Analysis of changes in the action potential morphology of the mouse sinoatrial node true pacemaker cells during ontogenetic development in vitro and in silico.

BACKGROUND: Maturation of the mouse is accompanied by the increase in heart rate. However, the mechanisms underlying this process remain unclear. We performed an action potentials (APs) recordings in mouse sinoatrial node (SAN) true pacemaker cells and in silico analysis to clarify the mechanisms underlying pre-postnatal period heart rate changes. RESULTS: The APs of true pacemaker cells at different stages had similar configurations and dV/dtmax values. The cycle length, action potential duration (APD90), maximal diastolic potential (MDP), and AP amplitude decreased, meanwhile the velocity of diastolic depolarization (DDR) increased from E12.5 stage to adult. Using a pharmacological approach we found that in SAN true pacemaker cells ivabradine reduces the DDR and the cycle length significantly stronger in E12.5 than in newborn and adult mice, whereas the effects of Ni2+ and nifedipine were significantly stronger in adult mice. Computer simulations further suggested that the density of the hyperpolarization-activated pacemaker сurrent (If) decreased during development, whereas transmembrane and intracellular Ca2+ flows increased. CONCLUSIONS: The ontogenetic decrease in IK1 density from E12.5 to adult leads to depolarization of MDP to the voltage range in which calcium currents are activated, thereby shifting the balance from the "membrane-clock" to the "calcium-clock."

Proposed general diagnostic criteria for secondary headaches.

BACKGROUND: The distinction between a pre-existing primary headache and a secondary headache at the onset of a disorder is important and has not been taken into account in the International Classification of Headache Disorders-3. This study aimed to improve the general diagnostic criteria for secondary headaches using results of our previous studies. MATERIALS AND METHODS: We analyzed characteristics of headaches including their changes in intensity, duration, frequency, localization and side, development of new accompanying symptoms, and therapeutic response at the onset of transient ischemic attacks (TIA) (n = 120, mean age 56.1, 55% females) and ischemic stroke (n = 550, mean age 63.1, 56% females) compared to the control group (n = 192, mean age 58.7, 64% females). RESULTS: Headache of a new type occurred in 8.4% of ischemic stroke patients and 5% of TIA patients on the day of admission but did not occur at all in the control group. Pre-existing headache with a change of at least one characteristic occurred significantly more often in stroke (5.4%) and TIA (7.5%) than in the control group (1%) (p = 0.01 and p = 0.003 respectively). CONCLUSION: The presence of a new type of headache and a pre-existing headache with altered characteristics in close temporal relation to a disorder indicates causality. Based on these data we propose revised general diagnostic criteria for secondary headaches.

Safety and tolerability of monoclonal antibodies targeting the CGRP pathway and gepants in migraine prevention: A systematic review and network meta-analysis.

BACKGROUND: Direct comparisons of the tolerability and safety of migraine preventive treatments targeting the calcitonin gene-related peptide pathway are lacking. This study aimed to compare the safety and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies and gepants in migraine prevention. METHODS: A network meta-analysis of phase 3 randomized controlled trials assessing the safety and tolerability of anti-calcitonin gene-related peptide monoclonal antibodies (erenumab, eptinezumab, fremanezumab, or galcanezumab) and gepants (atogepant, rimegepant) in migraine prevention was performed. Primary outcomes were treatment-emergent adverse events and serious adverse events. Secondary outcomes included any adverse events, adverse events leading to treatment discontinuation and individual adverse events. RESULTS: We included 19 randomized controlled trials, comprising 14,584 patients. Atogepant 120 mg (OR 2.22, 95% CI [1.26, 3.91]) and galcanezumab 240 mg (OR 1.63, 95% CI [1.33, 2.00]) showed the largest odds of treatment-emergent adverse events compared to placebo. While eptinezumab 30 mg had greater odds of adverse events leading to treatment discontinuation (OR 2.62, 95% CI [1.03,6.66]). No significant differences in serious adverse events were found between active treatments and placebo. Eptinezumab was associated with the lowest odds of treatment-emergent adverse events and serious adverse events compared to placebo, whereas erenumab was associated with the lowest odds of any adverse events and quarterly fremanezumab with the lowest odds of treatment discontinuation due to adverse events. CONCLUSION: Monoclonal antibodies targeting the calcitonin gene-related peptide pathway and gepants are a safe and well tolerated option for migraine prevention.

