STUDY QUESTION
Does the prewash total motile sperm count (TMSC) have a better predictive value for spontaneous ongoing pregnancy (SOP) than the World Health Organization (WHO) classification system?
...SUMMARY ANSWER
The prewash TMSC shows a better correlation with the spontaneous ongoing pregnancy rate (SOPR) than the WHO 2010 classification system.
WHAT IS KNOWN ALREADY
According to the WHO classification system, an abnormal semen analysis can be diagnosed as oligozoospermia, astenozoospermia, teratozoospermia or combinations of these and azoospermia. This classification is based on the fifth percentile cut-off values of a cohort of 1953 men with proven fertility. Although this classification suggests accuracy, the relevance for the prognosis of an infertile couple and the choice of treatment is questionable. The TMSC is obtained by multiplying the sample volume by the density and the percentage of A and B motility spermatozoa.
STUDY DESIGN, SIZE, DURATION
We analyzed data from a longitudinal cohort study among unselected infertile couples who were referred to three Dutch hospitals between January 2002 and December 2006. Of the total cohort of 2476 infertile couples, only the couples with either male infertility as a single diagnosis or unexplained infertility were included (n = 1177) with a follow-up period of 3 years.
PARTICIPANTS/MATERIALS, SETTING, METHODS
In all couples a semen analysis was performed. Based on the best semen analysis if more tests were performed, couples were grouped according to the WHO classification system and the TMSC range, as described in the Dutch national guidelines for male infertility. The primary outcome measure was the SOPR, which occurred before, during or after treatments, including expectant management, intrauterine insemination, in vitro fertilization or intracytoplasmic sperm injection. After adjustment for the confounding factors (female and male age, duration and type of infertility and result of the postcoital test) the odd ratios (ORs) for risk of SOP for each WHO and TMSC group were calculated. The couples with unexplained infertility were used as reference.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 514 couples did and 663 couples did not achieve a SOP. All WHO groups have a lower SOPR compared with the unexplained group (ORs varying from 0.136 to 0.397). Comparing the couples within the abnormal WHO groups, there are no significant differences in SOPR, except when oligoasthenoteratozoospermia is compared with asthenozoospermia OR 0.501 (95% CI 0.311–0.809) and teratozoospermia OR 0.499 (95% CI: 0.252–0.988), and oligoasthenozoospermia is compared with asthenozoospermia OR 0.572 (95% CI: 0.373–0.877). All TMSC groups have a significantly lower SOPR compared with the unexplained group (ORs varying from 0.171 to 0.461). Couples with a TMSC of <1 × 106 and 1–5 × 106 have significantly lower SOPR compared with couples with a TMSC of 5–10 × 106 respectively, OR 0.371 (95% CI: 0.215–0.64) and OR 0.505 (95% CI: 0.307–0.832).
LIMITATIONS, REASON FOR CAUTION
To include all SOPs during the follow-up period of 3 years, couples were not censured at the start of treatment.
WIDER IMPLICATIONS OF THE FINDINGS
Roughly, three prognostic groups can be discerned: couples with a TMSC <5, couples with a TMSC between 5 and 20 and couples with a TMSC of more than 20 × 106 spermatozoa. We suggest using TMSC as the method of choice to express severity of male infertility.
STUDY FUNDING/COMPETING INTEREST(S)
None.
In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor ...multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets.
In this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers.
The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days 95% confidence interval {CI}, 1.89 to 2.83 vs. 2.88 days 95% CI, 2.68 to 3.56, P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period.
Among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317 .).
BACKGROUND
This study examined the relationship between emotional distress as measured by the Hospital Anxiety and Depression Scale (HADS) and the Fertility Quality of Life (FertiQoL) questionnaire.
...METHODS
The FertiQoL and HADS were distributed to a random sample of 785 patients attending 29 Dutch clinics for medically assisted reproduction. FertiQoL was psychometrically tested for reliability. Pearson's correlations were calculated between subscales of FertiQoL and HADS. Using an independent t-test, differences between patient subgroups were computed for both instruments. The threshold for clinically meaningful depression/anxiety on the HADS subscales was used to ascertain the critical threshold for high distress on the FertiQoL scales.
RESULTS
FertiQoL and HADS were completed by 583 patients (response 74%). Reliability of FertiQoL scales was high (reliability coefficient between 0.72 and 0.91). Significant negative correlations were found between FertiQoL subscales and HADS scores for anxiety and depression, ranging from −0.29 to −0.71. Means on FertiQoL scales and HADS scales of couples undergoing an assisted reproductive technology (ART) treatment and a non-ART treatment did not differ significantly. Patients scoring above the HADS threshold for pathology on anxiety had an average FertiQoL score of 58.8, whereas patients exceeding the HADS depression threshold had a FertiQoL total score of 51.9 (range 0–100).
