European Academy of Neurology and European Federation of Neurorehabilitation Societies guideline on pharmacological support in early motor rehabilitation after acute ischaemic stroke.

BACKGROUND AND PURPOSE: Early pharmacological support for post-stroke neurorehabilitation has seen an abundance of mixed results from clinical trials, leaving practitioners at a loss regarding the best options to improve patient outcomes. The objective of this evidence-based guideline is to support clinical decision-making of healthcare professionals involved in the recovery of stroke survivors. METHODS: This guideline was developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. PubMed, Cochrane Library and Embase were searched (from database inception to June 2018, inclusive) to identify studies on pharmacological interventions for stroke rehabilitation initiated in the first 7 days (inclusive) after stroke, which were delivered together with neurorehabilitation. A sensitivity analysis was conducted on identified interventions to address results from breaking studies (from end of search to February 2020). RESULTS: Upon manually screening 17,969 unique database entries (of 57,001 original query results), interventions underwent meta-analysis. Cerebrolysin (30 ml/day, intravenous, minimum 10 days) and citalopram (20 mg/day, oral) are recommended for clinical use for early neurorehabilitation after acute ischaemic stroke. The remaining interventions identified by our systematic search are not recommended for clinical use: amphetamine (5, 10 mg/day, oral), citalopram (10 mg/day, oral), dextroamphetamine (10 mg/day, oral), Di-Huang-Yi-Zhi (2 × 18 g/day, oral), fluoxetine (20 mg/day, oral), lithium (2 × 300 mg/day, oral), MLC601(3 × 400 mg/day, oral), phosphodiesterase-5 inhibitor PF-03049423 (6 mg/day, oral). No recommendation 'for' or 'against' is provided for selegiline (5 mg/day, oral). Issues with safety and tolerability were identified for amphetamine, dextroamphetamine, fluoxetine and lithium. CONCLUSIONS: This guideline provides information for clinicians regarding existing pharmacological support in interventions for neurorecovery after acute ischaemic stroke. Updates to this material will potentially elucidate existing conundrums, improve current recommendations, and hopefully expand therapeutic options for stroke survivors.

Use of Sperm Parameters to Predict Clinical Pregnancy with Intrauterine Insemination.

OBJECTIVE: To test the hypothesis that morphology is the best predictor of clinical pregnancy (CP) when employing intrauterine insemination (IUI). STUDY DESIGN: We retrospectively reviewed a registry of 527 couples who collectively underwent 1,027 IUI cycles, testing sperm parameters and other variables with univariate and multivariate analyses for association with CP. With the literature scant regarding the impact of sperm morphology on IUI outcome, we determined semen parameter threshold values in our patient population and compared them to published reference range values. A logistic regression model was used to determine predictors of CP. RESULTS: Fecundity was 12.9% per cycle and fertility was 23.3% by the third attempted cycle. Morphology was the most significant parameter predicting CP with IUI. Motility was also significant when employing our new threshold values. Using receiver operator characteristic curve analysis, values 16% morphology and 69% motility were found to be the optimal threshold values for achieving CP. CONCLUSION: Morphology was the best predictor of CP. When considering IUI, the best chance of clinical pregnancy occurs when both motility and morphology values are above normal thresholds.

Intraoperative utilization of dexamethasone/bupivacaine/gentamicin solution in laparoscopic assisted vaginal hysterectomy and pain management.