Sex steroid hormones and epilepsy: Effects of hormonal replacement therapy on seizure frequency of postmenopausal women with epilepsy-A systematic review.

BACKGROUND AND PURPOSE: Hormonal replacement therapy (HRT) is used for symptomatic treatment of menopause. Some evidence suggests a proconvulsant effect of estrogen and an anticonvulsant role of progesterone. Thus, the use of exogenous sex steroid hormones might influence the course of epilepsy in peri- and postmenopausal women with epilepsy (WWE). We conducted a systematic review on the impact of HRT on the frequency of seizures of WWE. METHODS: PubMed and Scopus were searched for articles published from inception until August 2022. Abstracts from the past 5 years from the European Academy of Neurology and European Epilepsy Congresses were also reviewed. Article reference lists were screened, and relevant articles were retrieved for consultation. Interventional and observational studies on WWE and animal models of estrogen deficiency were included. Critical appraisal was performed using the revised Cochrane risk-of-bias tool for randomized trials and ROBINS-E tool. RESULTS: Of 497 articles screened, 13 studies were included, including three human studies. One cross-sectional study showed a decrease in seizure frequency in WWE using combined HRT, a case-control study showed an increase in comparison with controls, and a randomized clinical trial found a dose-dependent increase in seizure frequency in women with focal epilepsy taking combined HRT. Ten studies addressing the impact of HRT in rat models were also included, which showed conflicting results. CONCLUSIONS: There is scarce evidence of the impact of HRT in WWE. Further studies should evaluate the harmful potential, and prospective registries are needed for monitoring this population.

Kinetic analysis of a complete nitrifier reveals an oligotrophic lifestyle.

Nitrification, the oxidation of ammonia (NH3) via nitrite (NO2-) to nitrate (NO3-), is a key process of the biogeochemical nitrogen cycle. For decades, ammonia and nitrite oxidation were thought to be separately catalysed by ammonia-oxidizing bacteria (AOB) and archaea (AOA), and by nitrite-oxidizing bacteria (NOB). The recent discovery of complete ammonia oxidizers (comammox) in the NOB genus Nitrospira, which alone convert ammonia to nitrate, raised questions about the ecological niches in which comammox Nitrospira successfully compete with canonical nitrifiers. Here we isolate a pure culture of a comammox bacterium, Nitrospira inopinata, and show that it is adapted to slow growth in oligotrophic and dynamic habitats on the basis of a high affinity for ammonia, low maximum rate of ammonia oxidation, high growth yield compared to canonical nitrifiers, and genomic potential for alternative metabolisms. The nitrification kinetics of four AOA from soil and hot springs were determined for comparison. Their surprisingly poor substrate affinities and lower growth yields reveal that, in contrast to earlier assumptions, AOA are not necessarily the most competitive ammonia oxidizers present in strongly oligotrophic environments and that N. inopinata has the highest substrate affinity of all analysed ammonia oxidizer isolates except the marine AOA Nitrosopumilus maritimus SCM1 (ref. 3). These results suggest a role for comammox organisms in nitrification under oligotrophic and dynamic conditions.

Migraine: epidemiology and systems of care.

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.

Mapping of European activities on the integration of sex and gender factors in neurology and neuroscience.

