Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

The use of anthropometric measures in the prediction of incident gout: results from a Swedish community-based cohort study.

Objectives: To study associations between different anthropometric measures and incident gout, and to find the best predictive measure. Method: We used the baseline investigation from the Malmö Diet and Cancer study, excluding cases of prevalent gout (n = 28 081). Cox regression for each anthropometric measurement was calculated per standard deviation increment for men and women, with hazard ratios (HRs) and 95% confidence intervals (CIs), using a hospital diagnosis of incident gout (M10) during follow-up as the outcome. Incremental C-statistics for each anthropometric measure were used to determine the measure with the best predictive capacity, in models adjusted for age, socio-economic data, lifestyle factors, comorbidities, and antihypertensive medications. Results: The study population included 11 049 men and 17 032 women, with 633 incident gout cases, 393 in men (3.6%) and 240 in women (1.4%). For both men and women, the five anthropometric measurements with highest C-statistics were weight, body mass index (BMI), waist circumference (WC), hip circumference, and waist-to-height ratio; in men, the measurement with the highest C-statistic was BMI (0.7361; fully adjusted HR 1.52, 95% CI 1.39-1.68), and in women WC (0.8085; fully adjusted HR 1.62, 95% CI 1.46-1.81). The increment in C-statistic with anthropometric measures was good, around 0.035. Waist-to-hip ratio, waist-to-hip-to-height ratio, body fat percentages, and especially A Body Shape Index had lower C-statistics. Conclusions: Both BMI and WC showed good predictive ability for incident gout. The clinically used cut-offs for BMI and WC appeared to be relevant in the assessment of increased risk of gout.

Prediction of persistent ectopic pregnancy after laparoscopic salpingostomy.

OBJECTIVE: To evaluate whether preoperative measurements of progesterone and hCG in serum can predict the risk of needing a second therapeutic intervention after laparoscopic salpingostomy. METHODS: In 158 patients with unruptured tubal pregnancies smaller than 4 cm, serum progesterone and hCG levels were measured in two venous blood samples taken preoperatively. Fourteen complicated cases, in which a second therapeutic intervention was necessary, were compared with 144 uncomplicated cases. RESULTS: Eleven of the 14 complicated cases (79%) had preoperative progesterone values exceeding 35 nmol/L, whereas this was true for only 15 (10%) of the uncomplicated cases. Among the complicated cases, 12 (86%) had preoperative daily hCG changes above 100 IU/L, compared to 44 (31%) of the uncomplicated cases. Cases with a progesterone level above 35 nmol/L and a daily hCG change exceeding 100 IU/L had a 61% risk for a second therapeutic intervention, whereas with a progesterone value below 35 nmol/L and/or a daily hCG change of less than 100 IU/L, the risk was only 2%. CONCLUSION: The risk for a second therapeutic intervention after laparoscopic salpingostomy for ectopic pregnancy can be predicted by the combined use of two sequential serum hCG samples and one serum progesterone sample, the last of each taken within 24 hours preoperatively.

Regulation of corpus luteum function in early human pregnancy.

OBJECTIVE: To investigate the capacity of the human corpus luteum (CL) of pregnancy to form cyclic adenosine-3',5'-monophosphate (cAMP) and P in vitro in response to hCG and prostaglandin (PG) E2. DESIGN: Six women undergoing sterilization concomitant with legal abortion and eight women undergoing surgery for ectopic pregnancy were included. Human chorionic gonadotropin was analyzed preoperatively in two serum samples. The CL were excised and luteal specimens were incubated for 2 hours in the presence or absence of hCG or PGE2. The tissue concentrations of cAMP and P concentrations in the incubation media were measured. The in vitro results were correlated to the preoperative daily change in serum hCG. RESULTS: In CL from pregnancies with normally rising serum hCG levels, the addition of hCG in vitro did not affect luteal cAMP or P production. In pregnancies with plateauing and/or decreasing serum hCG levels, the addition of hCG in vitro significantly stimulated cAMP and P formation, and this stimulatory effect correlated significantly with the preoperative daily change in serum hCG. In contrast to hCG, PGE2 had the same stimulatory effect in vitro on CL specimens from both normal and pathological pregnancies. This effect did not correlate with the preoperative daily change in serum hCG. CONCLUSIONS: Prostaglandin E2 stimulates all CL, irrespective of any changes in preoperative serum hCG levels. In contrast, the stimulatory effect of hCG in vitro does not correlate with changes in serum hCG, and thus CL from pregnancies with normally rising serum hCG levels are refractory to hCG in vitro.

