BACKGROUND
Across the developed world couples are postponing parenthood. This review assesses the consequences of delayed family formation from a demographic and medical perspective. One main focus ...is on the quantitative importance of pregnancy postponement.
METHODS
Medical and social science databases were searched for publications on relevant subjects such as delayed parenthood, female and male age, fertility, infertility, time to pregnancy (TTP), fetal death, outcome of medically assisted reproduction (MAR) and mental well-being.
RESULTS
Postponement of parenthood is linked to a higher rate of involuntary childlessness and smaller families than desired due to increased infertility and fetal death with higher female and male age. For women, the increased risk of prolonged TTP, infertility, spontaneous abortions, ectopic pregnancies and trisomy 21 starts at around 30 years of age with a more pronounced effects >35 years, whereas the increasing risk of preterm births and stillbirths starts at around 35 years with a more pronounced effect >40 years. Advanced male age has an important but less pronounced effect on infertility and adverse outcomes. MAR treatment cannot overcome the age-related decline in fecundity.
CONCLUSIONS
In general, women have partners who are several years older than themselves and it is important to focus more on the combined effect of higher female and male age on infertility and reproductive outcome. Increasing public awareness of the impact of advanced female and male age on the reproductive outcome is essential for people to make well-informed decisions on when to start family formation.
STUDY QUESTION
What is the prevalence in a normal population of polycystic ovary syndrome (PCOS) according to the Rotterdam criteria versus revised criteria including anti-Müllerian hormone (AMH)?
...SUMMARY ANSWER
The prevalence of PCOS was 16.6% according to the Rotterdam criteria. When replacing the criterion for polycystic ovaries by antral follicle count (AFC) > 19 or AMH > 35 pmol/l, the prevalence of PCOS was 6.3 and 8.5%, respectively.
WHAT IS KNOWN ALREADY?
The Rotterdam criteria state that two out of the following three criteria should be present in the diagnosis of PCOS: oligo-anovulation, clinical and/or biochemical hyperandrogenism and polycystic ovaries (AFC ≥ 12 and/or ovarian volume >10 ml). However, with the advances in sonography, the relevance of the AFC threshold in the definition of polycystic ovaries has been challenged, and AMH has been proposed as a marker of polycystic ovaries in PCOS.
STUDY DESIGN, SIZE, DURATION
From 2008 to 2010, a prospective, cross-sectional study was performed including 863 women aged 20–40 years and employed at Copenhagen University Hospital, Rigshospitalet, Denmark.
PARTICIPANTS/MATERIAL, SETTING, METHODS
We studied a subgroup of 447 women with a mean (±SD) age of 33.5 (±4.0) years who were all non-users of hormonal contraception. Data on menstrual cycle disorder and the presence of hirsutism were obtained. On cycle Days 2–5, or on a random day in the case of oligo- or amenorrhoea, sonographic and endocrine parameters were measured.
MAIN RESULTS AND THE ROLE OF CHANCE
The prevalence of PCOS was 16.6% according to the Rotterdam criteria. PCOS prevalence significantly decreased with age from 33.3% in women < 30 years to 14.7% in women aged 30–34 years, and 10.2% in women ≥ 35 years (P < 0.001). In total, 53.5% fulfilled the criterion for polycystic ovaries with a significant age-related decrease from 69.0% in women < 30 years to 55.8% in women aged 30–34 years, and 42.8% in women ≥ 35 years (P < 0.001). AMH or age-adjusted AMH Z-score was found to be a reliable marker of polycystic ovaries in women with PCOS according to the Rotterdam criteria area under the curve (AUC) 0.994; 95% confidence interval (CI): 0.990–0.999 and AUC 0.992 (95% CI: 0.987–0.998), respectively, and an AMH cut-off value of 18 pmol/l and AMH Z-score of −0.2 showed the best compromise between sensitivity (91.8 and 90.4%, respectively) and specificity (98.1 and 97.9%, respectively). In total, AFC > 19 or AMH > 35 occurred in 17.7 and 23.0%, respectively. The occurrence of AFC > 19 or AMH > 35 in the age groups < 30, 30–34 and ≥ 35 years was 31.0 and 35.7%, 18.8 and 21.3%, and 9.6 and 18.7%, respectively. When replacing the Rotterdam criterion for polycystic ovaries by AFC > 19 or AMH > 35 pmol/l, the prevalence of PCOS was 6.3 or 8.5%, respectively, and in the age groups < 30, 30–34 and ≥ 35 years, the prevalences were 17.9 and 22.6%, 3.6 and 5.6%, and 3.6 and 4.8%, respectively.