BACKGROUND: Neurological disorders pose a profound unmet medical need for which new solutions are urgently needed. The consideration of both biological (sex) and socio-cultural (gender) differences between men and women is necessary to identify more efficacious, safer and tailored treatments. Approaches for putting sex and gender medicine into practice have gathered momentum across Europe, but it is currently unclear to what extent they have been implemented in the field of neurology and neuroscience. METHODS: We mapped current activities in research, funding and education aimed at integrating sex and gender consideration in neuroscience and neurology in Europe. We examined and analyzed data gathered from (1) literature searches, (2) policy documents and reports by the European Commission and national funding agencies, (3) web-based searches, (4) "Web of Science", and (5) searches of project databases of funding agencies. An informative / non-systematic search was performed for sections on policies and funding, education, basic research, while a systematic literature and database review was conducted forquantitative analysis of research output and funded projects in terms of sex and gender analysis. RESULTS: Our mapping shows that there is a growing interest and attention towards sex and gender consideration in neurological fields, both from funding agencies and researchers. However, most activities, especially for education, are limited to the individual motivation of researchers and are not organically built within curricula and strategic research priorities. DISCUSSION: We recommend actions that might help increase the consideration of sex and gender specifically in the field of neuroscience and neurology.

Diagnostic criteria for acute headache attributed to ischemic stroke and for sentinel headache before ischemic stroke.

BACKGROUND: Defining the relationship between a headache and stroke is essential. The current diagnostic criteria of the ICHD-3 for acute headache attributed to ischemic stroke are based primarily on the opinion of experts rather than on published clinical evidence based on extensive case-control studies in patients with first-ever stroke. Diagnostic criteria for sentinel headache before ischemic stroke do not exist. The present study aimed to develop explicit diagnostic criteria for headache attributed to ischemic stroke and for sentinel headache. METHODS: This prospective case-control study included 550 patients (mean age 63.1, 54% males) with first-ever ischemic stroke and 192 control patients (mean age 58.7, 36% males) admitted to the emergency room without any acute neurological deficits or severe disorders. Standardized semi-structured interview forms were used to evaluate past and present headaches during face-to-face interviews by a neurologist on admission to the emergency room in both groups of patients. All headaches were diagnosed according to the ICHD-3. We tabulated the onset of different headaches before a first-ever ischemic stroke and at the time of onset of stroke. We divided them into three groups: a new type of headache, the previous headache with altered characteristics and previous unaltered headaches. The same was done for headaches in control patients within one week before admission to the hospital and at the time of entry. These data were used to create and test diagnostic criteria for acute headache attributed to stroke and sentinel headache. RESULTS: Our previous studies showed that headache at onset of ischemic stroke was present in 82 (14.9%) of 550 patients, and 81 (14.7%) patients had sentinel headache within the last week before a stroke. Only 60% of the headaches at stroke onset fulfilled the diagnostic criteria of ICHD-3. Therefore, we proposed alternative criteria with a sensitivity of 100% and specificity of 97%. Besides, we developed diagnostic criteria for sentinel headache for the first time with a specificity of 98% and a sensitivity of 100%. CONCLUSIONS: We suggest alternative diagnostic criteria for acute headache attributed to ischemic stroke and new diagnostic criteria for sentinel headache with high sensitivity and specificity.

Persistent headache after first-ever ischemic stroke: clinical characteristics and factors associated with its development.

BACKGROUND: It is poorly described how often headache attributed to stroke continues for more than 3 months, i.e. fulfils the criteria for persistent headache attributed to ischemic stroke. Our aims were: 1) to determine the incidence of persistent headache attributed to past first-ever ischemic stroke (International headache society categories 6.1.1.2); 2) to describe their characteristics and acute treatment; 3) to analyse the prevalence of medication overuse headache in patients with persistent headache after stroke; 4) to evaluate factors associated with the development of persistent headache after stroke. METHODS: The study population consisted of 550 patients (mean age 63.1, 54% males) with first-ever ischemic stroke, among them 529 patients were followed up at least three months after stroke. Standardized semi-structured interview forms were used to evaluate these headaches during professional face-to-face interviews at stroke onset and telephone interviews at 3 months. RESULTS: At three months, 61 patients (30 women and 31 men, the mean age 60.0) of 529 (11.5%) follow-up patients had a headache after stroke: 34 had a new type of headache, 21 had a headache with altered characteristics and 6 patients had a headache without any changes. Therefore 55 (10.4%) patients had a persistent headache attributed to ischemic stroke. Their clinical features included: less severity of accompanying symptoms, slowly decreasing frequency and development of medication overuse headache in one-third of the patients. The following factors were associated with these headaches: lack of sleep (29.1%, p = 0.009; OR 2.3; 95% CI 1.2-4.3), infarct in cerebellum (18.2%, p = 0.003; OR 3.0; 95% CI 1.4-6.6), stroke of undetermined etiology (50.9%, p = 0.003; OR 2.3; 95% CI 1.3-4.1), less than 8 points by NIHSS score (90.9%, p = 0.007; OR 3.4; 95% CI 1.4-8.6) and low prevalence of large-artery atherosclerosis (12.7%, p = 0.006; OR 0.3; 95% CI 0.2-0.80). CONCLUSION: Persistent headache attributed to ischemic stroke is not rare and frequently leads to medication overuse. The problem is often neglected because of other serious consequences of stroke but actually, it has a considerable impact on quality of life. It should be a focus of interest in the follow-up of stroke patients.