Effects of indomethacin on follicular structure, vascularity, and function over the periovulatory period in women.

OBJECTIVE: To assess the effect of indomethacin (taken at defined times) on follicular rupture, indexes of intrafollicular blood flow, and steroidogenesis. PARTICIPANTS: Six healthy volunteers awaiting treatment for infertility by IVF-ET during subsequent natural cycles. INTERVENTIONS: All women were examined (at least every 8 hours) by transvaginal ultrasonography with color Doppler imaging and had samples of blood taken for hormone analysis. A self-test for urinary LH was performed before each scan. Indomethacin was first taken (50 mg three times per day) according to the maximum follicular diameter (first four women) or when the LH dipstick gave a positive result; the drug was taken for > or = 3 days. RESULTS: Follicular rupture was delayed in five of six cases (by 2 to 12 days). There was a reduction in intrafollicular peak systolic velocity before and after the positive urinary LH test compared with historical controls. Three follicles (50% of women) with the highest peak systolic velocity had an hemorrhagic appearance and persisted longer. There was no significant effect on menstrual cycle length or the levels of circulating FSH, E2, LH, or P. CONCLUSION: Indomethacin administered at the time of a positive self-test for urinary LH can delay follicular rupture with an associated reduction in intrafollicular blood flow but with no apparent effects on hormonal or menstrual status.

Preovulatory changes of blood flow in different regions of the human follicle.

OBJECTIVE: To assess regional changes in ultrasound-derived indices of blood flow in the dominant human follicle after the plasma LH surge. DESIGN: A cross-sectional, prospective study. SETTING: Reproductive medicine unit at a university. PATIENT(S): Women attending an assisted conception clinic to determine the appropriate time to transfer previously frozen embryos during a natural cycle. INTERVENTION(S): Transvaginal ultrasonography with color Doppler imaging and pulsed Doppler spectral analysis was used to obtain indices of blood flow and velocity from vessels in the base, lateral part, and apex of the dominant follicle on days 10-12 (from day 1 of menses) and after the LH surge, but before rupture. Immunoassays were used to measure the blood concentrations of LH twice daily (at 8-10 A.M. and 4-6 P.M.) from cycle day 10. MAIN OUTCOME MEASURE(S): The pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV), and time-averaged maximum velocity (TAMXV) in the uterine arteries and three regions of the dominant follicle (apical, lateral, and basal parts); follicular volume; the day and time of the onset of the LH surge (defined as first concentration of LH > 22 U/L) and the times of each scan. RESULT(S): Twenty-two women (aged 28-39 years) were studied and seven were scanned on days 10-12. A retrospective examination of the data from the remainder showed that eight were scanned < 20 hours after onset of the LH surge and seven were scanned > 20 hours after the onset of the LH surge. There was a significant increase in follicular volume after the LH surge. The PI was similar in vessels from the base (0.86 +/- 0.11; mean +/- SEM), lateral part (0.72 +/- 0.51) and apex (0.67 +/- 0.09) at cycle days 10-12 and then gradually decreased in the apex. There were similar changes in the RI. The PSV (mean +/- SEM; cm/s) was similar in vessels from the base (10.1 +/- 1.64), lateral side (8.2 +/- 1.43), and apex (9.2 +/- 1.91) in follicles of days 10-12. Within 20 hours of the onset of the LH surge, the PSV had increased in basal vessels (23.4 +/- 4.10), remained similar in lateral vessels (11.64 +/- 3.18), and was undetectable in apex vessels from six of eight follicles. Twenty hours after the LH surge, there was no pulsatile blood flow observed in the apical part of the follicle, but there was a sustained high PSV in the base (15.73 +/- 3.42) and lateral side (9.02 +/- 1.5). There were corresponding changes in the TAMXV. CONCLUSION(S): During the ovulatory process there are prominent changes in the regional blood flow of the follicle with a marked increase of the flow to the base of the follicle and a concomitant decrease of blood flow to the apex. These changes may be essential for the release of a mature oocyte.

