The influence of lung metastases on the clinical course of gestational trophoblastic neoplasia: a historical cohort study.

OBJECTIVE: To evaluate whether gestational trophoblastic neoplasia (GTN) patients with lung metastases have more adverse outcomes such as resistance to chemotherapy, recurrence or death of disease compared with patients without lung metastases. DESIGN: Historical observational cohort study. SETTING: The Netherlands. POPULATION: We identified 434 GTN patients (72 patients with lung metastases, 362 patients without metastases) between 1990 and 2012 registered in the Dutch national databases. METHODS: Baseline characteristics, recurrence rates, Methotrexate (MTX) remission rates and deaths from disease were compared between patients with lung metastases (group I) and without lung metastases (group II) using the Fisher exact test or Mann-Whitney U-test where applicable. MAIN OUTCOME MEASURES: Methotrexate resistance, recurrences and survival. RESULTS: Methotrexate resistance did not differ between group I and group II (62.9 versus 72.7% P = 0.19). However, the observed recurrence rate was significantly increased in patients with lung metastases compared with patients without metastases (16.7 versus 2.2% P < 0.0001), also after correction for antecedent pregnancy and interval (from the end of the antecedent pregnancy until the start of treatment). Disease-specific survival was 91.7% in the group with lung metastases and 100% in the patients without metastases (P < 0.0001). CONCLUSIONS: Although lung metastases are considered to be associated with a low risk of adverse outcomes, their presence appears to increase the risk for recurrence and death of disease. Further research is needed to evaluate whether the presence of lung metastases is an independent risk factor that needs adjustment in the FIGO scoring system and clinical classification system. TWEETABLE ABSTRACT: In gestational trophoblastic neoplasia (GTN) recurrence is more often observed in the case of lung metastases.

Historical epidemiology of hepatitis C virus (HCV) in select countries - volume 2.

Chronic hepatitis C virus (HCV) infection is a leading cause of liver related morbidity and mortality. In many countries, there is a lack of comprehensive epidemiological data that are crucial in implementing disease control measures as new treatment options become available. Published literature, unpublished data and expert consensus were used to determine key parameters, including prevalence, viremia, genotype and the number of patients diagnosed and treated. In this study of 15 countries, viremic prevalence ranged from 0.13% in the Netherlands to 2.91% in Russia. The largest viremic populations were in India (8 666 000 cases) and Russia (4 162 000 cases). In most countries, males had a higher rate of infections, likely due to higher rates of injection drug use (IDU). Estimates characterizing the infected population are critical to focus screening and treatment efforts as new therapeutic options become available.

Strategies to manage hepatitis C virus (HCV) infection disease burden - volume 2.

The hepatitis C virus (HCV) epidemic was forecasted through 2030 for 15 countries, and the relative impact of two scenarios was considered: (i) increased treatment efficacy while holding the treated population constant and (ii) increased treatment efficacy and increased annual treated population. Increasing levels of diagnosis and treatment, in combination with improved treatment efficacy, were critical for achieving substantial reductions in disease burden. In most countries, the annual treated population had to increase several fold to achieve the largest reductions in HCV-related morbidity and mortality. This suggests that increased capacity for screening and treatment will be critical in many countries. Birth cohort screening is a helpful tool for maximizing resources. In most of the studied countries, the majority of patients were born between 1945 and 1985.

The present and future disease burden of hepatitis C virus (HCV) infections with today's treatment paradigm - volume 2.

Morbidity and mortality attributable to chronic hepatitis C virus (HCV) infection are increasing in many countries as the infected population ages. Models were developed for 15 countries to quantify and characterize the viremic population, as well as estimate the number of new infections and HCV related deaths from 2013 to 2030. Expert consensus was used to determine current treatment levels and outcomes in each country. In most countries, viremic prevalence has already peaked. In every country studied, prevalence begins to decline before 2030, when current treatment levels were held constant. In contrast, cases of advanced liver disease and liver related deaths will continue to increase through 2030 in most countries. The current treatment paradigm is inadequate if large reductions in HCV related morbidity and mortality are to be achieved.

Health-seeking behaviour among adults with prolonged cough in Vietnam.