CONCLUSIONS
Our study confirms the expected negative relation between quality of life as measured by FertiQoL and anxiety and depression. The data support that FertiQoL reliably measures QoL in women facing infertility. FertiQoL enables clinicians to tailor care more specifically to the patient in a comprehensive way.
Cerebral autoregulation may become impaired after stroke. To provide a review of the nature and extent of any autoregulation impairment after stroke and its course over time, a technique allowing ...repeated bedside measurements with good temporal resolution is required. Transcranial Doppler (TCD) in combination with continuous blood pressure measurements allows noninvasive continuous bedside investigation with high temporal resolution of the dynamic and the steady-state components of cerebral autoregulation. Therefore, this review focuses on all TCD studies on cerebral autoregulation in the setting of documented ischemic stroke.
PubMed and EMBASE were searched for studies of stroke, autoregulation, and TCD. Studies were either acute phase (<96 hours after index stroke) or chronic phase (>96 hours after index stroke) autoregulation studies. Quality of studies was studied in a standardized fashion.
Twenty-three studies met the inclusion criteria. General agreement existed on cerebral autoregulation being impaired, even after minor stroke. Bilateral impairment of autoregulation was documented, particularly after lacunar stroke. Studies showed progressive deterioration of cerebral autoregulation in the first 5 days after stroke and recovery over the next 3 months. Impaired cerebral autoregulation as assessed by TCD was related to neurological deterioration, the necessity for decompressive surgery, and poor outcome. Synthesis of the data of various studies was, however, limited by studies not meeting key methodological criteria for observational studies.
TCD in combination with continuous blood pressure measurement offers a method with a high temporal resolution feasible for bedside evaluation of cerebral autoregulation in the stroke unit. TCD studies have shown impairment of cerebral autoregulation in various subtypes of ischemic stroke. To improve the synthesis of data from various research groups, there is urgent need for standardization of methodology of TCD studies in cerebral autoregulation.
BACKGROUND A substantial number of subfertile couples discontinues fertility care before achieving pregnancy. Most studies on dropouts are related to IVF. The aim here is to examine dropout rates at ...all stages of fertility care. METHODS We analysed a consecutive cohort of 1391 couples, referred to our secondary care hospital between January 2002 and December 2006. Discontinuation rates were studied at six stages. Stage I: immediately after first visit, Stage II: during diagnostic workup, Stage III: after finishing diagnostic workup but before treatment, Stage IV: during or after non-IVF treatment, Stage V: during IVF, Stage VI: after at least 3 cycles of IVF. Reasons to discontinue and spontaneous pregnancy rates after discontinuation were secondary outcomes. RESULTS In our cohort 319 couples dropped out of fertility care, 76.8%, 95% confidence interval (CI): 72.2–81.4 on their own initiative and 23.2% (95% CI: 18.6–27.8) on doctor's advice. Percentage (95% CI) of couples discontinuing per stage were: Stage I 6.0% (3.4–8.6), Stage II 3.4% (1.5–5.5), Stage III 35.7% (30.5–41.0), Stage IV 23.5% (18.9–28.2), Stage V 17.9% (13.7–22.1) and Stage VI 13.5% (9.7–17.2). Main reasons for dropout (%, 95% CI) were ‘emotional distress’ (22.3%, 17.7–26.8), ‘poor prognosis’ (18.8%, 14.5–23.1) and ‘reject treatment’ (17.2%, 13.1–21.4). The spontaneous ongoing pregnancy rate after discontinuation was 10% (6.7–13.3). CONCLUSION About half of the couples stopped before any fertility treatment was started and one-third stopped after at least one IVF cycle. The main reasons for withdrawal were emotional distress and poor prognosis. This insight may help to improve quality of patient care by making care more responsive to the needs and expectations of subfertile couples.
ADAMTS13-neutralizing IgG autoantibodies are the major cause of acquired thrombotic thrombocytopenic purpura (TTP).
To analyze the IgG subclass distribution of anti-ADAMTS13 antibodies and a ...potential relationship between subclass distribution and disease prognosis.
An enzyme-linked immunosorbent assay-based method was used to quantify the relative amounts of IgG subclasses of anti-ADAMTS13 antibodies in acquired TTP plasma.