Ultrasound studies of vascular and morphological changes in the human corpus luteum during the menstrual cycle.

OBJECTIVE: To determine changes in corpus luteum (CL) volume, echogenicity, vascularity, and P production relative to a positive test result for urinary LH and day 1 of next menses. SUBJECTS: Thirteen healthy volunteers (age 23 to 32 years). INTERVENTIONS: All women underwent transvaginal ultrasonography on cycle day 11 and a urinary LH self-test was used daily. The plan was to rescan all women immediately after a positive test result and then at least every 48 hours (until day 6 of the next cycle); samples of peripheral blood were taken for analysis. MAIN OUTCOME MEASURES: The times of follicular rupture, a positive urinary LH test, and the start of menses; CL volume and echogenicity, maximum peak systolic velocity and minimum impedance, the circulating levels of serum P, E2, LH, and FSH. RESULTS: Nine women fulfilled criteria for an ovulatory cycle. There was a good correlation between peak systolic velocity, CL volume, and the concentration of serum P from day 4 to 10 after a positive LH test. Peak systolic velocity reached a maximum value between days 7 and 9 relative to a positive urinary LH test and started to decline from day 1 of menses minus 3, 4 days. CONCLUSION: Changes in peak systolic velocity from the time of a positive urinary LH self-test might be a useful adjunct for monitoring CL function.

[Of what significance is abnormal result of smear test? Anxiety because of insufficient information in connection with abnormal result of cervical smear test]. / Vad betyder cellförändringarna? Dålig information om avvikande cytologprov skapar onödig oro.

The purpose of the study was to investigate possible differences in psychological response between two groups of women after pathological cervical smear tests (CIN I or recurrent CIN I and/or CIN II-III respectively). 43 women participated. A standardised questionnaire was used. In 75 percent of the cases the result was given over the telephone. The number of women who reacted with medium to strong anxiety in the CIN I group (15/22) did not differ from those in the group with CIN II-III (15/21). 45 percent of the women in the CIN I group thought their lesions to be malignant. 64 percent of the women in the CIN I group, as compared to 38 percent of the women in the CIN II-III group, benefitted from the additional information they asked for and received. A majority of the women would have liked more information as well as the opportunity to discuss the findings in a more personal way.

[Aids in the management of pathological pregnancies. Advances in current knowledge of corpus luteum function]. / Hjälp vid handläggning av patologiska graviditeter. Ny kunskap om gulkroppens funktion.

Technological advances during the past decade have yielded new knowledge of luteal function and its regulation. A number of new substances with luteotrophic and lutcolytic properties have been identified in the corpus luteum, and the picture which emerges of the mechanisms responsible for physiological luteolysis is becoming increasingly complex. As luteal function/regulation during the menstrual cycle in the absence of pregnancy differs both from that in normal pregnancy, and from that in pathological pregnancy, these advances in our knowledge should prove clinically useful, particularly with regard to the early diagnosis and management of pathological pregnancy.

Prediction of persistent trophoblastic activity after local prostaglandin F2 alpha injection for ectopic pregnancy.