LIMITATIONS, REASON FOR CAUTION
The participants of the study were all health-care workers, which may be a source of selection bias. Furthermore, the exclusion of hormonal contraceptive users from the study population may have biased the results, potentially excluding women with symptoms of PCOS.
WIDER IMPLICATIONS OF THE FINDINGS
AMH may be used as a marker of polycystic ovaries in PCOS. However, future studies are needed to validate AMH threshold levels, and AMH Z-score may be appropriate to adjust for the age-related decline in the AFC.
STUDY FUNDING/COMPETING INTEREST(S)
None.
TRIAL REGISTRATION NUMBER
Not applicable.
To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT).
Adult patients with brain metastases received WBRT and were randomized to ...receive placebo or memantine (20 mg/d), within 3 days of initiating radiotherapy for 24 weeks. Serial standardized tests of cognitive function were performed.
Of 554 patients who were accrued, 508 were eligible. Grade 3 or 4 toxicities and study compliance were similar in the 2 arms. There was less decline in delayed recall in the memantine arm at 24 weeks (P = .059), but the difference was not statistically significant, possibly because there were only 149 analyzable patients at 24 weeks, resulting in only 35% statistical power. The memantine arm had significantly longer time to cognitive decline (hazard ratio 0.78, 95% confidence interval 0.62-0.99, P = .01); the probability of cognitive function failure at 24 weeks was 53.8% in the memantine arm and 64.9% in the placebo arm. Superior results were seen in the memantine arm for executive function at 8 (P = .008) and 16 weeks (P = .0041) and for processing speed (P = .0137) and delayed recognition (P = .0149) at 24 weeks.
Memantine was well tolerated and had a toxicity profile very similar to placebo. Although there was less decline in the primary endpoint of delayed recall at 24 weeks, this lacked statistical significance possibly due to significant patient loss. Overall, patients treated with memantine had better cognitive function over time; specifically, memantine delayed time to cognitive decline and reduced the rate of decline in memory, executive function, and processing speed in patients receiving WBRT. RTOG 0614, ClinicalTrials.gov number CT00566852.
Abstract It remains controversial whether anti-Müllerian hormone (AMH) concentration is influenced by hormonal contraception. This study quantified the effect of hormonal contraception on both ...endocrine and sonographic ovarian reserve markers in 228 users and 504 non-users of hormonal contraception. On day 2–5 of the menstrual cycle or during withdrawal bleeding, blood sampling and transvaginal sonography was performed. After adjusting for age, ovarian reserve parameters were lower among users than among non-users of hormonal contraception: serum AMH concentration by 29.8% (95% CI 19.9 to 38.5%), antral follicle count (AFC) by 30.4% (95% CI 23.6 to 36.7%) and ovarian volume by 42.2% (95% CI 37.8 to 46.3%). AFC in all follicle size categories (small, 2–4 mm; intermediate, 5–7 mm; large, 8–10 mm) was lower in users than in non-users of hormonal contraception. A negatively linear association was observed between duration of hormonal-contraception use and ovarian reserve parameters. No dose–response relation was found between the dose of ethinyloestradiol and AMH or AFC. This study indicates that ovarian reserve markers are lower in women using sex steroids for contraception. Thus, AMH concentration and AFC may not retain their accuracy as predictors of ovarian reserve in women using hormonal contraception. Serum anti-Müllerian hormone (AMH) concentration is an indirect marker of the number of small follicles in the ovary and thereby the ovarian reserve. The AMH concentration is now widely used as one of the markers of the ovarian reserve in ovarian hormonal stimulation regimens. Hence the AMH concentration in a patient is used to decide the dose of the ovarian hormonal stimulation prior to IVF treatment. In some infertile patients, hormonal contraception is used prior to ovarian hormonal stimulation and therefore it is important to clarify whether serum AMH concentration is influenced by the use of sex steroids. The aim of this study was to quantify the potential effect of hormonal contraception on the ovarian function by hormonal analyses and ovarian ultrasound examination. Examinations were performed in the early phase of the menstrual cycle or the hormone-free interval of hormonal contraception. We compared the AMH concentration, the antral follicle count (AFC) and the ovarian volume in 228 users versus 504 non-users of hormonal contraception. Users of hormonal contraception had 29.8% lower AMH concentration, 30.4% lower AFC and 42.2% lower ovarian volume than non-users. These findings were more pronounced with increasing duration of hormonal contraception. No dose–response relation was found between the dose of ethinylestradiol and the impact on serum AMH and AFC. The study indicates that ovarian reserve markers are lower in women using sex steroids for contraception. Thus, serum AMH concentration and AFC may not retain their accuracy as predictors of the ovarian reserve in women using hormonal contraception.