OBJECTIVE: To assess health-seeking behaviour among adults with prolonged cough in a population-based, nationally representative sample in Vietnam. METHODS: Cross-sectional survey conducted from September 2006 to July 2007. All inhabitants aged ≥15 years were invited for screening for cough, history of tuberculosis (TB) treatment and chest X-ray (CXR) examination. TB suspects, defined as any survey participant with CXR abnormalities consistent with TB, or productive cough for more than 2 weeks or TB treatment either currently or in the preceding 2 years submitted sputum specimens for smear examination and culture and provided information on health-seeking behaviour in an in-depth interview. RESULTS: Of 94 179 persons participating in the survey, 4.6% had prolonged productive cough. Forty-four percentage of those had sought health care and reported pharmacies (35%), commune health posts (29%), public hospitals (24%) and private physicians (10%) as first point of contact. Only 7% had undergone sputum smear examination. Of TB suspects with prolonged productive cough, 2.9% were diagnosed with TB; 10.2% of these reported smear and 21.9% reported X-ray examination when visiting a health care facility. The average patient delay was 4.1 weeks (95% CI: 3.9-4.4) among cough suspects and 4.0 weeks (95% CI: 3.1-4.9) among TB cases. CONCLUSIONS: In this Vietnamese survey, nearly half of persons with cough for more than 2 weeks had visited a health care provider. The commonest first health facility contacted was the pharmacy. Sputum smears were rarely examined, except in the provincial TB hospital. Our findings highlight the need to improve diagnostic practices by retraining health staff on the performance of sputum examination for TB suspects.

High tuberculosis prevalence in a psychiatric hospital in Vietnam.

Little is known about tuberculosis (TB) prevalence in psychiatric hospitals in Vietnam, but prevalence may be higher than in the general population. We assessed the TB prevalence among in-patients of a psychiatric hospital in 2005 in Danang City, Vietnam. Of 300 in-patients, 70 had an abnormal X-ray or prolonged cough, and underwent sputum smear examinations. The prevalence of smear-positive TB was 0.33% (1/300, 95%CI 0.008-1.9). Twenty-three (7.7%) patients had X-ray lesions suggesting active TB and 22 (7.3%) had a history of TB treatment. TB prevalence was high in this psychiatric hospital, and TB infection control needs strengthening.

Low tuberculosis notification in mountainous Vietnam is not due to low case detection: a cross-sectional survey.

BACKGROUND: Studies show that tuberculosis notification declines with increasing altitude. This can be due to declining incidence or declining case detection. In Vietnam notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in Vietnam in general (69/100,000 population). In order to clarify whether this is explained by low incidence or low case detection, we aimed to assess the prevalence of new smear-positive tuberculosis among adults with prolonged cough in three mountainous provinces in central Vietnam. METHODS: A house-to-house survey of persons (> or = 15 years) was carried out in twelve randomly selected districts in 2003. Three sputum specimens were microscopically examined of persons reporting a prolonged cough (> or = 3 weeks). Case detection was assessed by the ratio between notification and prevalence. RESULTS: Of 68,946 included persons (95% response), 1,298 (1.9% 95%CI 1.8-2.2) reported a prolonged cough. Of these, eighteen were sputum smear-positive of whom two had had anti-tuberculosis treatment. The prevalence of new smear-positive tuberculosis was 27/100,000 (95%CI 11-44/100,000) and the notification rate was 44/100,000 among persons > or = 15 years. The estimated case detection rate was 76%. CONCLUSION: Low tuberculosis notification in this mountainous setting is probably a true reflection of low tuberculosis incidence. Possible causes for low incidence in mountainous areas include low transmission rates or altitude-related differences in pathology.

Steep increases in tuberculosis notification among young men in the industrialised districts of Danang, Vietnam.

BACKGROUND: Tuberculosis (TB) notification is increasing among young adults in urban provinces in Vietnam, despite having achieved World Health Organization targets for treatment success and case detection. OBJECTIVES: To identify causes for non-declining TB case rates in an urban area of Vietnam, and to describe trends in new smear-positive pulmonary TB notification by age, sex and district in the period 1999-2004 in Danang City, Vietnam. RESULTS: Age and sex-standardised notification rates declined by 1.3% (95%CI -2.3-0.3%) annually. Notification rates among men aged 15-44 in Danang City increased significantly (5%, 95%CI 2.4-7.7 annually), most notably in industrialised districts (>or=12% annually). CONCLUSION: TB notification rates among young men in an urban setting in Vietnam increased most notably in industrialised districts. We hypothesise that this is due to poor living and working conditions and internal migration rather than to an emerging human immunodeficiency virus epidemic.

