Carbonic anhydrase inhibitors prevent presymptomatic capillary flow disturbances in a model of cerebral amyloidosis.

To enhance early diagnosis and treatment of Alzheimer·s disease (AD), understanding the pathological changes before symptoms arise is crucial. The continuum model of AD suggest that Aß beta (Aß) accumulation precedes symptoms by at least 15 years, with vascular changes detectable around this time. Disturbances in capillary flow dynamics have been linked to reduced oxygen delivery to brain tissue, but evidence in presymptomatic AD remains elusive. We examined capillary flow dynamics in presymptomatic Tg-SwDI mice and the capacity of carbonic anhydrase inhibitors (CAIs) to prevent capillary flow disturbances. Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and Aß load in cognitively normal 9-10-month-old Tg-SwDI mice. Treated mice showed ameliorated capillary flow disturbances, enhanced oxygen availability, and reduced Aß load. These findings underscore the importance of capillary flow disturbances in presymptomatic AD and highlight CAIs· potential for preserving vascular integrity in early AD.

Disparities in the access to atrial fibrillation ablation in Denmark - Who gets ablated, who neglected?

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia associated with reduced quality of life that can lead to serious complications such as stroke, and heart failure. Ablation is a safe and effective treatment for AF but is not offered equally to all patients. PURPOSE: To identify the demographic groups more or less likely to undergo AF ablation. METHODS: All patients with newly diagnosed AF between 2010 and 2018 were identified in the Danish nationwide registries. The association between gender, age, level of education and attachment to the job market, and the likelihood of receiving AF ablation was investigated using multivariable Cox proportional-hazard analysis. Cumulative incidence was calculated using the Aalen-Johansen estimator. RESULTS: A total of 176,248 patients were included. Men were more likely to receive ablation than women (7% vs 3%). Patients aged 25-44 and 45-64 were most likely to receive ablation, while only 0.7% of patients aged 80 or above received ablation. The rate of ablation significantly decreased with decreasing level of education. Full-time employed patients were most likely to receive ablation, followed by self-employed, unemployed, on sick leave, undergoing education, and early retired patients. Retired patients were the least likely to receive ablation (3%). CONCLUSION: This study found that women, older patients, patients with lower levels of education, and patients on social benefits are less likely to receive AF ablation. These findings suggest that there are significant social and economic disparities in AF ablation treatment in Denmark.

Cerebral microvascular changes in healthy carriers of the APOE-ɛ4 Alzheimer's disease risk gene.

APOE-ɛ4 is a genetic risk factor for Alzheimer's disease (AD). AD is associated with reduced cerebral blood flow (CBF) and with microvascular changes that limit the transport of oxygen from blood into brain tissue: reduced microvascular cerebral blood volume and high relative transit time heterogeneity (RTH). Healthy APOE-ɛ4 carriers reveal brain regions with elevated CBF compared with carriers of the common ɛ3 allele. Such asymptomatic hyperemia may reflect microvascular dysfunction: a vascular disease entity characterized by suboptimal tissue oxygen uptake, rather than limited blood flow per se. Here, we used perfusion MRI to show that elevated regional CBF is accompanied by reduced capillary blood volume in healthy APOE-ɛ4 carriers (carriers) aged 30-70 years compared with similarly aged APOE-ɛ3 carriers (noncarriers). Younger carriers have elevated hippocampal RTH and more extreme RTH values throughout both white matter (WM) and cortical gray matter (GM) compared with noncarriers. Older carriers have reduced WM CBF and more extreme GM RTH values than noncarriers. Across all groups, lower WM and hippocampal RTH correlate with higher educational attainment, which is associated with lower AD risk. Three days of dietary nitrate supplementation increased carriers' WM CBF but caused older carriers to score worse on two of six aggregate neuropsychological scores. The intervention improved late recall in younger carriers and in noncarriers. The APOE-ɛ4 gene is associated with microvascular changes that may impair tissue oxygen extraction. We speculate that vascular risk factor control is particularly important for APOE-ɛ4 carriers' healthy aging.