Adequately controlling pain is a key component of postoperative care after a hysterectomy. The purpose of this study was to evaluate the effects of two intraperitoneal (IP) administered solutions during Laparoscopic Assisted Vaginal Hysterectomy (LAVH), on the amount of postoperative self-administered morphine. In this prospective, randomized, double blinded study, twenty women undergoing LAVH randomly distributed to two treatment groups: (1) 100 ml dexamethasone/ bupivacaine/ gentamicin (DMG) solution: 60 cc injected vaginally at cuff and 40 cc placed topically via laparoscopy over intra-peritoneal postoperative surfaces (IP) and 5 ml bupivacaine or 5 ml saline injected at the laparoscopic incision sites, (2) 100 ml saline solution: 60 cc injected vaginally at cuff and 40 cc placed topically via laparoscopy over intra-peritoneal postoperative surfaces (IP) and 5 ml bupivacaine or 5 ml saline injected at the laparoscopic incision sites. The amount of morphine utilized by the patients was documented from their patient controlled anesthesia (PCA) pump. Patient parameters recorded included perceived pain score, height, weight, age, race, reason for surgery, pre-surgery medications, American Society of Anesthesiologist (ASA) classification, length of the surgery and estimated blood loss (EBL). Age, EBL, length of surgery, and ASA classification were not significantly different between the groups. The postoperative amount of morphine utilized was higher at 4 (p=.02) and 16 hours (p = .04) and tended to be higher at 8, 12 hours (p=.06), and 24 hours (p=.09) in the saline IP group. Overall the saline IP group (n=10) used (median; range) 21.5; 8-82 mg of morphine while the DMG IP group (n=10) used 10.5; 1-23 mg. No participants reported a postoperative infection. This study demonstrates that intraoperative utilization of DMG solution during LAVH enables patients clinically to have less perceived pain and subsequently tend to utilize about half the amount of morphine, helping to avoid the potential harmful side effects and adverse reactions of morphine.

Serum anti-endometrial antibodies and first trimester pregnancy loss.

Serum anti-endometrial antibodies (AEA) have been studied as a marker for endometriosis and implantation failure. We sought to determine if the presence of AEA in the serum of pregnant patients is associated with first trimester pregnancy loss including complete abortion. This is a prospective pilot case control study of 30 patients presenting with first trimester pregnancy loss compared to a control group of 30 first trimester pregnant patients with a normal course for the presence of serum AEA. The control group was selected using propensity matching of patient characteristics. AEA assays were performed by a single operator blinded to clinical status of patients. The mean maternal age in the study and control groups was not statistically significant (26.1 +/- 5.7 vs. 24.2 +/- 4.5 years, p < 0.155). A history of pregnancy loss was not significantly greater in the study group (12/30 = 40.0%) as compared to the control group (8/30 = 26.7%, p < 0.412). In both study and control groups, 40% of the samples tested positive for AEA; therefore, we found no evidence of an association between the presence of AEA and pregnancy loss. These findings in our pilot study suggest that presence of serum AEA does not appear to be a marker for early pregnancy loss.

Serum and peritoneal fluid antiendometrial antibodies in assisted reproduction.

OBJECTIVE: To study the impact of surgically verified endometriosis and serum and peritoneal fluid antiendometrial antibodies (AEA) on pregnancy outcomes in gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT) and in vitro fertilization (IVF) patients using assisted reproductive technologies (ART). STUDY DESIGN: Surgical evaluation of endometriosis and collection of serum and peritoneal fluid was performed at the time of laparoscopy. For patients who did not undergo laparoscopy, only serum samples were obtained. Sera and peritoneal fluid were tested by indirect immunofluorescence for AEA. RESULTS: There was no correlation between surgically verified endometriosis, serum or peritoneal fluid AEA and clinical pregnancy in patients undergoing ART. There was no significant difference in surgically verified endometriosis in patients who delivered and those who miscarried (p < 0.0594), whereas serum (p < 0.0223) and peritoneal fluid (p < 0.0032) AEA showed differences. In the total group of 352 ART patients, positive serum AEA was statistically significant in those who miscarried vs. those who delivered (p < 0.0000). CONCLUSION: Endometriosis does not significantly impair the pregnancy potential of ART patients, but it may be associated with miscarriage. The presence of serum and peritoneal fluid AEA correlate better with miscarriage than surgically verified endometriosis.

A randomized controlled trial to test efficacy and safety of thrombectomy in stroke with extended lesion and extended time window.