A total of 60 patients underwent injection of prostaglandin (PG)F2 alpha into the affected tube and corpus luteum. Two serum samples, with a mean interval of 2.1 days, were taken pre-operatively and human chorionic gonadotrophin (HCG) and progesterone were determined by fluoroimmunoassay retrospectively. Cases requiring a second intervention (n = 8) were compared with uncomplicated cases (n = 52). The receiver-operator characteristic curve was used to determine optimal discriminatory levels of each diagnostic test. Among the complicated cases, 75% had progesterone values > 20 nmol/l and 100% had a daily HCG increase > 50 IU/l. The corresponding figures for the uncomplicated cases were 17% and 23% respectively. A 'high-risk' group representing 12% of the patient material was identified, and was biochemically profiled by serum progesterone values > 20 nmol/l, together with daily HCG changes > +50 IU/l/day. These patients had an 86% risk for a second intervention. Conversely, 88% of patients had only a 4% risk for such an intervention. We conclude that the combined use of two sequential serum HCG samples and one serum progesterone sample, the last of each taken not more than 24 h pre-operatively, can predict the risk for a complicated course following local injection of 15-methyl-PGF2 alpha for small tubal pregnancies.

Cell characteristics and function of two enriched fraction of human luteal cells prolonged culture.

Two subpopulations of steroidogenic cells exist in the corpus luteum of most species. The aims of the present study were to characterize these cells and to study their function during long-term culture. Human corpora lutea from early and late luteal phases were treated by mechanical and enzymatic digestion, followed by density sedimentation. Five distinct cell bands were obtained, two of which produced large amounts of progesterone. These were characterized according to density, size, steroidogenic enzymes, and numbers. More than 75% of cells expressed immunoreactive 3beta-hydroxydehydrogenase (3beta-HSD). Cells of higher density/smaller size were obtained in increasing numbers during the luteal phase and were more numerous compared with large cells. Under basal, human chorionic gonadotrophin (HCG)-, and prostaglandin E(2)-stimulated culture conditions, progesterone synthesis was greater in large cells of the early, but not late, luteal phase. Both cell fractions obtained from late, in contrast to early, luteal phase increased their basal progesterone production during the culture period of 9 days. We conclude that this technique for luteal cell isolation in the human yields two distinct subpopulations of steroidogenic cells, which respond differently to luteotrophic stimuli. We also conclude that cells of late luteal phase readily increase their progesterone synthesis over a period of 9 days, indicating a transition to longevity.

Ultrasound studies of vascular and morphological changes in the human uterus after a positive self-test for the urinary luteinizing hormone surge.

The aim of the study reported here was to establish complementary data for changes in uterine size, echogenicity and vascularity during the menstrual cycle relative to a positive self-test for urinary luteinizing hormone (LH) and day 1 of next menses. Thirteen volunteers (aged 23-32 years) with apparently regular menstrual cycles were recruited from the nursing staff. The plan was to examine all women by transvaginal ultrasonography with colour Doppler imaging on day 11 of the menstrual cycle. A urinary LH self-test was to be used daily until a positive result was obtained and the women were to be re-scanned daily until the dominant follicle had ruptured. All women were then to be scanned at least every 48 h (within +/- 2 h of the same time of day) until day 6 of the next menstrual cycle. Matched samples of peripheral blood were taken at the time of each scan for hormone analysis. The main outcome measures were the times of follicular rupture, a positive test result for urinary LH and the start of menses, uterine volume, cavity length, endometrial thickness and grade, pulsatility index (PI), and time-averaged and peak systolic maximum velocities in uterine and radial arteries and in subendometrial vessels. Nine women fulfilled the criteria for an ovulatory cycle, and seven provided data over the complete study. The principal changes relative to a positive urinary LH test were (i) a continued rise in endometrial thickness to days 3 and 4 (this index then remained relatively constant, but the layered appearance was lost) and (ii) a gradual decrease in the uterine arterial PI. There was a significant rise in uterine volume, cavity length and uterine arterial PI around the time of the next menses, and a fall in endometrial thickness and blood velocity in the uterine and radial arteries and subendometrial vessels. The data may have implications for the assessment of reproductive status and the design of future studies on disorders of implantation or menstruation.