Shedding Light on the Black Box of Rehabilitation: Differential Short- and Long-Term Effects of Multidisciplinary Multiple Sclerosis Rehabilitation.

BACKGROUND: The study of the effectiveness of multidisciplinary rehabilitation (MDR) and how the symptoms and needs of individuals with multiple sclerosis (MS) interplay with the diversity of MDR interventions is still a conundrum, often referred to as a black box. METHODS: We conducted a partial crossover randomized controlled trial with follow-ups at 1 (discharge), 6, and 12 months. Based on their rehabilitation goals, each patient was categorized into 1 of 5 main focus areas (MFAs) prior to admission: Resilience, Cognitive Function, Energy, Physical Function, and Personal Needs. The Functional Assessment of Multiple Sclerosis (FAMS) instrument scores were the primary outcome. RESULTS: MFA groups varied in age (P = .036), MS type (P = .002), Expanded Disability Status Scale score (P < .001), time since diagnosis (P = .002), and FAMS at baseline (P < .001), as well as in composition and quantity of MDR services. At discharge, significant FAMS improvements were found in all 5 MFA groups (FAMS change > 10.4, P < .05), but the affected subdimensions and persistence of improvements varied among MFA groups. At the 6-month follow-up, estimates of controlled differences in FAMS were 9.9 (P =.001), 5.6 (P = .196), 8.5 (P = .008), -1.4 (P = .548), and 17.9 (P = .012) for the Resilience, Cognitive Function, Energy, Physical Function, and Personal Needs groups, respectively. CONCLUSIONS: This study demonstrated that inpatient MDR improves functioning and health-related quality of life in people with MS; the type, degree, and persistence of the benefits are associated with a patient's main focus area of rehabilitation, which signifies the importance of the goal-setting process in MDR.

Understanding the incidence of atrial fibrillation and stroke in hypertrophic cardiomyopathy patients: insights from Danish nationwide registries.

AIMS: The treatment of atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) can be challenging since AF aggravates symptoms and increases the risk of stroke. Which factors contribute to the development of AF and stroke in HCM remains unknown. The aim of this study was to determine the incidence of AF and stroke in HCM patients and identify the risk factors. METHODS AND RESULTS: Using Danish national registries, all HCM patients from 2005 to 2018 were included. The association between HCM, incident AF, and stroke was investigated using multivariable Cox proportional hazards analysis. Cumulative incidences were calculated using the Aalen-Johansen estimator. Among the 3367 patients without prevalent AF, 24% reached the endpoint of incident AF with death as a competing risk. Median follow-up time was 4 years. Atrial fibrillation incidence was equal between sexes and increased for patients with ischaemic heart disease [IHD; hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.08-1.63], hypertension (HT) (HR 1.36, 95% CI 1.14-1.67), and obstructive HCM (HR 1.27, 95% CI 1.05-1.52). Seven per cent developed stroke, with no difference detected stratifying for the presence of AF. Sub-analysis revealed that when AF was treated with oral anticoagulants (OACs), stroke was less likely (HR 0.4, 95% CI 0.18-0.86, P = 0.02). However, 34% of patients were not receiving adequate anticoagulation following AF diagnosis. CONCLUSION: Obstructive HCM, HT, and IHD were associated with increased risk of AF. Prevalent AF alone was not predictive of stroke; however, AF patients treated with OAC were significantly less likely to develop stroke, suggesting that this development is driven by the protective effect of OAC. Despite this, 34% of patients did not receive OAC.

Long-Term Cardiovascular Risk Associated With Treatment of Attention-Deficit/Hyperactivity Disorder in Adults.

