The basic reproduction number (R
), also called the basic reproduction ratio or rate or the basic reproductive rate, is an epidemiologic metric used to describe the contagiousness or transmissibility ...of infectious agents. R
is affected by numerous biological, sociobehavioral, and environmental factors that govern pathogen transmission and, therefore, is usually estimated with various types of complex mathematical models, which make R
easily misrepresented, misinterpreted, and misapplied. R
is not a biological constant for a pathogen, a rate over time, or a measure of disease severity, and R
cannot be modified through vaccination campaigns. R
is rarely measured directly, and modeled R
values are dependent on model structures and assumptions. Some R
values reported in the scientific literature are likely obsolete. R
must be estimated, reported, and applied with great caution because this basic metric is far from simple.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper we compare a number of common strategies for constructing discrete choice experiments. Two of the strategies, including one based on theoretical constructions for optimal discrete ...choice experiments, produce designs that are better than those that come about from random grouping and from using the L
MA construction. A simple account of this theoretical construction is given.
The use of β-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β-blockers could be used ...in combination with chemotherapy for the treatment of neuroblastoma.
Seven β-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma.
Three β-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, β-blockers alone transiently slowed tumour growth as compared with vehicle only (P<0.01). More importantly, when used in combination, β-blockers significantly increased the tumour regression induced by vincristine (P<0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P<0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P<0.01).
β-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.
Exosomes are released by most cells and can be isolated from all biofluids including urine. Exosomes are small vesicles formed as part of the endosomal pathway that contain cellular material ...surrounded by a lipid bilayer that can be traced to the plasma membrane. Exosomes are potentially a more targeted source of material for biomarker discovery than unfractionated urine, and provide diagnostic and pathophysiological information without an invasive tissue biopsy. Cytoplasmic contents including protein, mRNA, miRNA, and lipids have all been studied within the exosomal fraction. Many prospective urinary exosomal biomarkers have been successfully identified for a variety of kidney or genitourinary tract conditions; detection of systemic conditions may also be possible. Isolation and analysis of exosomes can be achieved by several approaches, although many require specialized equipment or involve lengthy protocols. The need for timely analysis in the clinical setting has driven considerable innovation with several promising options recently emerging. Consensus on exosome isolation, characterization, and normalization procedures would resolve critical clinical translational bottlenecks for existing candidate exosomal biomarkers and provide a template for additional discovery studies.
Many factors can negatively impact perinatal outcomes, including inappropriate gestational weight gain (GWG). Despite having the greatest potential to influence maternal and infant health, there is a ...lack of consensus regarding the GWG consistent with a healthy pregnancy. To date, GWG in Northern Tasmania remains understudied. We investigated how maternal pre-pregnancy body mass index (BMI) is related to weight gain during pregnancy and weight retention post-partum, and how maternal pre-pregnancy BMI is related to the mode of delivery. Approximately 300 Tasmanian mothers (n = 291 for mode of delivery and n = 282 for GWG) were included in this study. Analysis of variance and chi square tests were conducted to assess differences in BW of mothers across BMI categories and differences between categorical variables; respectively. Based on pre-pregnancy BMI, mothers were assigned to one of three groups, with healthy weight (<25 kg m-2), with overweight (25-29.9 kg m-2), or with obesity (>30 kg m-2). Pre-pregnancy BMI and body weight (BW) were significantly associated (p<0.001) with post-partum BW at 3 and 6 months. Only 25% of mothers with a normal weight BMI, 34% with overweight and 13% with obesity, achieved the Institute of Medicine (IOM) recommendation for GWG. Interestingly, a number of women in our cohort lost weight during gestation (1.5, 9 and 37% in <25, 25-29.9 and >30 kg m-2 groups, respectively). Further, women with obesity showed the lowest level of BW fluctuation and retained less weight post-partum. The highest number of caesarean sections were observed in mothers who exceeded GWG recommendations. Most mothers either exceeded or failed to achieve IOM recommendations for GWG. To improve the generalisability of these findings, this study should be replicated in a larger representative sample of the Tasmanian maternal population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prospective cohort study.
To characterize the cerebrospinal fluid (CSF) concentrations of glial fibrillary acidic protein, neuron specific enolase (NSE), S-100β, tau and neurofilament heavy chain ...(NFH) within 24 h of an acute traumatic spinal cord injury (SCI), and to correlate these concentrations with the baseline severity of neurologic impairment as graded by the American Spinal Injury Association impairment scale (AIS).
A lumbar puncture was performed to obtain CSF from 16 acute traumatic SCI patients within 24 h post injury. Neurological examinations were performed within 24 h of injury and again at 6 or 12 months post injury. The correlations between the CSF concentrations and initial AIS were calculated by using Pearson correlation coefficients. In addition, an independent Student's t-test was used to test for differences in CSF concentrations between patients of different AIS grades.
The CSF NSE concentrations were significantly correlated with the baseline neurologic impairment being either 'motor complete' (AIS A, B) or 'motor incomplete' (AIS C, D) (r=0.520, P<0.05). The mean S-100β concentration in motor complete patients was significantly higher compared with motor incomplete patients; 377.2 μg l(-1) (s.d.±523 μg l(-1)) vs 57.1 μg l(-1) (s.d.±56 μg l(-1)) (P<0.05), respectively. Lastly, the mean NFH concentration in motor complete patients was significantly higher compared with motor incomplete patient, 11 813 ng l(-1) (s.d.±16 195 ng l(-1)) vs 1446.8 ng l(-1) (s.d.±1533 ng l(-1)), (P<0.05), respectively.