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Global losses of biodiversity are occurring at an unprecedented rate, but causes are often unidentified. Genomic data provide an opportunity to isolate drivers of change and even predict future ...vulnerabilities. Atlantic salmon (Salmo salar) populations have declined range-wide, but factors responsible are poorly understood. Here, we reconstruct changes in effective population size (N
) in recent decades for 172 range-wide populations using a linkage-based method. Across the North Atlantic, N
has significantly declined in >60% of populations and declines are consistently temperature-associated. We identify significant polygenic associations with decline, involving genomic regions related to metabolic, developmental, and physiological processes. These regions exhibit changes in presumably adaptive diversity in declining populations consistent with contemporary shifts in body size and phenology. Genomic signatures of widespread population decline and associated risk scores allow direct and potentially predictive links between population fitness and genotype, highlighting the power of genomic resources to assess population vulnerability.
To analyze the relationship between pre-treatment measurements of tumor oxygen tension (pO
2) and survival in advanced head and neck cancer.
Eppendorf pO
2 measurements in 397 patients from seven ...centers were analyzed using the fraction of pO
2 values ≤2.5
mmHg (HP
2.5), ≤5
mmHg (HP
5) and median tumor pO
2 (mmHg) as descriptors. All patients had intended curative radiation therapy alone or as pre- or post-operative radiotherapy or radio-chemotherapy according to the practice at each center.
The degree of hypoxia varied between tumors with an overall median tumor pO
2=9
mmHg (range 0–62
mmHg), a median HP
2.5=19% (range 0–97%) and HP
5=38%, (range 0–100%). By quadratic regression median tumor pO
2 correlated with Hb (2
P=0.026,
n=357), while HP
2.5 or HP
5 did not. HP
2.5 above the population median was the only parameter that associated with poor overall survival (Kaplan Meier analysis,
P=0.006). In a multivariate Cox Proportional Hazards analysis, stratified according to institution HP
2.5 was by far the most statistically significant factor in explaining the variability in survival. After adjusting for HP
2.5, clinical stage, radiation dose and surgery hemoglobin concentration was not significant in the model. The prognostic model shows that the 5-year survival is almost constant for HP
2.5 values in the range from 0 to 20%, whereas the 5-year survival approaches 0% in the most hypoxic tumors.
This study provides evidence that tumor hypoxia is associated with a poor prognosis in patients with advanced head and neck cancer.
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Abstract
STUDY QUESTION
Do infertile patients below the age of 40 years have a lower ovarian reserve, estimated by anti-Müllerian hormone (AMH) and total antral follicle count (AFC), than women of ...the same age with no history of infertility?
SUMMARY ANSWER
Serum AMH and AFC were not lower in infertile patients aged 20–39 years compared with a control group of the same age with no history of infertility.
WHAT IS KNOWN ALREADY?
The management of patients with a low ovarian reserve and a poor response to controlled ovarian stimulation (COS) remains a challenge in assisted reproductive technologies (ART). Both AMH levels and AFC reflect the ovarian reserve and are valuable predictors of the ovarian response to exogenous gonadotrophins. However, there is a large inter-individual variation in the age-related depletion of the ovarian reserve and a broad variability in the levels of AMH and AFC compatible with conception. Women with an early depletion of the ovarian reserve may experience infertility as a consequence of postponement of childbearing. Thus, low ovarian reserve is considered to be overrepresented among infertile patients.