Headache at onset of first-ever ischemic stroke: Clinical characteristics and predictors.

No studies have prospectively investigated headache at onset of first-ever ischemic stroke along with a large concurrent control group. Our aims were to answer two important questions: (i) Are headaches at stroke onset causally related to the stroke, and what are their typical clinical characteristics? (ii) What etiology of stroke is associated with these headaches? The study population consisted of 550 patients (mean age = 63.1, 54% males) with first-ever ischemic stroke and 192 control patients (mean age = 58.7, 36% males) admitted to the emergency room without any acute neurological deficits or serious disorders. All data were collected prospectively, using a standardized case-report form during face-to-face interviews by neurologists. Headache at onset of ischemic stroke was present in 82 (14.9%) of 550 patients. More than half (56%) had a new type of headache (mainly migraine-like) simultaneously with stroke onset, and 36% had headache with altered characteristics (mainly tension-type-like headache). Headaches were associated with cardioembolism (p = 0.002, odds ratio [OR] = 2.4, 95% confidence interval [CI] = 1.4-4.1), posterior circulation stroke (p = 0.01, OR = 2.0, 95% CI = 1.2-3.5), infarcts >15 mm (p = 0.03, 95% CI = 1.1-2.7), infarcts of the cerebellum (p = 0.02, OR = 2.3, 95% CI = 1.1-4.8), good neurological status (p = 0.01, OR = 2.5, 95% CI = 1.2-4.9), and low frequency of large-artery atherosclerosis (p = 0.004, OR = 0.4, 95% CI = 0.2-0.8). At stroke onset, headache of a new type and headache with altered characteristics were related to ischemic stroke. They were associated with certain etiologies of stroke.

Explicit Diagnostic Criteria for Transient Ischemic Attacks Used in the Emergency Department Are Highly Sensitive and Specific.

BACKGROUND: Making a correct diagnosis of a transient ischemic attack (TIA) is prone to errors because numerous TIA mimics exist and there is a shortage of evidence-based diagnostic criteria for TIAs. In this study, we applied for the first time the recently proposed explicit diagnostic criteria for transient ischemic attacks (EDCT) to a group of patients presenting to the emergency department of a large German tertiary care hospital with a suspected TIA. The aim was to determine the sensitivity and specificity of the EDCT in its clinical application. METHODS: A total of 128 patients consecutively presenting to the emergency department of the University Hospital of Lübeck, Germany, under the suspicion of a TIA were prospectively interviewed about their clinical symptoms at the time of presentation. The diagnosis resulting from applying the EDCT was compared to the diagnosis made independently by the senior physicians performing the usual diagnostic work-up ("gold standard"), allowing calculation of sensitivity and specificity of the EDCT. RESULTS: EDCT achieved a sensitivity of 96% and a specificity of 88%. When adding the additional criterion F ("the symptoms may not be better explained by another medical or mental disorder"), specificity significantly increased to 98%. CONCLUSIONS: The data show that the EDCT in its modified version as proposed by us are a highly useful tool for clinicians. They display a high sensitivity and specificity to accurately diagnose TIAs in patients referred to the emergency department with a suspected TIA.