Survival and relapse rate of tuberculosis patients who successfully completed treatment in Vietnam.

SETTING: Reported tuberculosis (TB) cure rates are high in Vietnam with the 8-month short-course chemotherapy regimen. However, long-term treatment outcomes are unknown. OBJECTIVE: To assess survival and relapse rates among patients successfully treated for new smear-positive pulmonary tuberculosis (PTB). METHODS: A cohort of patients treated in 32 randomly selected districts in northern Vietnam were followed up 12-24 months after reported cure or treatment success for survival and bacteriologically confirmed relapse. Measurements included sputum smear examination, culture and interview for recent treatment history. RESULTS: Of 304 patients included in the study, no information was available for 31 (10%) and 19 (6%) had died. Bacteriology results were available for 244 (80%). The median interval between treatment completion and follow-up was 19 months. Relapse was recorded in 21/244 (8.6%, 95%CI 5.4-13), including 9 (4%) with positive sputum smears, 3 (1%) with negative smears but positive culture and 9 (4%) who had started TB retreatment. Four of 12 culture-positive relapse cases (33%) had multidrug-resistant strains. If the definition of relapse was extended to include death, reportedly due to TB, the relapse proportion was 26/263 (9.9%, 95%CI 6.6-14). CONCLUSION: A substantial proportion of patients (15%) had died or relapsed after being successfully treated for TB in northern Vietnam.

Lower hormone dosage with improved cycle control.

Cycle control is a key factor that influences contraceptive acceptability and compliance. In combined oral contraceptives (COC), reducing the daily dose of ethinylestradiol (EE) can compromise cycle control. As NuvaRing, the novel combined contraceptive vaginal ring, releases only 15 microgram/day EE, it was therefore important to closely assess cycle control. A 1-year, multicenter study examined cycle control during NuvaRing use in 1,182 women. Withdrawal bleeding during the 1-week ring-free period occurred in 98.8% of cycles. Early withdrawal bleeding was relatively uncommon (5.6% of cycles); in 24.2% of cycles, withdrawal bleeding, comprising mainly spotting, extended into the next cycle. From cycle 1 onwards, there was a low incidence of irregular bleeding during the 3 weeks of ring use; on average, irregular bleeding occurred in only 4.4% of cycles and consisted mainly of spotting only. In a combined analysis, cycle control achieved using NuvaRing (n = 121) was compared with that of a standard COC containing 30 microg/day EE and 150 microgram/day levonorgestrel (n = 126) over six cycles. Late withdrawal bleeding was significantly more frequent with the COC in all cycles. Irregular bleeding occurred in < 5% of all cycles with NuvaRing and between 5.4% and 38.8% per cycle with the COC. Significantly more women using NuvaRing experienced an ideal 'intended bleeding pattern' compared with COC users at every cycle. This excellent cycle control with NuvaRing is expected to improve convenience and acceptability and result in a high level of compliance.

Lower hormone dosage with improved cycle control.

Cycle control is a key factor that influences contraceptive acceptability and compliance. In combined oral contraceptives (COC), reducing the daily dose of ethinylestradiol (EE) can compromise cycle control. As NuvaRing, the novel combined contraceptive vaginal ring, releases only 15 µg/day EE, it was therefore important to closely assess cycle control. A 1-year, multicenter study examined cycle control during NuvaRing use in 1182 women. Withdrawal bleeding during the 1-week ring-free period occurred in 98.8% of cycles. Early withdrawal bleeding was relatively uncommon (5.6% of cycles); in 24.2% of cycles, withdrawal bleeding, comprising mainly spotting, extended into the next cycle. From cycle 1 onwards, there was a low incidence of irregular bleeding during the 3 weeks of ring use; on average, irregular bleeding occurred in only 4.4% of cycles and consisted mainly of spotting only. In a combined analysis, cycle control achieved using NuvaRing (n = 121) was compared with that of a standard COC containing 30 µg/day EE and 150 µg/day levonorgestrel (n = 126) over six cycles. Late withdrawal bleeding was significantly more frequent with the COC in all cycles. Irregular bleeding occurred in < 5% of all cycles with NuvaRing and between 5.4% and 38.8% per cycle with the COC. Significantly more women using NuvaRing experienced an ideal 'intended bleeding pattern' compared with COC users at every cycle. This excellent cycle control with NuvaRing is expected to improve convenience and acceptability and result in a high level of compliance.

