I'll cut through the bullshit and show you exactly what happened. It suggests that there's an important story here, too, in a way that says to the reader: and you want to know. A line like "This is what happened," doesn't actually say anything--there's zero action or context -- but it doesn't matter. It's a voice, and an invitation, that's very difficult for me to refuse. It's like finding a good friend who has valuable information to share.
Here's somebody, it says, who can provide entertainment, an escape, and maybe even a way of looking at the world that will open your eyes.
In fiction, that's irresistible. It's why we read. We've talked so much about the reader, but you can't forget that the opening line is important to the writer, too. To the person who's actually boots-on-the-ground. Because it's not just the reader's way in, it's the writer 's way in also, and you've got to find a doorway that fits us both. I think that's why my books tend to begin as first sentences -- I'll write that opening sentence first, and when I get it right I'll start to think I really have something.
When I'm starting a book, I compose in bed before I go to sleep. I will lie there in the dark and think. I'll try to write a paragraph. An opening paragraph. And over a period of weeks and months and even years, I'll word and reword it until I'm happy with what I've got. If I can get that first paragraph right, I'll know I can do the book. Because of this, I think, my first sentences stick with me. They were a doorway I went through. I remember them! The opening line of It is "The terror that would not end for another 28 years, if it ever did, began so far as I can know or tell, with a boat made from a sheet of newspaper floating down a gutter swollen with rain.
But I can tell you right now that the best first line I ever wrote -- and I learned it from Cain, and learned it from Fairbairn -- is the opening of Needful Things. It's the story about this guy who comes to town, and uses grudges and sleeping animosities among the townspeople to whip everyone up into a frenzy of neighbor against neighbor. And so the story starts off with an opening line, printed by itself on a page in point type:. All there by itself on one page, inviting the reader to keep reading.
It suggests a familiar story; at the same time, the unusual presentation brings us outside the realm of the ordinary. And this, in a way, is a promise of the book that's going to come. The story of neighbor against neighbor is the oldest story in the world, and yet this telling is I hope strange and somehow different.
Sometimes it's important to find that kind of line: one that encapsulates what's going to happen later without being a big thematic statement. Still, I don't have a lot of books where that opening line is poetry or beautiful. Sometimes it's perfectly workman-like. You try to find something that's going to offer that crucial way in, any way in, whatever it is as long as it works. This approach is closer to what worked for in my new book, Doctor Sleep. All I remember is wanting to leapfrog from the timeframe of The Shining into the present by talking about presidents, without using their names.
The peanut farmer president, the actor president, the president who played the saxophone, and so on. The sentence is:. It's supposed to do three things. It sets you in time. It sets you in place. And it recalls the ending of the book -- though I don't know it will do much good for people who only saw the movie, because the hotel doesn't burn in the movie. There is limited evidence to evaluate second-line therapies in patients with HIV who fail first-line treatment with a WHO-recommended regimen.
One randomised trial in patients and two observational studies both of low quality suggest no difference in virological suppression whether or not lamivudine is maintained in a second-line regimen. While outcomes of second-line regimens with boosted PIs are favourable in general, there are no studies comparing boosted PIs directly in populations starting second-line regimens. Current recommendations are based on available resources and patient- and public-health-level considerations. If treatment failure occurs, a change to second-line therapy is necessary.
Electronic databases and conference proceedings were searched with relevant search terms without limits to language. Randomised controlled trials of HIV-infected adolescent and adult patients administered second-line ART after virologic failure of a first-line regimen were included.
Observational studies were included given the insufficient number of trials identified. The primary outcome measure included mortality. Secondary outcome measures included rate of adverse events, change in mean CD4 cell count, clinical resolution of symptoms, proportion of patients achieving undetectable viral load VL and acquisition of genotypic mutations. As these change with growth, drug doses must be adjusted in order to avoid the risk of underdosing.
Standardization is important and it is recommended that health-care workers be provided with tables of simplified drug doses for administration. Such tables may vary with the local availability of ARV drugs and formulations. WHO has developed prototype weight-band based dosing tables, as well as tools to assist countries with the standardization and calculation of drug doses iv see Annex E. Studies of many different potent ARV regimens in children have demonstrated that similar improvements to those obtained in adults are seen in morbidity, mortality and surrogate markers [ 38 , 47 - 52 ].