IgG(4) (52/58, 90%) was the most prevalent IgG subclass in patients with acquired TTP, followed by IgG(1) (52%), IgG(2) (50%), and IgG(3) (33%). IgG(4) was found either alone (17/52) or with other IgG subclasses (35/52). IgG(4) was not detected in 10% of the patients. There was an inverse correlation between the frequency and abundance of IgG(4) and IgG(1) antibodies (P < 0.01). Patients with high IgG(4) levels and undetectable IgG(1) are more prone to relapse than patients with low IgG(4) levels and detectable IgG(1).
All IgG subclasses of anti-ADAMTS13 antibodies were detected in patients with acquired TTP, with IgG(4), followed by IgG(1), antibodies dominating the anti-ADAMTS13 immune response. Levels of IgG(4) could be useful for the identification of patients at risk of disease recurrence.
Essentials
Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality.
Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was ...studied.
Fewer caplacizumab‐treated patients had a major TE event, an exacerbation, or died versus placebo.
Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP.
Summary
Background
Acquired thrombotic thrombocytopenic purpura (aTTP) is a life‐threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti‐von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment.
Objective
The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura‐related death during the study.
Methods
The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for ‘embolic and thrombotic events’ was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo.
Results
Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo‐treated patients died from aTTP during the study.
Conclusion
In total, 11.4% of caplacizumab‐treated patients and 43.2% of placebo‐treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.
The coherent elastic scattering of neutrinos off nuclei has eluded detection for four decades, even though its predicted cross section is by far the largest of all low-energy neutrino couplings. This ...mode of interaction offers new opportunities to study neutrino properties and leads to a miniaturization of detector size, with potential technological applications. We observed this process at a 6.7σ̃ confidence level, using a low-background, 14.6-kilogram CsINa scintillator exposed to the neutrino emissions from the Spallation Neutron Source at Oak Ridge National Laboratory. Characteristic signatures in energy and time, predicted by the standard model for this process, were observed in high signal-to-background conditions. Improved constraints on nonstandard neutrino interactions with quarks are derived from this initial data set.
STUDY QUESTION
Do the quality of life (QoL) and the risk factors for emotional problems during and after treatment of infertile women differ from their partners?
SUMMARY ANSWER
Women have lower ...levels of fertility-related QoL, and more and differing risk factors for emotional problems during and after treatment than their partners.
WHAT IS KNOWN ALREADY?
The psychological impact of infertility in patients negatively affects their QoL and is also related to increased discontinuation of treatment. Moreover, psychological factors might positively affect pregnancy rates. However, it is still unclear if differences in QoL and emotional status exist between infertile women and their partners. So far, research mainly focused on generic instruments to measure patients' QoL in the area of fertility care.
STUDY DESIGN, SIZE, DURATION
A cross-sectional study of infertile couples within 32 Dutch fertility clinics.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We included infertile women and their partners (both heterosexual and lesbian couples) under any treatment and at any stage of treatment in one of the 32 participating clinics. Per clinic, 25–75 patients were randomly selected depending on clinic size. In total, 1620 women and their partners were invited separately to complete the FertiQoL and SCREENIVF questionnaires to measure their level of QoL and risk factors for emotional problems during and after treatment, respectively.
MAIN RESULTS AND THE ROLE OF CHANCE
A total of 946 women (response rate 58%) and 670 partners (response rate 41%) completed the questionnaire set. As 250 women and 150 partners were already pregnant, questionnaires from 696 women and 520 partners could be analysed. Women scored significantly lower on the FertiQoL total scores B = −6.31; 95% confidence interval (CI) = −7.63 to 4.98 and three of the FertiQoL subscales (Emotional, Mind–Body and Social) than their partners, indicating lower QoL. Scores on the SCREENIVF questionnaire were significantly higher for women (B = 0.22; 95% CI = 0.06–0.38), indicating that women are more at risk for developing emotional problems (and these factors differed from those of their partners) during and after fertility treatment than their partners.
LIMITATIONS, REASONS FOR CAUTION
Although the number of participants is high (n = 1216), the relatively low response rate, especially for partners (41%), may have influenced the results through selection bias. An analysis of non-responders could not be performed. The FertiQoL and SCREENIVF questionnaires, which have been validated only in women starting a first IVF cycle, should also be validated for studying partners. In addition, the SCREENIVF questionnaire has been validated in Dutch women only and further research in an international setting is also required.
WIDER IMPLICATIONS OF THE FINDINGS
Our study results represent the Dutch infertile population as more than one-third of all Dutch clinics participated in the study. As the FertiQoL questionnaire is an internationally validated questionnaire already, these results can be put in a more broader and international perspective.
STUDY FUNDING/COMPETING INTEREST(S)
This work was supported by Merck Sharp & Dohme (MSD), The Netherlands. There are no competing interests.
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