A large observational clinical evaluation of a desogestrel-containing combiphasic oral contraceptive in Germany.

OBJECTIVE: The aim of this observational study was to assess the influence of a new combiphasic oral contraceptive on cycle control, tolerability and acne in a large cohort of women who wanted to switch from their previous oral contraceptive. METHODS: A total of 2,280 women were enrolled in this clinical evaluation at 232 centers in Germany. All women switched from their previous pill to a combiphasic oral contraceptive containing ethinylestradiol and desogestrel (combiphasic EE/DSG; comprising 25 microg desogestrel and 40 microg ethinylestradiol for 7 days followed by 125 microg desogestrel and 30 microg ethinylestradiol for 15 days and then a 6-day pill-free interval) for three cycles. RESULTS: Most women (53%) had previously used a monophasic oral contraceptive containing 20 or 30-35 microg ethinylestradiol. The most frequent reasons for switching were bleeding irregularities (41% of women), other menstrual disorders (27%) and migraine/headache (10%). After switching to combiphasic EE/DSG, cycle control improved significantly: the incidences of spotting and breakthrough bleeding decreased from 33% and 23% of women, respectively, before the start of the study, to 7% and 3% of women at the end of the study period. At the end of the study, acne was no longer present in 37% of the 592 women who had acne at the start of the study, and subjective complaints such as headaches were less frequent than before. Most women were satisfied or very satisfied with the combiphasic oral contraceptive and 89% wished to continue using it. CONCLUSIONS: The results of this observational clinical evaluation indicate that in everyday use, for women who wish to switch from another oral contraceptive, combiphasic EE/DSG is an effective and well-tolerated oral contraceptive, which improves cycle control and has a beneficial effect on acne.

Multicenter study of the efficacy, cycle control and tolerability of a phasic desogestrel-containing oral contraceptive.

OBJECTIVE: To investigate the efficacy, cycle control and tolerability of a phasic oral contraceptive containing ethinylestradiol 35/30/30 microg and desogestrel 50/100/150 microg. METHODS: A multicenter study was conducted involving 2070 healthy, fertile women, who received study treatment for six treatment cycles. RESULTS: Most of the participants (79%) had previously been using an alternative oral contraceptive. In 10,408 treatment cycles, two women became pregnant while on treatment (Pearl index, 0.25). The incidence of irregular bleeding was 10% before treatment, rising to 27% at cycle 1, and decreasing to 11% by cycle 6. Irregular bleeding was mainly due to spotting rather than breakthrough bleeding and the incidence of breakthrough bleeding remained below 2.2% for most of the study period. Only 1.8% of women withdrew due to bleeding irregularities. First-time oral contraceptive users initially experienced more irregular bleeding than switchers but these differences lessened over time. The most common adverse events during treatment were headache, breast tenderness and nausea. The incidence of these adverse events fell to below pretreatment levels with continued use. CONCLUSION: The phasic preparation was effective and well tolerated.

The National Leprosy Control Programme of Zimbabwe a data analysis, 1983-1992.

Prevalence and detection rates of leprosy in Zimbabwe as well as patient characteristics were reported by the National Leprosy Control Programme over the 10-year period 1983-1992. The control programme made a new start in 1983 when multidrug therapy was introduced. Prevalence per 10,000 population declined steeply from 3.78 in 1983 to 0.52 in 1987. Prevalence continued to decline to 0.22 in 1992 and was highest in the north-eastern provinces. After an initial increase, the detection rate per 10,000 had declined from 0.19 in 1985 to 0.08 in 1992. The proportion of refugees among new cases had gradually increased since 1988 and amounted to one third in 1991 and 1992. An analysis of records of 802 cases who were newly detected from 1983 to 1992 showed that 51% were of the multibacillary (MB) type, 33% had visible disabilities at detection, 5% were under 15 years of age while the average delay time was 2.6 years. Patients with disabilities reported a longer delay time, were more often men and had more often the MB type of leprosy. The data suggest that transmission of leprosy is low but that cases are not diagnosed early enough to prevent transmission altogether.

A comparison of the cycle control and tolerability of two ultra low-dose oral contraceptives containing 20 micrograms ethinylestradiol and either 150 micrograms desogestrel or 75 micrograms gestodene.

