SAA/PON1 was reduced after the lifestyle intervention (P < .01) and further reduced after bariatric surgery (P < .0001). Neither the lifestyle intervention nor bariatric surgery had any effect on CEC., Conclusions: Lifestyle intervention followed by bariatric surgery in 34 morbidly obese patients showed favorable effects on TGs, LDL-C, and apoB. HDL cholesterol and apoA1 was increased, apoB/apoA1 ratio as well as SAA/PON1 ratio reduced, but bariatric surgery did not influence CEC., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

BackgroundThere is no consensus on optimal Vitamin D status. The objective of this study was to estimate the extent to which vitamin D status predicts illness duration and treatment failure in children with severe pneumonia by using different cutoffs for vitamin D concentration.MethodsWe measured the plasma concentration of 25(OH)D in 568 children hospitalized with World Health Organization-defined severe pneumonia. The associations between vitamin D status, using the most frequently used cutoffs for vitamin D insufficiency (25(OH)D<50 and <75 nmol/l), and risk for treatment failure and time until recovery were analyzed in multiple logistic regression and Cox proportional hazards models, respectively.ResultsOf the 568 children, 322 (56.7%) had plasma 25(OH)D levels ≥75 nmol/l, 179 (31.5%) had levels of 50-74.9 nmol/l, and 67 (%) had levels <50 nmol/l. Plasma 25(OH)D <50 nmol/l was associated with increased risk for treatment failure and longer time until recovery.ConclusionOur findings indicate that low vitamin D status (25(OH)D<50 nmol/l) is an independent risk factor for treatment failure and delayed recovery from severe lower respiratory infections in children.

Poor vitamin D status has been associated with increased risk and severity of respiratory tract infections. Whether or not inflammation and infection affects 25-hydroxy vitamin D (25(OH)D) concentration is controversial and is important in the interpretation of observational studies using plasma-25(OH)D as a biomarker for status. Our objectives were to measure whether 25(OH)D concentration was altered by an episode of acute lower respiratory tract infection and whether markers of inflammation predicted the 25(OH)D concentration. Children aged 2-35 months with severe ( n = 43) and non-severe ( n = 387) community-acquired, WHO-defined pneumonia were included. 25(OH)D concentration and inflammatory markers (cytokines, chemokines, and growth factors) were measured in plasma during the acute phase and 14, 45, and 90 days later. Predictors for 25(OH)D concentrations were identified in multiple linear regression models. Mean 25(OH)D concentration during the acute phase and after recovery (14, 45, and 90 days) was 84.4 nmol/L ± 33.6, and 80.6 ± 35.4, respectively. None of the inflammatory markers predicted 25(OH)D concentration in the multiple regression models. Age was the most important predictor for 25(OH)D concentration, and there were no differences in 25(OH)D concentrations during illness and after 14, 45, and 90 days when adjusting for age. Infection and inflammation did not alter the 25(OH)D concentration in young children with acute lower respiratory tract infections., Competing Interests: The authors declare no conflict of interest.

In the past 15 years, treatment outcomes for hematologic malignancies have improved substantially. However, drug prices have also increased drastically. This commentary examines the value of the treatment of hematologic malignancies at current prices in the United States through a reanalysis of a systematic review evaluating 29 studies of 9 treatments for 4 hematologic malignancies. Incremental cost-effectiveness ratios (ICERs) were calculated on the basis of drug prices in the United States in 2014. Sixty-three percent of the studies (15 of 24) had ICERs higher than $50,000 per quality-adjusted life-year (QALY), the benchmark widely used by health economists to define cost-effectiveness. In studies evaluating the current standard-of-care treatments for chronic myeloid leukemia, the ICERs for tyrosine kinase inhibitors versus hydroxyurea or interferon ranged from $210,000 to $426,000/QALY. The lower ICER values were mostly obtained from 11 studies evaluating rituximab, which was approved by the Food and Drug Administration in 1997 (ICER range, $37,000-$69,000/QALY). In conclusion, the costs of the majority of new treatments for hematologic cancers are too high to be deemed cost-effective in the United States., (© 2015 American Cancer Society.)