RATIONALE: The benefit of thrombectomy in patients with intracranial large vessel occlusion of the anterior circulation has been shown in selected patients in previous randomized controlled trials, but patients with extended ischemic lesions were excluded in the majority of these trials. TENSION aims to demonstrate efficacy and safety of thrombectomy in patients with extended lesions in an extended time window (up to 12 h from onset or from last seen well). DESIGN: TENSION is an investigator-initiated, randomized controlled, open label, blinded endpoint, European, two-arm, postmarket study to compare the safety and effectiveness of thrombectomy as compared to best medical care alone in stroke patients with extended stroke lesions defined by an Alberta Stroke Program Early Computed Tomography Scan score of 3-5 and in an extended time window. In an adaptive design study, up to 665 patients will be randomized. OUTCOMES: Primary efficacy endpoint will be clinical outcome defined by the modified Rankin Scale at 90-day poststroke. The main safety endpoint will be death and dependency (modified Rankin Scale 4-6) at 90 days. Additional effect measures include adverse events, health-related quality of life, poststroke depression, and costs utility assessment. DISCUSSION: TENSION may make effective treatment available for patients with severe stroke in an extended time window, thereby improving functional outcome and quality of life of thousands of stroke patients and reducing the individual, societal, and economic burden of death and disability resulting from severe stroke. TENSION is registered at ClinicalTrials.gov (ClinicalTrials.gov Identifier NCT03094715).

Double vs. single intrauterine insemination per cycle: use in gonadotropin cycles and in diagnostic categories of ovulatory dysfunction and male factor infertility.

OBJECTIVE: To evaluate the effectiveness of offering double intrauterine insemination (IUI) to clients in our fertility program. STUDY DESIGN: In this prospective, nonrandomized study, 595 couples with ovulatory dysfunction, endometriosis, male factor, unexplained, tubal factor and combined diagnoses utilizing clomiphene citrate-hCG (CC-hCG), CC-gonadotropin-hCG (CC-Gn-hCG), Gn-hCG, lupron-Gn-hCG (L-Gn-hCG) or luteinizing hormone (LH) surge monitoring of natural cycles were offered single or double IUI in a total of 1276 cycles. Single IUIs were performed at 36 hours following hCG or the day following LH surge; double IUIs were performed 18 and 36 hours following hCG or the day of and day following LH surge. Single versus double IUI clinical pregnancy outcomes were compared between ovarian stimulation protocols and diagnostic categories. RESULTS: One hundred ten clinical pregnancies occurred for 508 couples in 999 single IUI cycles (fecundity, 11.0%); 45 clinical pregnancies for 174 couples occurred in 277 double IUI cycles (16.2%, p < 0.004). The single IUI group was younger than the double IUI group (32.8 vs. 33.7, p < 0.004). Differences for fecundity were noted regarding diagnostic categories between single and double IUI groups (ovulation dysfunction, 12.9% vs 19.5%, p < 0.048, and male factor, 7.9% vs. 17.5%, p < 0.030) and ovulation protocols (CC-Gn-hCG, 13.0% vs. 21.3%, p < 0.031, and L-Gn-hCG, 4.2% vs. 25.0%, p < 0.002). CONCLUSION: Double IUI is superior to single IUI overall, especially when comparing Gn-containing ovarian stimulation protocols or within the ovulatory dysfunction and male factor diagnostic categories.

Stroke and Universal Design.

Universal Design (UD) is usually stated to be "for all ages and abilities". Given that stroke is a major source of disability, it is important that UD recommendations take stroke-specific problems into account. Within the framework of EU project STARR, we have investigated user requirements of stroke survivors. In this project we have used a mix of interviews, focus groups, design workshops and technology tests to come up with a set of design recommendations, which we present as a first step towards universal design recommendations which are inclusive for stroke survivors. Our general recommendations are: make it fun, do not make people fail, empower and encourage. The technology needs to be highly adaptable to different sets of abilities. Safety, but also aesthetics and simplicity is important, but it is pointed out that designs should not be "childish" - this can be felt to be degrading. It is important to be able to see and follow your progress and win small victories often. Consider social applications and activities - being able to connect to others in the same situation can enable discussions and provide peer support. More stroke consequence specific recommendations are to design to allow one-sided use (hemiplegia), avoid sensory and activity overload (fatigue), complement speech with images (aphasia), limit demand on memory, support learning and avoid errors (memory problems), and include multiple modalities in your design (reduced vision or hearing).

PRECIOUS: PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke. Rationale and design of a randomised, open, phase III, clinical trial with blinded outcome assessment.