Complete nitrification by Nitrospira bacteria.

Nitrification, the oxidation of ammonia via nitrite to nitrate, has always been considered to be a two-step process catalysed by chemolithoautotrophic microorganisms oxidizing either ammonia or nitrite. No known nitrifier carries out both steps, although complete nitrification should be energetically advantageous. This functional separation has puzzled microbiologists for a century. Here we report on the discovery and cultivation of a completely nitrifying bacterium from the genus Nitrospira, a globally distributed group of nitrite oxidizers. The genome of this chemolithoautotrophic organism encodes the pathways both for ammonia and nitrite oxidation, which are concomitantly activated during growth by ammonia oxidation to nitrate. Genes affiliated with the phylogenetically distinct ammonia monooxygenase and hydroxylamine dehydrogenase genes of Nitrospira are present in many environments and were retrieved on Nitrospira-contigs in new metagenomes from engineered systems. These findings fundamentally change our picture of nitrification and point to completely nitrifying Nitrospira as key components of nitrogen-cycling microbial communities.

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.

Proposed new diagnostic criteria for chronic migraine.

INTRODUCTION: ICHD-3 criteria for chronic migraine (CM) include a mixture of migraine and tension-type-like headaches and do not account for patients who have a high frequency of migraine but no other headaches. MATERIALS AND METHODS: Patients from the Danish Headache Center and their relatives with ICHD-3 defined CM were compared with patients with high frequency episodic migraine (HFEM). Danish registries were used to compare the socioeconomic impact in these two groups. A Russian student population was used to determine the generalizability of the number of patients fulfilling CM and the proposed diagnostic criteria for CM. RESULTS: There was no difference in the demographic profile between the two groups in the Danish cohort. The number of lifelong or annual attacks (p > 0.3), comorbid diseases, or self-reported effect of triptans (p = 1) did not differ. HFEM patients purchased more triptans than CM patients (p = 0.01). CM patients received more early pension (p = 0.00135) but did not differ from HFEM patients with regard to sickness benefit (p = 0.207), cash assistance (p = 0.139), or rehabilitation benefit (p = 1). DISCUSSION: Patients with HFEM are comparable to CM patients with regard to chronicity and disability. We therefore suggest classifying CM as ≥ 8 migraine days per month (proposed CM), disregarding the need for ≥ 15 headache days per month. The proposed diagnostic criteria for CM approximately doubled the number of patients with CM in both the Danish and the Russian materials. Extending the definition of CM to include patients with HFEM will ensure that patients with significant disease burden and unmet treatment needs are identified and provided appropriate access to the range of treatment options and resources available to those with CM. CONCLUSION: Patients with migraine on eight or more days but not 15 days with headache a month are as disabled as patients with ICHD-3 defined CM. They should be included in revised diagnostic criteria for chronic migraine.

Sentinel headache as a warning symptom of ischemic stroke.

BACKGROUND: There are no previous controlled studies of sentinel headache in ischemic stroke. The purpose of the present study was to evaluate the presence of such headache, its characteristics and possible risk factors as compared to a simultaneous control group. METHODS: Eligible patients (n = 550) had first-ever acute ischemic stroke with presence of new infarction on magnetic resonance imaging with diffusion-weighted imaging (n = 469) or on computed tomography (n = 81). As a control group we studied in parallel patients (n = 192) who were admitted to the emergency room without acute neurological deficits or serious neurological or somatic disorders. Consecutive patients with stroke and a simultaneous control group were extensively interviewed soon after admission using validated neurologist conducted semi-structured interview forms. Based on our previous study of sentinel headache in transient ischemic attacks we defined sentinel headache as a new type of headache or a previous kind of headache with altered characteristics (severe intensity, increased frequency, absence of effect of drugs) within seven days before stroke. RESULTS: Among 550 patients with stroke 94 patients (17.1%) had headache during seven days before stroke and 12 (6.2%) controls (p < 0.001; OR 3.9; 95% CI 1.7-5.8). Totally 81 patients (14.7%) had sentinel headache within the last week before stroke and one control. Attacks of arrythmia during seven days before stroke were significantly associated with sentinel headache (p = 0.04, OR 2.3; 95% CI 1.1-4.8). CONCLUSIONS: A new type of headache and a previous kind of headache with altered characteristics during one week before stroke are significantly more prevalent than in controls. These headaches represent sentinel headaches. Sudden onset of such headaches should alarm about stroke.

