Pneumonia is a major cause of severe illness in children. In a study of community-acquired pneumonia requiring hospitalization among U.S. children, those younger than 2 years of age were most ...affected, and viruses were most commonly found.
Pneumonia is a leading cause of hospitalization among children in the United States,
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with medical costs estimated at almost $1 billion in 2009.
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Despite this large burden of disease, critical gaps remain in our knowledge about pneumonia in children.
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Contemporary estimates of the incidence and microbiologic causes of hospitalization for community-acquired pneumonia among children in the United States would be of value.
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Most recent published estimates of the incidence of pneumonia have used administrative data, which are limited because a strict clinical and radiographic definition of community-acquired pneumonia is difficult to apply to such data and because diagnostic testing . . .
Operations management (OM) in the public policy context is extremely complex with many mutually interacting factors characterized by feedback loops, delays and nonlinearities, as well as multiple ...stakeholders pursuing divergent objectives. Prior researchers have called for a systems approach in these contexts, arguing that standard OM methodologies such as mathematical programming, and queuing theory often cannot fully address these problems. Researchers have employed one such systems approach, system dynamics, successfully for decades for studying OM problems in public policy because it can address such complexity and can also integrate disciplines from outside OM such as political science, epidemiology, ecology, etc.
In this paper, we create a roadmap for researchers—both those who are familiar with systems dynamics and those who are not—for the expanded use of system dynamics studying public policy‐related OM problems. We review and organize relevant system dynamics literature in both traditional operations management venues as well as public policy venues unfamiliar to OM audiences. We then identify a set of interesting open questions and potential system dynamics building blocks for answering them by topic. Leveraging this review, we describe under what conditions system dynamics is most appropriate. We then identify several overarching methodological and domain gaps for future research.
Finally, we build on previous work to extend a process for using system dynamics with traditional operations management methodologies. It separates model building into two sequential phases: consensus‐building models and detailed operational models. It also incorporates scenario planning and feedback from implementation outcomes.
In an open-label, pragmatic trial, patients with cardiovascular disease were randomly assigned to a strategy of 81 mg or 325 mg of aspirin daily. A substantial proportion of those assigned to the ...325-mg dose switched to the 81-mg dose, and there were no significant differences in cardiovascular events or major bleeding between the two groups.
Summary Background The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus (HCV) NS5B polymerase. We assessed the safety and efficacy of sofosbuvir in combination ...with pegylated interferon alfa-2a (peginterferon) and ribavirin in non-cirrhotic treatment-naive, patients with HCV. Methods For this open-label, randomised phase 2 trial, we recruited patients from 42 centres in the USA and Puerto Rico between March 23, 2011, and Sept 21, 2011. Patients were eligible for inclusion if they had chronic HCV infection (genotypes 1, 4, 5, or 6), were aged 18 years or older, and had not previously received treatment for HCV infection. Using a computer-generated randomisation sequence, we randomly assigned patients with HCV genotype-1 to one of three cohorts (A, B, and C; in a 1:2:3 ratio), with randomisation stratified by IL28B (CC vs non-CC allele) and HCV RNA (<800 000 IU/mL vs ≥800 000 IU/mL). Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks (cohort A) or for 24 weeks (cohort B), or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin (cohort C). We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 (SVR24) by intention-to-treat analysis. This trial is registered with ClinicalTrials.gov , number NCT01329978. Results We enrolled 316 patients with HCV genotype-1: 52 to cohort A, 109 to cohort B, and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B (we detected no patients with genotype 5). In patients with HCVgenotype-1, SVR24 was achieved by 46 patients (89%, 95% CI 77–96) in cohort A, 97 patients (89%, 82–94) in cohort B, and by 135 (87%, 81–92) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B (p=0·94), or in cohort C (p=0·78). Nine (82%) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24. Seven patients, all with genotype-1 infection, relapsed after completion of assigned treatment. The most common adverse events that led to the discontinuation of any study drug—anaemia and neutropenia—were associated with peginterferon and ribavirin treatment. Three (6%) patients in cohort A, 18 (14%) patients in cohort B, and three (2%) patients in cohort C discontinued treatment because of an adverse event. Interpretation Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks, but these finding will have to be substantiated in phase 3 trials. These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection, including those with cirrhosis. Funding Gilead Sciences.
Kisspeptin gene and protein expression are down-regulated in a state of leptin deficiency and in response to diet-induced obesity.
The hormone leptin modulates a diverse range of biological ...functions, including energy homeostasis and reproduction. Leptin promotes GnRH function via an indirect action on forebrain neurons. We tested whether leptin deficiency or leptin resistance due to a high-fat diet (HFD) can regulate the potent reproductive neuropeptide kisspeptin. In mice with normalized levels of estradiol, leptin deficiency markedly reduced kisspeptin gene expression, particularly in the arcuate nucleus (ARC), and kisspeptin immunoreactive cell numbers in the rostral periventricular region of the third ventricle (RP3V). The HFD model was used to determine the effects of diet-induced obesity and central leptin resistance on kisspeptin cell number and gene expression. DBA/2J mice, which are prone to HFD-induced infertility, showed a marked decrease in kisspeptin expression in both the RP3V and ARC and cell numbers in the RP3V after HFD. This is the first evidence that kisspeptin can be regulated by HFD and/or increased body weight. Next we demonstrated that leptin does not signal (via signal transducer and activator of transcription 3 or 5, or mammalian target of rapamycin) directly on kisspeptin-expressing neurons in the RP3V. Lastly, in leptin receptor-deficient mice, neither GnRH nor kisspeptin neurons were activated during a preovulatory-like GnRH/LH surge induction regime, indicating that leptin's actions on GnRH may be upstream of kisspeptin neurons. These data provide evidence that leptin's effects on reproductive function are regulated by kisspeptin neurons in both the ARC and RP3V, although in the latter site the effects are likely to be indirect.