OBJECTIVE: To compare the cycle control and tolerability of two oral contraceptives containing 20 micrograms ethinylestradiol and either 150 micrograms desogestrel or 75 micrograms gestodene. METHODS: A randomized, multicenter study was conducted in which 1016 healthy adult women received the desogestrel (n = 509) or the gestodene (n = 507) preparation for six treatment cycles. RESULTS: No significant differences in bleeding patterns were detected between the two treatments. The incidence and duration of irregular bleeding decreased markedly, and to a similar extent, during each treatment. The occurrence of irregular bleeding per cycle decreased from 24.6 to 9.4% in the desogestrel group and from 19.7 to 8.6% in the gestodene group. Its duration fell from 1.1 to 0.2 days and from 0.9 to 0.3 days, respectively. There was a consistently low incidence of amenorrhea (1.0-2.8%). There were no significant differences between treatments for the incidence, intensity or emergence of dysmenorrhea. During both treatments, the incidence of premenstrual syndrome and complaints such as breast tenderness, nausea and headache dropped markedly. CONCLUSION: Ultra low-dose oral contraceptives containing desogestrel or gestodene offer equivalent, good cycle control and improvements in dysmenorrhea and premenstrual syndrome and have similar, excellent tolerability profiles.

The effects of cimetidine, ranitidine and famotidine on the single-dose pharmacokinetics of naproxen and its metabolites in humans.

We studied the effects of cimetidine, ranitidine and famotidine on the kinetics of naproxen. The mean t1/2 beta of naproxen in 6 subjects was 25.7 +/- 5.4 h (range 16 to 36). Naproxen acyl glucuronide accounts for 50.9 +/- 6.9% of the dose, its isomerized isoglucuronide for 6.8 +/- 2.6%, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 4.1% and its isoglucuronide for 5.5 +/- 1.5% (n = 6). Naproxen (1.3 +/- 1.1%) and O-desmethylnaproxen (0.6 +/- 0.4%) are excreted in negligible amounts. Cimetidine, ranitidine and famotidine all reduced significantly the t1/2 beta of naproxen by 50% from 25 h to 13 h and the t1/2 alpha from 4.0 h to 1.1 h. No effect of the H2 antagonists was observed on the absorption of naproxen. They also reduced the Vss of naproxen by 50%. The amount of naproxen acyl glucuronide, naproxen isoglucuronide and O-desmethylnaproxen acyl glucuronide excreted in the urine, remained unchanged, 60%, 7%, and 14% respectively.

The pharmacokinetics of naproxen, its metabolite O-desmethylnaproxen, and their acyl glucuronides in humans. Effect of cimetidine.

1. The pharmacokinetics of 500 mg naproxen given orally were described in 10 subjects using a direct h.p.l.c. analysis of the acyl glucuronide conjugates of naproxen and its metabolite O-desmethylnaproxen. 2. The mean elimination half-life of naproxen was 24.7 +/- 6.4 h (range 7 to 36 h). 3. Naproxen acyl glucuronide accounted for 50.8 +/- 7.3% of the dose recovered in the urine, its isomerised conjugate isoglucuronide for 6.5 +/- 2.0%, O-desmethylnaproxen acyl glucuronide for 14.3 +/- 3.4%, and its isoglucuronide for 5.5 +/- 1.3%. Naproxen and O-desmethylnaproxen were excreted in negligible amounts (< 1%). 4. Even though the urine pH of the subjects was kept acid in order to stabilize the acyl glucuronides, isomerisation took place in blood. 5. The extents of plasma binding of the unconjugated compounds were 98% (naproxen) and 100% (O-desmethylnaproxen), while naproxen acyl glucuronide binding was 92%; that of its isomer isoglucuronide 66%. O-desmethylnaproxen acyl glucuronide was 72% bound and its isoglucuronide was 42% bound. 6. Cimetidine (400 mg twice daily) decreased the t1/2 of naproxen by 39-60% (mean 47.3 +/- 11.5%; P = 0.0014) from 24.7 +/- 6.4 h to 13.2 +/- 1.0 h. It increased (10%) the urinary recovery of naproxen acyl glucuronide (P = 0.0492). The urinary recoveries of naproxen isoglucuronide and O-desmethylnaproxen acyl glucuronide remained unchanged.

O-Dealkylation and N4-acetylation of sulpha-2-monomethoxine by the turtle Pseudemys scripta elegans.

Sulpha-2-monomethoxine is N4-acetylated to an extent of 12% of the dose by Pseudemys scripta elegans; 48% is excreted unchanged. No O-dealkylation of the 2-methoxy group takes place.