Future targets for migraine treatment beyond CGRP.

BACKGROUND: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. FINDINGS: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. CONCLUSION: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis.

INTRODUCTION: Headache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce. MATERIAL AND METHODS: We searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8-18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted. RESULTS: Out of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9-14%], 8% for migraine without aura (MwoA) [95%CI: 5-12%], 3% for migraine with aura (MwA) [95%CI:2-4%] and 17% for tension-type headache (TTH) [95% CI: 12-23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53-70%], with prevalence in females and males of 38% [95% CI: 16-66%] and 27% [95% CI: 11-53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking. CONCLUSION: We found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

Genetics of migraine: where are we now?

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes.

The sense of stopping migraine prophylaxis.

INTRODUCTION: Migraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making. METHODS: Three different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar. DISCUSSION: Reasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month. There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated. CONCLUSION: Translational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine.

New biochemical, immune and molecular markers in lung cancer: Diagnostic and prognostic opportunities.

Lung cancer is one of the most common neoplasms and the leading cause of cancer-related deaths worldwide. Despite recent progress in understanding the pathomechanisms of lung cancer, it is frequently associated with late diagnosis, high incidence of metastases and poor response to treatment. Thus, there is extensive research in the field of biomarkers that aims to optimize management of lung cancer. The aim of this study was to review the current perspectives of a wide spectrum of circulating molecules that seem promising as new potential biomarkers of lung cancer. Among these, biochemical (active proteins), immunological (immunocompetent cells, cytokines, chemokines, and antibodies) and genetic (circulating tumor DNA, cell-free DNA and microRNA) markers are presented and discussed. The use of these markers would support the early detection of lung cancer and might be used for predicting disease progression, response of the disease to targeted therapies, monitoring the course of treatment, and developing individualized diagnostic and therapeutic strategies. Special attention was given to potential markers of nervous system involvement in the course of lung cancer, due to its prevalence and devastating impact. Limitations of the potential biomarkers are also outlined and future directions of investigations in this field highlighted, with the aim of improving the accuracy and practical utility of these biomarkers.

What can we learn from the online learning experiences of medical students in Poland during the SARS-CoV-2 pandemic?

BACKGROUND: In March 2020, due to the SARS-CoV-2 pandemic, the Polish government ordered the closing of all medical faculties, with an obligatory shift to online learning. This lockdown continued, with a short period of blended learning, over the time of summer 2020. Distance learning had previously been rarely used within Polish medical schools, so such a sudden transfer was a major challenge. The aim of the study was to explore undergraduates' perception of online teaching provided at Polish medical faculties during the pandemic and to analyze how these experiences may inform future curriculum development. METHODS: The online survey was addressed to undergraduates at Polish medical faculties in November 2020. The questions captured demographics, epidemiological data and students' perception of various aspects of online teaching. Responses were subjected to thematic analysis and their distribution compared considering demographic parameters . RESULTS: Six hundred twenty students from thirteen medical faculties responded to the survey. Major benefits from online teaching perceived by respondents included increased convenience, enhanced quality, a sense of comfort and safety. Major complaints were associated with unsatisfactory content, technical issues, difficulties engaging, poor organization and lack of social life. Students claimed that online teaching required more self-directed learning and discipline and 57.9% considered this impact as negative. 44.5% of respondents took part in educational online activities beyond their scheduled classes. For 49.2% online examinations were reported as more stressful and for 24.8% - less stressful than traditional ones. Differences in the opinions on online teaching were found between men and women, students in early and senior years, Polish and non-Polish ones. CONCLUSIONS: The sudden move online inevitably was problematic for students. Their perspective afforded us the opportunity to consider shortcomings of pre-pandemic undergraduate curriculum. Online education requires a more self-directed learning, which was challenging for many students, so further enhancement of more autonomous study skills seems necessary. Distress expressed by students indicates the need for urgent support with mental health issues.