38 Best First Lines in Novels (YA Edition) | HuffPost
EFV is not currently recommended for use in children less than 3 years of age due to lack of information on appropriate dosing. Data from a recent meta-analysis and from observational studies confirm that HIV-infected infants exposed to NNRTIs through infant prophylaxis or maternal treatment or prophylaxis have demonstrable viral resistance [ 53 , 54 ].
An observational study [ 53 ] and a recent RCT [ 55 ] demonstrate that response to NVP-containing first-line treatment regimens may be compromised in infants and older children who acquire HIV despite intrapartum or peripartum exposure to NVP. There are two exceptions: the use of EFV should be avoided in adolescent girls due to the teratogenic potential of EFV in the first trimester of pregnancy and in children less than 3 years of age due to lack of appropriate dosing information in this age group.
See Table 10 for a summary of recommended first-line ART regimens for infants and children. The use of a triple NRTI regimen i. Of concern is the somewhat lower virological potency of this regimen compared with a two-class triple-drug combination in adult studies [ 57 - 60 ].
Currently, a triple NRTI regimen is only recommended in children less than three years of age who are receiving treatment for TB, a situation where NVP may not be an optimal choice because of drug interactions with rifampicin see Chapter This regimen could be considered for adolescents who may become pregnant, or adolescents with anticipated or documented poor adherence see Chapter It is usually given twice daily in children and has been incorporated into a number of FDCs.
Once-daily dosing is possible in older children. Emtricitabine FTC is a newer NRTI that has recently been included in WHO's recommended first-line regimens for adults as an option and is also available for use in children; it can be given once daily. FTC is structurally related to 3TC and shares its resistance profile [ 61 ]. Where available, it can be used in children more than three months of age as an alternative to 3TC [ 62 ]. Stavudine d4T initially is better tolerated than AZT and does not require haemoglobin or laboratory monitoring.
However, among the NRTIs, d4T has been most often associated with lipoatrophy and lactic acidosis [ 63 ]. In addition, peripheral neuropathy, elevated hepatic transaminases and pancreatitis have been observed.
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Zidovudine AZT is generally well tolerated in children but has been associated with metabolic complications, although to a lesser extent than d4T. Initial drug-related side-effects are more frequent with AZT and the drug can cause severe anaemia and neutropenia; haematological monitoring is advised [ 64 ]. This is particularly important in areas where malaria is endemic or where malnutrition is common and anaemia is highly prevalent in young children.
38 Best First Lines in Novels (YA Edition)
Data from clinical trials indicate a similar safety profile in children to that in adults, with very little haematological toxicity [ 65 ]. However, two large clinical trials found an association between ABC and myocardial infarction in adults [ 66 , 67 ] but a meta-analysis from 54 clinical trials of ABC and another more recent clinical trial did not find this predisposition to cardiovascular diseases [ 68 , 69 ].
The frequency of ABC hypersensitivity in other regions is not known. In infants and children suspected of having a hypersensitivity reaction, ABC should be stopped and never restarted see Annex F. Tenofovir TDF is included as an option for first-line regimens in adults.
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In adults, TDF is generally well tolerated [ 72 ] although there are numerous reports of renal insufficiency [ 73 - 75 ]. Because of limited paediatric safety data especially the potential for effects on bone mineralization , the use of TDF in younger children is not yet recommended. A study in 16 HIV-infected children age range 6.
However, a study using TDF as part of salvage therapy in children age range 8. Subsequent research has shown similar results [ 78 ], suggesting that TDF may be of limited use in prepubertal children. Additional clinical trials in ART-naive children as young as 2 years are ongoing. Its use is usually reserved for second-line regimens see Chapter The decision to use d4T, AZT or ABC in the first-line regimen needs to be made at the country level on the basis of local considerations, but it is recommended that at least two of these NRTIs be available to allow the substitution of one drug for the other should there be toxicity.
Fewer laboratory monitoring requirements may be a good reason to favour d4T over AZT as the chosen NRTI component, in particular, during the rapid scale-up of programmes. However, there is a long term risk of toxicity, particularly lipoatrophy in children treated with d4T-containing regimens. The use of d4T is being reduced in adults because d4T toxicity is frequently irreversible. D4T toxicity relates to the intracellular accumulation of the drug and its metabolites, and the subsequent poisoning of mitochondrial function.
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This explains why d4T toxicity develops gradually, over a longer time frame than toxicity to other ARVs. In children, however, d4T clearance is enhanced and intracellular levels are typically lower than in adults. Children can and do develop d4T toxicity but it is reported less often than in adults [ 64 , 79 - 81 ].