ICHD-3 is significantly more specific than ICHD-3 beta for diagnosis of migraine with aura and with typical aura.

BACKGROUND: In the emergency room, distinguishing between a migraine with aura and a transient ischemic attack (TIA) is often not straightforward and mistakes can be harmful to both the patient and to society. To account for this difficulty, the third edition of the International Classification of Headache disorders (ICHD-3) changed the diagnostic criteria of migraine with aura. METHODS: One hundred twenty-eight patients referred to the emergency room at the University Hospital of Lübeck, Germany with a suspected TIA were prospectively interviewed about their symptoms leading to admission shortly after initial presentation. The diagnosis that resulted from applying the ICHD-3 and ICHD-3 beta diagnostic criteria was compared to the diagnosis made independently by the treating physicians performing the usual diagnostic work-up. RESULTS: The new ICHD-3 diagnostic criteria for migraine with aura and migraine with typical aura display an excellent specificity (96 and 98% respectively), and are significantly more specific than the previous ICHD-3 beta classification system when it comes to diagnosing a first single attack (probable migraine with aura and probable migraine with typical aura). CONCLUSIONS: The ICHD-3 is a highly useful tool for the clinical neurologist in order to distinguish between a migraine with aura and a TIA, already at the first point of patient contact, such as in the emergency department or a TIA clinic.

Diagnostic Accuracy of the Explicit Diagnostic Criteria for Transient Ischemic Attack: A Validation Study.

Background and Purpose- The clinical diagnosis of a transient ischemic attack (TIA) can be difficult. Evidence-based criteria hardly exist. We evaluated if the recently proposed Explicit Diagnostic Criteria for TIA (EDCT), an easy to perform clinical tool focusing on type, duration, and mode of onset of clinical features, would facilitate the clinical diagnosis of TIA. Methods- We used data from patients suspected of a TIA by a general practitioner and referred to a TIA service in the region of Utrecht, the Netherlands, who participated in the MIND-TIA (Markers in the Diagnosis of TIA) study. Information about the clinical features was collected with a standardized questionnaire within 72 hours after onset. A panel of 3 experienced neurologists ultimately determined the definite diagnosis based on all available diagnostic information including a 6-month follow-up period. Two researchers scored the EDCT. Sensitivity, specificity, and predictive values of the EDCT were assessed using the panel diagnosis as reference. A secondary analysis was performed with modified subcriteria of the EDCT. Results- Of the 206 patients, 126 (61%) had a TIA (n=104) or minor stroke (n=22), and 80 (39%) an alternative diagnosis. Most common alternative diagnoses were migraine with aura (n=24; 30.0%), stress related or somatoform symptoms (n=16; 20.0%), and syncope (n=9; 11.3%). The original EDCT had a sensitivity of 98.4% (95% CI, 94.4-99.8) and a specificity of 61.3% (49.7-71.9). Negative and positive predictive values were 96.1% (86.0-99.0) and 80.0% (75.2-84.1), respectively. The modified EDCT showed a higher specificity of 73.8% (62.7-83.0) with the same sensitivity and a similar negative predictive value of 96.7%, but a higher positive predictive value of 85.5% (80.3-89.5). Conclusions- The EDCT has excellent sensitivity and negative predictive value and could be a valuable diagnostic tool for the diagnosis of TIA.

Mechanical zona pellucida removal of vitrified-warmed human blastocysts does not affect the clinical outcome.