New methods of differentiation between primary and secondary hypertension in a pediatric population: A single-center experience.

BACKGROUND: Kidney diseases are the main causative factors of secondary hypertension (HTN) in children. Although primary HTN is less common in the pediatric population, its increasing prevalence, especially among teenagers, makes early diagnosis an emerging issue. OBJECTIVES: To analyze the potential differences between primary HTN and HTN secondary to renal diseases, in order to tailor diagnostic procedures to pediatric patients with suspicion of HTN. MATERIAL AND METHODS: A retrospective evaluation was performed of medical records of 168 children (aged from 1 month to 18 years) diagnosed with arterial HTN in the Pediatric Nephrology Department of Wroclaw Medical University (Poland). The comparative analysis concerned demographics, causes of HTN, clinical picture, laboratory tests, and parameters of ambulatory blood pressure monitoring (ABPM). RESULTS: Out of 168 children, 47% were diagnosed with primary HTN and 53% with secondary renal HTN. The patients with primary HTN were significantly older than those with HTN secondary to renal disease. Among the children with primary HTN, 26% were overweight and 42% were obese; among those with renal HTN, the proportions were 16% and 19%, respectively. The patients with primary HTN had significantly higher body mass index (BMI) percentiles and z-scores, and tended toward higher pulse pressure (PP) values. In the group with secondary HTN, ABPM parameters of diastolic blood pressure (DBP) and total cholesterol were significantly elevated. The BMI z-scores correlated positively with PP in the whole group. CONCLUSIONS: As expected, HTN secondary to renal disease prevails in younger children, but primary HTN has become an emerging issue in teenagers. The diagnostics of HTN secondary to kidney disease have revealed risk factors worsening the prognosis, including higher values of cholesterol or of parameters connected with DBP. Primary HTN risk factors include obesity and a tendency towards higher PP values.

Social participation of patients with multiple sclerosis.

BACKGROUND: The effect multiple sclerosis (MS) has on the social functioning and integration of patients has been recently considered as an important factor of the disease. OBJECTIVES: To assess social participation of MS patients with regard to demographic and disease-related variables. MATERIAL AND METHODS: The study comprised 201 MS patients: 140 women, 61 men, aged 24-69 years. The World Health Organization Disability Assessment Schedule (WHODAS 2.0) was applied to assess the aspects of social functioning and the Beck Depression Inventory (BDI) was applied to evaluate the level of depression. Disease duration, degree of disability in Expanded Disability Status Scale (EDSS), most disabling symptoms and type of treatment were determined. WHODAS 2.0 scores (total and within particular domains) and their relationships with age, gender, disease-related variables and level of depression were analyzed. RESULTS: The results of WHODAS 2.0 for 27.4% of patients exceeded the 90th percentile compared to the population norms (with the highest scores for "getting around" and "participation in society" domains). The results of BDI and WHODAS 2.0 were strongly correlated (p < 0.001; ß = 0.73) and mobility impairment was related to both of them (p < 0.001; ß = -0.12 and 0.25, respectively). Other disabling symptoms were associated with scores in domains "understanding and communicating", "getting around" and "participation in society". CONCLUSIONS: Social participation of the MS patients is affected by the impact of disease and associated with depression. Particular symptoms of neurological deficit (motor and visual impairment, fatigue) influence social functioning more than general disease-related variables.

Early Complications in Patients Undergoing Elective Open Surgery for Infrarenal Aortic Aneurysms.