STUDY DESIGN, SIZE, DURATION
A prospective cohort study including 382 women with a male partner referred to fertility treatment at Rigshospitalet, Copenhagen, Denmark during 2011–2013 compared with a control group of 350 non-users of hormonal contraception with no history of infertility recruited during 2008–2010.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Included patients and controls were aged 20–39 years. Women with polycystic ovary syndrome were excluded. On Cycle Days 2–5, AFC and ovarian volume were measured by transvaginal sonography, and serum levels of AMH, FSH and LH were assessed.
MAIN RESULTS AND THE ROLE OF CHANCE
Infertile patients had similar AMH levels (11%, 95% confidence interval (CI): −1;24%) and AFC (1%, 95% CI: −7;8%) compared with controls with no history of infertility in an age-adjusted linear regression analysis. The prevalence of very low AMH levels (<5 pmol/l) was similar in the two cohorts (age-adjusted odds ratio: 0.9, 95% CI: 0.5;1.7). The findings persisted after adjustment for smoking status, body mass index, gestational age at birth, previous conception and chronic disease in addition to age.
LIMITATIONS, REASON FOR CAUTION
The comparison of ovarian reserve parameters in women recruited at different time intervals could be a reason for caution. However, all women were examined at the same centre using the same sonographic algorithm and AMH immunoassay.
WIDER IMPLICATIONS OF THE FINDINGS
This study indicates that the frequent observation of patients with a poor response to COS in ART may not be due to an overrepresentation of women with an early depletion of the ovarian reserve but rather a result of the expected age-related decline in fertility.
STUDY FUNDING/COMPETING INTEREST(S)
The study received funding from MSD and the Interregional European Union (EU) projects ‘ReproSund’ and ‘ReproHigh’. The authors have no conflict of interest.
TRIAL REGISTRATION NUMBER
Not applicable.
Local failure rates after radiation therapy (RT) for locally advanced non-small-cell lung cancer (NSCLC) remain high. Consequently, RT dose intensification strategies continue to be explored, ...including hypofractionation, which allows for RT acceleration that could potentially improve outcomes. The maximum-tolerated dose (MTD) with dose-escalated hypofractionation has not been adequately defined.
Seventy-nine patients with NSCLC were enrolled on a prospective single-institution phase I trial of dose-escalated hypofractionated RT without concurrent chemotherapy. Escalation of dose per fraction was performed according to patients' stratified risk for radiation pneumonitis with total RT doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiotherapy. The MTD was defined as the maximum dose with ≤ 20% risk of severe toxicity.
No grade 3 pneumonitis was observed and an MTD for acute toxicity was not identified during patient accrual. However, with a longer follow-up period, grade 4 to 5 toxicity occurred in six patients and was correlated with total dose (P = .004). An MTD was identified at 63.25 Gy in 25 fractions. Late grade 4 to 5 toxicities were attributable to damage to central and perihilar structures and correlated with dose to the proximal bronchial tree.
Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.
Background
Neutrophil‐lymphocyte ratio (NLR) is a measure of systemic inflammation that appears prognostic in localized and advanced non‐small cell lung cancer (NSCLC). Increased systemic ...inflammation portends a poorer prognosis in cancer patients. We hypothesized that low NLR at diagnosis is associated with improved overall survival (OS) in locally advanced NSCLC (LANSCLC) patients.
Patients and Methods
Records from 276 patients with stage IIIA and IIIB NSCLC treated with definitive chemoradiation with or without surgery between 2000 and 2010 with adequate data were retrospectively reviewed. Baseline demographic data and pretreatment peripheral blood absolute neutrophil and lymphocyte counts were collected. Patients were grouped into quartiles based on NLR. OS was estimated using the Kaplan‐Meier method. The log‐rank test was used to compare mortality between groups. A linear test‐for‐trend was used for the NLR quartile groups. The Cox proportional hazards model was used for multivariable analysis.