RESEARCH QUESTION: Does complete mechanical removal of the zona pellucida modify the outcome of transfer of vitrified-warmed human blastocysts? DESIGN: In a prospective randomized controlled study, 419 couples were allocated to either zona pellucida-free (n = 209) or zona intact (n = 210) vitrified-warmed embryo transfer. Main outcome measures included clinical pregnancy, implantation and ongoing pregnancy rates. RESULTS: Transfer of zona pellucida-free blastocysts resulted in clinical pregnancy, implantation and ongoing pregnancy rates (35,9%, 33,9% and 32,1%, respectively), similar to those achieved with zona intact control embryos (39%, 36,4% and 33,1%, respectively). CONCLUSION: Total mechanical removal of the zona pellucida did not affect the tested parameters of clinical outcomes.

New diagnostic criteria for headache attributed to transient ischemic attacks.

BACKGROUND: The International Classification of Headache Disorders diagnostic criteria for Headache Attributed to Transient Ischemic Attack (TIA) and many other secondary headaches are based primarily on the opinion of experts. The aim of this study was to field test, for the first time, the diagnostic criteria for headache attributed to TIA of the International Classification of Headache Disorders, 3rd edition (ICHD-3) and in case of their weaknesses to propose new diagnostic criteria. METHODS: Consecutive patients with Transient Ischemic Attack and a simultaneous control group were extensively interviewed soon after admission. Data were collected on previous headaches, headaches around the time of Transient Ischemic Attack and characteristics of the TIA using validated neurologist conducted semi-structured interview forms. The evidence of relevant infarction were excluded in patients with Transient Ischemic Attack using magnetic resonance imaging with diffusion-weighted imaging (n = 112) or computed tomography (n = 8). RESULTS: One hundred twenty patients with Transient Ischemic Attack and 192 controls were included. A new type of headache occurred within 24 h in 16 (13%) of patients with Transient Ischemic Attack and in no controls, a preexisting type of headache with altered characteristics occurred in 9 (7.5%) of patients with Transient Ischemic Attack and no in controls, headache without altered characteristics occurred in 8 (6.6%) of patients with Transient Ischemic Attack and in 9 (4.6%) controls. Only 24% of the headaches in patients with Transient Ischemic Attack (8 of 33 patients) fulfilled the diagnostic criteria of International Classification of Headache Disorders-3 and no control patients. We propose new criteria fulfilled by 94% of the headaches. Specificity remained excellent as only one of 192 controls had a headache fulfilling the proposed criterion C. CONCLUSIONS: Existing diagnostic criteria for headache attributed to TIA of the International Classification of Headache Disorders are too insensitive. We suggest new diagnostic criteria with high sensitivity and preserved specificity.

Prospective testing of ICHD-3 beta diagnostic criteria for migraine with aura and migraine with typical aura in patients with transient ischemic attacks.

Introduction The International Classification of Headache Disorders 3rd edition beta (ICHD-3 beta) gave alternative diagnostic criteria for 1.2 migraine with aura (MA) and 1.2.1 migraine with typical aura (MTA) in the appendix. The latter were presumed to better differentiate transient ischemic attacks (TIA) from MA. The aim of the present study was to field test that. Methods Soon after admission, a neurologist interviewed 120 consecutive patients diagnosed with TIA after MRI or CT. Semi-structured interview forms addressed all details of the TIA episode and all information necessary to apply the ICHD-3beta diagnostic criteria for 1.2, 1.2.1, A1.2 and A1.2.1. Results Requiring at least one identical previous attack, the main body and the appendix criteria performed almost equally well. But requiring only one attack, more than a quarter of TIA patients also fulfilled the main body criteria for 1.2. Specificity was as follows for one attack: 1.2: 0.73, A1.2: 0.91, 1.2.1: 0.88 and A1.2.1: 1.0. Sensitivity when tested against ICHD-2 criteria were 100% for the main body criteria (because they were unchanged), 96% for A1.2 and 94% for A1.2.1. Conclusion The appendix criteria performed much better than the main body criteria for 1.2 MA and 1.2.1 MTA when diagnosing one attack (probable MA). We recommend that the appendix criteria should replace the main body criteria in the ICHD-3.