OBJECTIVE: To assess the type and frequency of early postoperative complications in patients after open surgical infrarenal aneurysms repair and determination of their risk factors. STUDY DESIGN: An observational study Place and Duration of Study: The 4th Military Teaching Hospital in Wroclaw, Poland, from January 2012 to December 2016. METHODOLOGY: Analyses of medical records of 205 patients treated for infrarenal aneurysm with open surgery. Patients with clinical and radiological features of aneurysm rupture were excluded. Complications and early deaths (<30 days) were recorded. RESULTS: Men represented 170 (83%) of patients, the average age was 67.9 ± 6.68 years. Aneurysm diameter <60 mm occurred in 107 (52.2%) of patients, 60-80 mm in 76 (37.1%), and >80 mm in 22 (10.7%). Aortic prostheses (tube grafts) were implanted in 132 (64.4%) of patients and aorto-bifemoral (bifurcated) grafts in 73 (35.6%). The most common postoperative complications were: reoperation necessity (n=23; 11.2%), respiratory failure (n=21; 10.2%), respiratory tract infection (n=14; 6.8%), circulatory failure (n=14; 6.8%), lower limb ischemia (n=13; 6.3%), kidney failure (n=12; 5.9%), death (n=9; 4.4%), and surgical wound infection (n=9; 4.4%). Statistical analysis indicated intraoperative blood loss, duration of surgery, a larger aneurysm diameter, and diabetes as risk factors for early complications. CONCLUSION: Complications were the same as reported from other centres. There is a need to shorten surgery duration and minimise blood loss, as these modifiable factors were the predictors of early complications.

Oncologists and Breaking Bad News-From the Informed Patients' Point of View. The Evaluation of the SPIKES Protocol Implementation.

The way that bad news is disclosed to a cancer patient has a crucial impact on physician-patient cooperation and trust. Consensus-based guidelines provide widely accepted tools for disclosing unfavorable information. In oncology, the most popular one is called the SPIKES protocol. A 17-question survey was administered to a group of 226 patients with cancer (mean age 59.6 years) in order to determine a level of SPIKES implementation during first cancer disclosure. In our assessment, the patients felt that the highest compliance with the SPIKES protocol was with Setting up (70.6%), Knowledge (72.8%), and Emotions (75.3%). The lowest was with the Perception (27.7%), Invitation (30.4%), and Strategy & Summary (56.9%) parts. There could be improvement with each aspect of the protocol, but especially in Perception, Invitation, and Strategy & Summary. The latter is really important and must be done better. Older patients felt the doctors' language was more comprehensible (r = 0.17; p = 0.011). Patients' satisfaction of their knowledge about the disease and follow-up, regarded as an endpoint, was insufficient. Privacy was important in improving results (p < 0.01). In practice, the SPIKES protocol is implemented in a satisfactory standard, but it can be improved in each area, especially in Perception, Invitation, and Summary. It is suggested that more training should be done in undergraduate and graduate medical education and the effectiveness of the disclosure continue to be evaluated and improved.

Comparison of the Incidence of Complications and Secondary Surgical Interventions Necessary in Patients with Chronic Lower Limb Ischemia Treated by Both Open and Endovascular Surgeries.

BACKGROUND: Peripheral arterial disease (PAD) affects 3%-10% of the population before the age of 70 years and 15%-20% after that age.The aim of the study was to compare the incidence of complications and secondary interventions in patients who underwent each type of treatment. METHODS: We analyzed 734 medical records of the Department of Surgery at the 4th Military Teaching Hospital in Wroclaw, In total, 394 were operated on with open surgery; an endarterectomy (59.39%), a vascular prosthesis implantation (31.01%), or both of these techniques (6.6%), and 340 patients had angioplasty with (50.59%) or without stenting (49.41%). RESULTS: There were no statistically significant differences in the incidence of corresponding complications. The exception was the infection of the wound; significantly fewer were reported in the case of endovascular procedures (p = 0.0087). There were 12 occasions (3.53%) during endovascular surgeries when intraoperative conversion or re-operation using the open method occurred. In the case of open surgery, the mean hospital stay was 7.77 days (median: 8, mode: 8), while for endovascular management it was equal to 4.68 days (median: 4, mode: 3), p <0.0001. CONCLUSION: The endovascular method results in a similar re-operation rate and number of complications as open surgery.