Background: Children in low and middle-income countries have a high burden of pneumonia. Measuring the cytokine responses may be useful to identify novel markers for diagnosing, monitoring, and treating pneumonia., Objective: To describe and compare a wide range of inflammatory mediators in plasma from children with WHO-defined severe and non-severe community acquired pneumonia (CAP), and explore to what extent certain mediators are associated with severity and viral detection., Methods: We collected blood samples from 430 children with severe (n = 43) and non-severe (n = 387) CAP. Plasma from these children were analysed for 27 different cytokines, and we measured the association with age, disease severity and viral detection., Results: There were generally higher plasma concentrations of several cytokines with both pro-inflammatory and anti-inflammatory effects among children with severe CAP than in children with non-severe CAP. We found significantly higher concentrations of interleukin (IL)-1, IL-4, IL-6, IL-8, IL-9, IL-15, eotaxin, basic fibroblast growth factor (b-FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-α) in the group of severe CAP. Most of these associations persisted when adjusting for age in linear regression analyses. The cytokine response was strongly associated with age but to a lesser extent with viral etiology., Conclusion: The plasma concentrations of several cytokines, both with pro-inflammatory and anti-inflammatory effects, were higher among children with severe illness. In particular G-CSF and IL-6 reflected severity and might provide complementary information on the severity of the infection., Trial Registration: ClinicalTrials.gov NCT00148733.

Background: Pneumonia in young children is still the most frequent cause of death in developing countries. We aimed to identify predictors for recovery and treatment failure in children hospitalized with severe pneumonia., Methods: We enrolled 610 Nepalese children, aged 2 - 35 months from February 2006 to June 2008. Study participants were provided with standard treatment for pneumonia and followed up until discharge. Three multiple regression models representing clinical variables, clinical and radiological combined and all variables, including C-reactive protein (CRP) and viral etiology were used to assess the associations., Results: The median age of study participants was 6 months with 493 (82%) infants and 367 (61%) males. The median time (IQR) till recovery was 49 (31, 87) hours and treatment failure was experienced by 209 (35%) of the children. Younger age, hypoxia on admission and radiographic pneumonia were independent predictors for both prolonged recovery and risk of treatment failure. While wasting and presence of any danger sign also predicted slower recovery, Parainfluenza type 1 isolated from the nasopharynx was associated with earlier resolution of illness. Gender, being breastfed, stunting, high fever, elevated CRP, presence of other viruses and supplementation with oral zinc did not show any significant association with these outcomes., Conclusion: Age, hypoxia and consolidation on chest radiograph were significant predictors for time till recovery and treatment failure in children with severe pneumonia. While chest radiograph is not always needed, detection and treatment of hypoxia is a crucial step to guide the management of hospitalized children with pneumonia.