In this study we identified differences in the structural CSF biomarkers NSE, S-100β and NFH between motor complete and motor incomplete SCI patients. Our data showed no clear differences in any of the protein concentrations between the different AIS grades.
Abstract Background Cost-utility analyses (CUAs) are increasingly common in Australia. The EuroQol five-dimensional (EQ-5D) questionnaire is one of the most widely used generic preference-based ...instruments for measuring health-related quality of life for the estimation of quality-adjusted life years within a CUA. There is evidence that valuations of health states vary across countries, but Australian weights have not previously been developed. Methods Conventionally, weights are derived by applying the time trade-off elicitation method to a subset of the EQ-5D health states. Using a larger set of directly valued health states than in previous studies, time trade-off valuations were collected from a representative sample of the Australian general population (n = 417). A range of models were estimated and compared as a basis for generating an Australian algorithm. Results The Australia-specific EQ-5D values generated were similar to those previously produced for a range of other countries, but the number of directly valued states allowed inclusion of more interaction effects, which increased the divergence between Australia's algorithm and other algorithms in the literature. Conclusion This new algorithm will enable the Australian community values to be reflected in future economic evaluations.
Early diagnosis and improved treatment outcomes have increased breast cancer survival rates that, in turn, have led to increased numbers of women undergoing follow-up after completion of primary ...treatment. The current workload growth is unsustainable for breast cancer specialists who also provide care for women newly diagnosed or with a recurrence. Appropriate and acceptable follow-up care is important; yet, currently we know little about patient preferences. The aim of this study was to explore the preferences of Australian breast cancer survivors for alternative modes of delivery of follow-up services.
A self-administered questionnaire (online or paper) was developed. The questionnaire contained a discrete choice experiment (DCE) designed to explore patient preferences with respect to provider, location, frequency and method of delivery of routine follow-up care in years 3, 4 and 5 after diagnosis, as well as the perceived value of 'drop-in' clinics providing additional support. Participants were recruited throughout Australia over a 6-month period from May to October 2012. Preference scores and choice probabilities were used to rank the top 10 most preferred follow-up scenarios for respondents.
A total of 836 women participated in the study, of whom 722 (86.4%) completed the DCE. In the absence of specialist follow-up, the 10 most valued surveillance scenarios all included a Breast Physician as the provider of follow-up care. The most preferred scenario is a face-to-face local breast cancer follow-up clinic held every 6 months and led by a Breast Physician, where additional clinics focused on the side effects of treatment are also provided.
Beyond the first 2 years from diagnosis, in the absence of a specialist led follow-up, women prefer to have their routine breast cancer follow-up by a Breast Physician (or a Breast Cancer Nurse) in a dedicated local breast cancer clinic, rather than with their local General Practitioner. Drop-in clinics for the management of treatment related side effects and to provide advice to both develop and maintain good health are also highly valued by breast cancer survivors.
Calcium and bone metabolism remain key concerns for space travelers, and ground-based models of space flight have provided a vast literature to complement the smaller set of reports from flight ...studies. Increased bone resorption and largely unchanged bone formation result in the loss of calcium and bone mineral during space flight, which alters the endocrine regulation of calcium metabolism. Physical, pharmacologic, and nutritional means have been used to counteract these changes. In 2012, heavy resistance exercise plus good nutritional and vitamin D status were demonstrated to reduce loss of bone mineral density on long-duration International Space Station missions. Uncertainty continues to exist, however, as to whether the bone is as strong after flight as it was before flight and whether nutritional and exercise prescriptions can be optimized during space flight. Findings from these studies not only will help future space explorers but also will broaden our understanding of the regulation of bone and calcium homeostasis on Earth.
MRK-409 binds to α1-, α2-, α3- and α5-containing human recombinant
GABAA receptors with comparable high affinity (0.21–0.40 nM).
However, MRK-409 has greater agonist efficacy at the α3 compared with ...α1 subtypes
(respective efficacies relative to the full agonist chlordiazepoxide of 0.45 and 0.18). This
compound readily penetrates the brain in rats and occupies the benzodiazepine site of
GABAA receptors, measured using an in vivo 3Hflumazenil binding assay,
with an Occ50 of 2.2 mg/kg p.o. and a corresponding plasma EC50
of 115 ng/mL. Behaviourally, the α3-preferring agonist efficacy profile of MRK-409
produced anxiolytic-like activity in rodent and primate unconditioned and conditioned models of
anxiety with minimum effective doses corresponding to occupancies, depending on the particular
model, ranging from ∼35% to 65% yet there were minimal overt signs of
sedation at occupancies greater than 90%. In humans, however, safety and tolerability
studies showed that there was pronounced sedation at a dose of 2 mg, resulting in a
maximal tolerated dose of 1 mg. This 2 mg dose corresponded to a
Cmax
plasma concentration of 28 ng/mL, which, based on
the rodent plasma EC50 for occupancy of 115 ng/mL, suggested that sedation
in humans occurs at low levels of occupancy. This was confirmed in human positron emission
tomography studies, in which 11Cflumazenil uptake following a single dose of
1 mg MRK-409 was comparable to that of placebo, indicating that occupancy of
GABAA receptor benzodiazepine binding sites by MRK-409 was below the limits of
detection (i.e. <10%). Taken together, these data show that MRK-409 causes
sedation in humans at a dose (2 mg) corresponding to levels of occupancy considerably
less than those predicted from rodent models to be required for anxiolytic efficacy
(∼35–65%). Thus, the preclinical non-sedating anxiolytic profile of
MRK-409 did not translate into humans and further development of this compound was halted.
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