TASK DEFINITION: Given a passage with a context and an answer, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
PROBLEM: Context: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism.
Answer: Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).

SOLUTION: Does recurrent recessive mutation in deoxyguanosine kinase cause idiopathic noncirrhotic portal hypertension?

PROBLEM: Context: People with a history of rheumatic fever (RF) are at high risk of recurrent attacks and of developing rheumatic heart disease following a streptococcal throat infection. Giving penicillin to these people can prevent recurrent attacks of RF and subsequent rheumatic heart disease. However, there is no agreement on the most effective method of giving penicillin.', 'To assess the effects of different penicillin regimens and formulations for preventing streptococcal infection and RF recurrence.', 'We searched the Controlled Trials Register (Cochrane Library Issue 2, 2001), Medline (January 1966-July 2000), Embase (January 1985-July 2000), reference lists of articles, and contacted experts in the field.', 'Randomised and quasi-randomised studies comparing: (i) oral with intramuscular penicillin; and (ii) 2- or 3-weekly with 4-weekly intramuscular penicillin in patients with previous RF.', 'Two reviewers independently assessed trial quality and extracted data.', 'Six studies were included (1,707 patients). Data were not pooled because of clinical and methodological heterogeneity of the trials. Four trials (1,098 patients) compared intramuscular with oral penicillin and all showed that intramuscular penicillin was more effective in reducing RF recurrence and streptococcal throat infections than oral penicillin. One trial (360 patients) compared 2-weekly with 4-weekly intramuscular penicillin. Penicillin given every 2 weeks was better at reducing RF recurrence (relative risk (RR) 0.52, 95% confidence interval (CI): 0.33-0.83) and streptococcal throat infections (RR 0.60, 95% CI: 0.42-0.85). One trial (249 patients) showed that 3-weekly intramuscular penicillin injections reduced streptococcal throat infections (RR 0.67, 95% CI: 0.48-0.92) compared with 4-weekly intramuscular penicillin.
Answer: Intramuscular penicillin seemed to be more effective than oral penicillin in preventing RF recurrence and streptococcal throat infections. Two-weekly or 3-weekly injections appeared to be more effective than 4-weekly injections. However, the evidence is based on poor-quality trials and the use of outdated formulations of oral penicillin.

SOLUTION: Is intramuscular penicillin more effective than oral penicillin in secondary prevention of rheumatic fever -- a systematic review?

PROBLEM: Context: To investigate the effect of premenopausal obesity on circulating levels of estradiol, estrone, free testosterone, androstenedione, DHEAS, and immuno- and bioactive FSH and LH.', 'University clinic.', 'Premenopausal hirsute women, four obese and four nonobese, received leuprolide acetate depot [LD in monthly injections (7.5 mg, i.m.)] until estradiol levels decreased to menopausal values; single monthly injections of 15 and then 22.5 mg LD were given if estradiol remained higher than menopausal after 3 months.', 'Estradiol levels of nonobese women reached menopausal values with the 7.5-mg dose, and those of obese women were not significantly reduced with any LD dose. Estrone declined to menopausal levels with 7.5 mg LD, while free testosterone and androstenedione were diminished with 7.5 mg, but not further with 15 or 22.5 mg. Bioactive LH and the bioactive/immunoactive LH ratio were maximally suppressed with 7.5 mg LD; however, LD did not change bioactive FSH levels or the bioactive/immunoactive FSH ratio. These findings were not related to adiposity.
Answer: Premenopausal obesity affects circulating estradiol levels of hirsute women receiving LD. The effect does not reflect weight-related differences in circulating levels of androgens or bioactive gonadotropins. Premenopausal adiposity in hirsute women may influence the estrogenic milieu associated with desensitization to GnRH.

SOLUTION:
Does obesity affect circulating estradiol levels of premenopausal hirsute women receiving leuprolide acetate depot?