Results
The NLR was prognostic for OS (p < .0001). Median survival in months (95% confidence interval) for the first, second, third, and fourth quartile groups of the population distribution of NLR were 27 (19–36), 28 (22–34), 22 (12–31), and 10 (8–12), respectively. NLR remained prognostic for OS after adjusting for race, sex, stage, performance status, and chemoradiotherapy approach (p = .004).
Conclusion
To our knowledge, our series is the largest to demonstrate that baseline NLR is a significant prognostic indicator in LANSCLC patients who received definitive chemoradiation with or without surgery. As an indicator of inflammatory response, it should be explored as a potential predictive marker in the context of immunotherapy and radiation therapy.
Implications for Practice
Neutrophil‐lymphocyte ratio measured at the time of diagnosis was associated with improved overall survival in 276 patients with stage IIIA and IIIB non‐small cell lung cancer (NSCLC) treated with definitive chemoradiation with or without surgery. To our knowledge, our series is the largest to demonstrate that baseline neutrophil‐lymphocyte ratio is a significant prognostic indicator in locally advanced NSCLC patients who received definitive chemoradiation with or without surgery. Neutrophil‐lymphocyte ratio is an inexpensive biomarker that may be easily utilized by clinicians at the time of locally advanced NSCLC diagnosis to help predict life expectancy.
摘要
背景. 中性粒细胞‐淋巴细胞比值（NLR）是全身炎症的衡量指标, 而后者在局部晚期非小细胞肺癌（NSCLC）中具有预后作用。癌症患者全身炎症增加意味着预后较差。我们假设局部晚期NSCLC（LANSCLC）患者诊断时NLR较低与总生存期（OS）改善相关。
患者和方法. 我们回顾性分析了2000年至2010年期间接受确定性放化疗联合或不联合手术治疗且具有充分数据的276例IIIA期和IIIB期NSCLC患者的记录。采集基线人口统计学数据和治疗前外周血中性粒细胞和淋巴细胞绝对计数。根据NLR四分位数对患者进行分组。采用Kaplan‐Meier法估计OS。采用时序检验比较各组的死亡率。采用线性趋势检验分析各个NLR四分位数组。使用Cox比例风险模型进行多变量分析。
结果. NLR是OS的预后指标（p<0.0001）。NLR人群分布的第一、二、三和四四分位数组的中位生存期（95%置信区间）分别为27（19‐36）、28（22‐34）、22（12‐31）和10（8‐12）个月。校正人种、性别、分期、体力状态和放化疗方法后, NLR仍然是OS的预后指标（p=0.004）。
结论. 据我们所知, 本研究是规模最大的证明基线NLR是接受过确定性放化疗联合或不联合手术治疗的LANSCLC患者的显著预后指标的研究。NLR是炎症反应的指标, 应将其作为免疫治疗和放射治疗的潜在预测标志物进行探索。
对临床实践的提示：在276例接受过确定性放化疗联合或不联合手术治疗的IIIA期和IIIB期NSCLC患者中, 诊断时测定的中性粒细胞‐淋巴细胞比值与总生存期改善相关。据我们所知, 本研究是规模最大的证明基线中性粒细胞‐淋巴细胞比值是接受过确定性放化疗联合或不联合手术治疗的局部晚期NSCLC患者的显著预后指标的研究。临床医生在诊断局部晚期NSCLC时可使用中性粒细胞‐淋巴细胞比值作为生物标志物, 该方法成本低廉且简单易行, 可帮助预测预期寿命。
Neutrophil‐lymphocyte ratio is a measure of systemic inflammation that appears prognostic in localized and advanced non‐small cell lung cancer. Increased systemic inflammation portends a poorer prognosis in cancer patients. This study explores whether low neutrophil‐lymphocyte ratio at diagnosis is associated with improved overall survival in patients with locally advanced non‐small cell lung cancer.
Abstract The International Commission on Radiation Units and Measurements (ICRU) Report Committee on “Bioeffect Modeling and Biologically Equivalent Dose Concepts in Radiation Therapy” is currently ...developing a comprehensive and consistent framework for radiobiological effect modeling based on the equieffective dose, EQD Xα/β , a concept encompassing BED and EQD2 as special cases.
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