Zinc is an essential micronutrient important for growth and for normal function of the immune system. Many children in developing countries have inadequate zinc nutrition. Routine zinc supplementation reduces the risk of respiratory infections and diarrhea, the two leading causes of morbidity and mortality in young children worldwide. In childhood diarrhea oral zinc also reduces illness duration and risk of persistent episodes. Oral zinc is therefore recommended for the treatment of acute diarrhea in young children. The results from the studies that have measured the therapeutic effect of zinc on acute respiratory infections, however, are conflicting. Moreover, the results of therapeutic zinc for childhood malaria also are so far not promising.This paper gives a brief outline of the current evidence from clinical trials on therapeutic effect of oral zinc on childhood respiratory infections, pneumonia and malaria and also of new evidence of the effect on serious bacterial illness in young infants., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Objectives: The aim of this study was to investigate if there are clinical signs which allow detection of malposition of the vertex on admission to the delivery unit, or when crossing the action line on the partogram., Study Design: Case-control study from 2007 to 2010 conducted on the delivery unit of Nordland Hospital, Bodø. Labours with malposition of the vertex (n = 171) were compared with a group with normal vertex presentation (n = 165). The positive predictive value was estimated for each sign using Bayes' rule., Main Outcome Measures: Magnitude of positive predictive value for each clinical sign., Results: The positive predictive values for malposition were 9% if the foetus were in a right position, 11% if the labour was induced, 5% if the foetus was above the ischial spines, 4% if the reason for admission was contractions and 6% if cervix was <3 cm., Conclusion: The ability of clinical assessment to predict malposition, either on admission or when crossing the action line on the partogram, was poor. Diagnosing malposition of the vertex requires other methods with a higher predictive value., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Outcomes of patients with acute myeloid leukemia (AML) who are refractory to high-dose Cytarabine (HiDAC)-based induction are dismal. Allogeneic hematopoietic stem cell transplantation (AHSCT) as initial salvage may be effective and potentially superior to conventional salvage chemotherapy. Eighteen percent (285 of 1597) of AML patients were primary refractory to HiDAC-based regimens at the MD Anderson Cancer Center between 1995 and 2009. AHSCT was the initial salvage in 28 cases. These patients were compared against 149 patients who received salvage chemotherapy, but never received AHSCT. Patients receiving salvage chemotherapy were older, had higher bone marrow blasts percentage, and higher incidence of unfavorable cytogenetics (P < 0.001). Median time from induction to AHSCT was 76 days. Objective response was achieved in 23 of 28 patients (82%) undergoing AHSCT. The incidence of grade III/IV acute and chronic graft versus-host-disease was 11% and 29%, respectively. Median follow up for living patients is 80 months. Median overall survival (OS) was 15.7 months and 2.9 months for AHSCT and chemotherapy, respectively (P < 0.001); the 3-year OS rates were 39% and 2%, respectively. ASHCT as initial salvage therapy was identified as an independent prognostic factor for survival in multivariate analysis (HR = 3.03; P < 0.001). Initial salvage therapy with AHSCT in patients with primary HiDAC refractory AML is feasible and may yield superior outcomes to salvage chemotherapy., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Recent developments in 3-dimensional echocardiography (3DE) have resulted in smaller probes, faster data acquisition and wider applicability. In spite of this, there is still an ongoing debate as to its ability to provide additional information to 2DE in general hospital clinical practice., Methods: A systematic literature search in EMBASE and MEDLINE was performed in order to identify original articles comparing the two techniques. Studies with a blinded comparison between 2DE and 3DE against a "gold standard" were included; these studies comprised patients with well defined inclusion and exclusion criteria. The number of patients, selection criteria, echo manufacturer, cardiac disorder, and types of comparisons, along with "gold standard" and principal results were compared., Results: A total of 836 original articles were identified, of which 35 were screened for eligibility. 20 studies from 18 publications were included for analysis. The results for LV assessment and reproducibility were clearly in favour of 3DE. In valvular heart disease the superiority of 3DE was also apparent, but was less convincing due to patient selection, methodological problems and the application of questionable "gold standards"., Conclusions: In patients with a regular heart rhythm and for whom it was possible to obtain good quality images the introduction of 3DE has improved the accuracy and reproducibility of LV volume and EF measurements. The results for valvular heart disease are still controversial. It does not seem justifiable to introduce 3DE into common cardiac practice. Further studies are needed in order to support such an implementation., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Globally, solid fuels are used by about 3 billion people for cooking. These fuels have been associated with many health effects, including acute lower respiratory infection (ALRI) in young children. Nepal has a high prevalence of use of biomass for cooking and heating., Objective: This case-control study was conducted among a population in the Bhaktapur municipality, Nepal, to investigate the relationship of cookfuel type to ALRI in young children., Methods: Cases with ALRI and age-matched controls were enrolled from an open cohort of children 2-35 months old, under active monthly surveillance for ALRI. A questionnaire was used to obtain information on family characteristics, including household cooking and heating appliances and fuels. The main analysis was carried out using conditional logistic regression. Population-attributable fractions (PAF) for stove types were calculated., Results: A total of 917 children (452 cases and 465 controls) were recruited into the study. Relative to use of electricity for cooking, ALRI was increased in association with any use of biomass stoves [odds ratio (OR) = 1.93; 95% CI: 1.24, 2.98], kerosene stoves (OR = 1.87; 95% CI: 1.24, 2.83), and gas stoves (OR = 1.62; 95% CI: 1.05, 2.50). Use of wood, kerosene, or coal heating was also associated with ALRI (OR = 1.45; 95% CI: 0.97, 2.14), compared with no heating or electricity or gas heating. PAFs for ALRI were 18.0% (95% CI: 8.1, 26.9%) and 18.7% (95% CI: 8.4%-27.8%), for biomass and kerosene stoves, respectively., Conclusions: The study supports previous reports indicating that use of biomass as a household fuel is a risk factor for ALRI, and provides new evidence that use of kerosene for cooking may also be a risk factor for ALRI in young children.