BACKGROUND: Elderly patients are at high risk of complications after stroke, such as infections and fever. The occurrence of these complications has been associated with an increased risk of death or dependency.Hypothesis: Prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first four days after stroke onset will improve functional outcome at 90 days in elderly patients with acute stroke. DESIGN: International, 3 × 2-factorial, randomised-controlled, open-label clinical trial with blinded outcome assessment (PROBE) in 3800 patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and an NIHSS score ≥ 6. Patients will be randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or usual care, started within 24 h after symptom onset and continued for four days or until complete recovery or discharge from hospital, if earlier.Outcome: The primary outcome measure is the score on the modified Rankin Scale at 90 days (± 14 days), as analysed with multiple regression.Summary: This trial will provide evidence for a simple, safe and generally available treatment strategy that may reduce the burden of death or disability in patients with stroke at very low costs.Planning: First patient included in May 2016; final follow-up of the last patient by April 2020.Registration: ISRCTN, ISRCTN82217627, https://doi.org/10.1186/ISRCTN82217627.

Intrauterine insemination results in couples requiring extended semen transport time.

PURPOSE: The purpose of the present study is to compare intrauterine insemination (IUI) pregnancy rates (PR) as a function of diagnosis and ovulation protocol utilizing an extended semen transport time. This allowed clients to conveniently collect IUI specimens in the comfort and privacy of their home. A single IUI per treatment cycle was performed. BASIC PROCEDURES: Three-hundred-ten consecutive infertilty couples having unexplained, male factor, ovulatory dysfunction, endometriosis, tubal factor or combined diagnostic factors receiving a total of 584 cycles of IUI were included. Ovulation protocols included LH surge, clomiphene citrate (CC)-hCG, CC-gonadotropins(Gn)-hCG, Gn-hCG or leuprolide acetate (L)-Gn-hCG followed 36-42 hours by a single IUI. Pregnancy rates per cycle (fecundity) and per couple (fertility) as a function of diagnosis, ovulation protocol and cycle number were evaluated. In each cycle the couples processed the specimen by adding sperm washing medium at room temperature to the specimen 30 min following collection and allowed it to incubate for two hours prior to IUI during transport. MAIN FINDINGS: Overall, fecundity was 11.8% (69/584) and fertility was 22.3% (69/310); respectively by diagnosis was: unexplained 22.6%, 38.8%; male factor 18.8%, 42.9%; ovulatory dysfunction 12.4, 22.6%; endometriosis 5.3%, 11.1%; tubal factor 7.6%,13.3%; and combined factors 9.7%, 20.0%. Unexplained vs endometriosis (P < 0.0001, P < 0.005), tubal factor (fecundity P < 0.008) and ovulatory dysfunction (fecundity P < 0.027) was statistically different. Male factor vs endometriosis (P < 0.011, P < 0.036) was significantly different. Ovulatory dysfunction vs endometriosis was significantly different (fecundity P < 0.027). Pregnancies by ovulation protocol: LH surge 4.5%,10.5%; CC-hCG 9.4%,14.9%; CC-Gn-hCG 13.7%, 23.7%; Gn-hCG 17.5%, 45.3%; L-Gn-hCG 3.5%, 6.7%. For Gn-hCG vs L-Gn-hCG (P < 0.009, P < 0.030) and LH surge (fecundity P < 0.033). CC-Gn-hCG vs CC-hCG (fertility P < 0.050) and L-Gn-hCG (P < 0.033, P < 0.034). Gn-hCG vs CC-hCG (fecundity P < 0.043). CONCLUSIONS: We conclude that IUI is effective when utilizing an extended transport time allowing most couples to collect the specimen at home and is most effective when utilizing Gn-hCG therapy. Based on our analysis, endometriosis, tubal factor and combined diagnostic categories should proceed earlier to higher level assisted reproductive technologies.

Conjuring up New Technology - Using Magic Objects in Co-Ideation with Stroke Survivors.