CRISPR-Cas9-associated base editing is a promising tool to correct pathogenic single nucleotide mutations in research or therapeutic settings. Efficient base editing requires cellular exposure to ...levels of base editors that can be difficult to attain in hard-to-transfect cells or in vivo. Here we engineer a chemically modified mRNA-encoded adenine base editor that mediates robust editing at various cellular genomic sites together with moderately modified guide RNA, and show its therapeutic potential in correcting pathogenic single nucleotide mutations in cell and animal models of diseases. The optimized chemical modifications of adenine base editor mRNA and guide RNA expand the applicability of CRISPR-associated gene editing tools in vitro and in vivo.
The mechanistic basis of the symptoms and signs of myocardial ischaemia in patients without obstructive coronary artery disease (CAD) and evidence of coronary microvascular dysfunction (CMD) is ...unclear. The aim of this study was to mechanistically test short-term late sodium current inhibition (ranolazine) in such subjects on angina, myocardial perfusion reserve index, and diastolic filling.
Randomized, double-blind, placebo-controlled, crossover, mechanistic trial in subjects with evidence of CMD invasive coronary reactivity testing or non-invasive cardiac magnetic resonance imaging myocardial perfusion reserve index (MPRI). Short-term oral ranolazine 500-1000 mg twice daily for 2 weeks vs. placebo. Angina measured by Seattle Angina Questionnaire (SAQ) and SAQ-7 (co-primaries), diary angina (secondary), stress MPRI, diastolic filling, quality of life (QoL). Of 128 (96% women) subjects, no treatment differences in the outcomes were observed. Peak heart rate was lower during pharmacological stress during ranolazine (-3.55 b.p.m., P < 0.001). The change in SAQ-7 directly correlated with the change in MPRI (correlation 0.25, P = 0.005). The change in MPRI predicted the change in SAQ QoL, adjusted for body mass index (BMI), prior myocardial infarction, and site (P = 0.0032). Low coronary flow reserve (CFR <2.5) subjects improved MPRI (P < 0.0137), SAQ angina frequency (P = 0.027), and SAQ-7 (P = 0.041).
In this mechanistic trial among symptomatic subjects, no obstructive CAD, short-term late sodium current inhibition was not generally effective for SAQ angina. Angina and myocardial perfusion reserve changes were related, supporting the notion that strategies to improve ischaemia should be tested in these subjects.
clinicaltrials.gov Identifier: NCT01342029.
Potentiating radiotherapy and chemotherapy by inhibiting DNA damage repair is proposed as a therapeutic strategy to improve outcomes for patients with solid tumors. However, this approach risks ...enhancing normal tissue toxicity as much as tumor toxicity, thereby limiting its translational impact. Using NU5455, a newly identified highly selective oral inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activity, we found that it was indeed possible to preferentially augment the effect of targeted radiotherapy on human orthotopic lung tumors without influencing acute DNA damage or a late radiation-induced toxicity (fibrosis) to normal mouse lung. Furthermore, while NU5455 administration increased both the efficacy and the toxicity of a parenterally administered topoisomerase inhibitor, it enhanced the activity of doxorubicin released locally in liver tumor xenografts without inducing any adverse effect. This strategy is particularly relevant to hepatocellular cancer, which is treated clinically with localized drug-eluting beads and for which DNA-PKcs activity is reported to confer resistance to treatment. We conclude that transient pharmacological inhibition of DNA-PKcs activity is effective and tolerable when combined with localized DNA-damaging therapies and thus has promising clinical potential.
This trial aims to investigate the effects of the ActTeens physical activity program, on adolescents' physical activity level, health-related fitness, cardiometabolic and mental health. The trial ...will aim to recruit ~140 adolescents (aged 13-14 years). Participants will be randomized into either intervention or control groups. The intervention will be guided by social cognitive theory and self-determination theory and implemented over one school term (24-weeks). The ActTeens Program will include: (1) structured physical activity sessions delivered within physical education, including movement-based games and dynamic stretching warm-ups; resistance training skill development; high-intensity training workouts; and cool-downs; (2) self-monitoring plus goal setting for physical activity by pedometer-smart wearable; and (3) healthy lifestyle guidance (social support) by WhatsApp® messages about healthy eating and regular physical activity for the intervention and parents groups. Study outcomes will be assessed at baseline, 24-weeks from baseline, and 12-months from baseline. Physical activity (accelerometer) is the primary outcome. Secondary outcomes include muscular and cardiorespiratory fitness, cardiometabolic profile, and mental health. A process evaluation will be conducted (i.e., recruitment, retention, attendance, and program satisfaction). This project will have the potential to address many questions and debates regarding the implementation of physical activity interventions in low-and- middle-income countries.
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