Ideation means to generate ideas, and when involving non-designers in these activities they need to be informed about the scope of the possibilities without limiting their imagination. This is a general challenge, which becomes particularly important when it comes to advanced technology ideation together with participants that may not have in-depth knowledge of technological designs and solutions. In this study, we supported the ideation process by presenting a kit of magic objects (consisting of cards and physical props) to stroke survivors participating in a co-design workshop carried out within the STARR EU project. The kit was seen to generally work well, but improvements are suggested for the introduction, the design of the cards and the number of objects used.

Managing reversal of direct oral anticoagulants in emergency situations. Anticoagulation Education Task Force White Paper.

Anticoagulation is the cornerstone of prevention and treatment of venous thromboembolism (VTE) and stroke prevention in patients with atrial fibrillation (AF). However, the mechanisms by which anticoagulants confer therapeutic benefit also increase the risk of bleeding. As such, reversal strategies are critical. Until recently, the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, apixaban, and edoxaban lacked a specific reversal agent. This report is based on findings from the Anticoagulation Education Task Force, which brought together patient groups and professionals representing different medical specialties with an interest in patient safety and expertise in AF, VTE, stroke, anticoagulation, and reversal agents, to discuss the current status of anticoagulation reversal and fundamental changes in management of bleeding associated with DOACs occasioned by the approval of idarucizumab, a specific reversal agent for dabigatran, as well as recent clinical data on specific reversal agents for factor Xa inhibitors. Recommendations are given for when there is a definite need for a reversal agent (e.g. in cases of life-threatening bleeding, bleeding into a closed space or organ, persistent bleeding despite local haemostatic measures, and need for urgent interventions and/or interventions that carry a high risk for bleeding), when reversal agents may be helpful, and when a reversal agent is generally not needed. Key stakeholders who require 24-7/around-the-clock access to these agents vary among hospitals; however, from a practical perspective the emergency department is recommended as an appropriate location for these agents. Clearly, the advent of new agents requires standardised protocols for treating bleeding on an institutional level.

Endometriosis-associated infertility: double intrauterine insemination improves fecundity in patients positive for antiendometrial antibodies.

PROBLEM: Prospective registry study evaluating effects of endometriosis (E) and serum antiendometrial antibodies (AEA) on fecundity in intrauterine insemination (IUI) cycles. METHOD OF STUDY: AEA assays on 572 consecutive women receiving 969 single and 274 double IUI cycles. Logistic regression was utilized. RESULTS: Fecundity was 11.5% (143/1243 cycles). Double IUI improved fecundity with significance achieved in certain study groups. Compared to the AEA- subgroup, all study groups except for the E+ AEA- group had significantly lower fecundity. Two study groups receiving double IUI had significantly increased fecundity, E- AEA+ (OR: 5.1, CI: 1.1-22.7, P=0.032) and E+ AEA+ (OR: 4.1, CI: 1.2-14.0, P=0.025) and significant predictors of pregnancy (E- AEA+, OR: 7.8, CI: 1.7-36.2, P=0.009 and E+ AEA+, OR: 4.2, CI: 1.2-15.1, P=0.026). CONCLUSION: Double IUI improves fecundity in AEA+ patients. E-associated infertility is better diagnosed by the AEA assay than by surgery. Double IUI should be attempted prior to assisted reproductive technologies in AEA+ patients with normal fallopian tubes.

Serum antiendometrial antibodies and diagnosis of endometriosis.

PROBLEM: The purpose of the present prospective multi-center study is to investigate the relationship between laparoscopic diagnosis of endometriosis and results of a serum antiendometrial antibody (AEA) assay. METHOD OF STUDY: Indirect immunofluorescence detection of AEA was performed on serum specimens from patients presenting with dysmenorrhea or chronic pelvic pain and infertility (n = 2609) utilizing frozen sections of endometrium acquired on cycle days 18-21 from normally cycling women without endometriosis. Diagnostic laparoscopy was performed within 1 year of AEA assay on 527 tested women. RESULTS: The relationship between the serum AEA and laparoscopic verification was characterized by a positive predictive value = 88%, negative predictive value = 86%, sensitivity = 87% and specificity = 87%. CONCLUSION: The AEA assay is a very good screening test for patients suspected of having endometriosis and should be utilized prior to laparoscopy in diagnostic categories of dysmenorrhea or chronic pelvic pain and infertility.