BACKGROUND: Incrementing numbers of patients treated for attention-deficit/hyperactivity disorder (ADHD) call for scrutiny concerning long-term drug-safety. OBJECTIVES: This study aims to investigate associations between long-term use of ADHD treatment and cardiovascular outcomes. METHODS: Using nationwide registers, adult patients first-time initiated on ADHD treatment between 1998 and 2020 were identified. Exposure groups were prior users, <1 defined daily dose (DDD) per day, ≥1 DDD per day determined at start of follow-up, and 1 year after patients' first claimed prescription. Outcomes were acute coronary syndromes, stroke, heart failure, and a composite of the above. RESULTS: At start of follow-up, 26,357, 31,211, and 15,696 individuals were correspondingly categorized as prior users (42% female, median age: 30 years [Q1-Q3: 23-41 years]), <1 DDD per day (47% female, median age: 31 years [Q1-Q3: 24-41 years]), and ≥1 DDD per day (47% female, median age: 33 years [Q1-Q3: 25-41 years]), respectively. Comparing ≥1 DDD per day with prior users, elevated standardized 10-year absolute risk of stroke (2.1% [95% CI: 1.8%-2.4%] vs 1.7% [95% CI: 1.5%-1.9%]), heart failure (1.2% [95% CI: 0.9%-1.4%] vs 0.7% [95% CI: 0.6%-0.8%]), and the composite outcome (3.9% [95% CI: 3.4%-4.3%] vs 3.0% [95% CI: 2.8 %-3.2%]) was found-with corresponding risk ratios of 1.2 (95% CI: 1.0-1.5), 1.7 (95% CI: 1.3-2.2), and 1.3 (95% CI: 1.1-1.5). No apparent associations were found for acute coronary syndrome (1.0% [95% CI: 0.8%-1.2%] vs 0.9% [95% CI: 0.8%-1.0%]). CONCLUSIONS: Possible associations between elevated long-term cardiovascular risk and increasing dosage of ADHD treatment use in a young patient group should warrant further investigation.

Effect of early cryoballoon ablation on atrial fibrillation recurrence-A Danish nationwide register study.

INTRODUCTION: Cryoballoon ablation is a safe and efficient rhythm control strategy in atrial fibrillation (AF) patients. The impact of time from diagnosis to ablation is unclear. The aim of this study was to examine the impact of timing of first-time cryoballoon ablation on AF recurrence in a nationwide cohort of AF patients. METHODS AND RESULTS: From nationwide registers, all AF patients ≥18 years of age who underwent first-time AF cryoballoon ablation in Denmark from 2012 to 2018 were included. The AF patients were stratified by ablation timing: Early group (≤1 year after AF diagnosis), intermediate group (1-3 years after AF diagnosis), and late group (≥3 years after AF diagnosis). By adjusted Cox regression models, the effect of timing on AF recurrence was examined. This study included 1064 AF patients with a median age of 63 years. Most patients were male (66%) and had paroxysmal AF (67%). The 1-year risk of AF recurrence increased from 31% in the early group to 41% and 44% in the intermediate and late group. The hazard ratios (95% confidence intervals) were 1.28 (0.95, 1.74) in the intermediate group and 1.42 (1.09, 1.86) in the late group when compared to the early group. Continuous diagnosis-to-ablation time seemed to have the greatest impact on AF recurrence within the first 2 years. CONCLUSION: In AF patients undergoing cryoballoon ablation, late timing of ablation was associated with a significantly higher AF recurrence rate when compared to early timing of ablation. These findings support early cryoballoon ablation to improve the outcomes after ablation.

Risk assessment of early therapeutic anticoagulation following cranial surgery: an institutional case series.

OBJECTIVE: Postoperative thrombotic complications represent a unique challenge in cranial neurosurgery as primary treatment involves therapeutic anticoagulation. The decision to initiate therapy and its timing is nuanced, as surgeons must balance the risk of catastrophic intracranial hemorrhage (ICH). With limited existing evidence to guide management, current practice patterns are subjective and inconsistent. The authors assessed their experience with early therapeutic anticoagulation (≤ 7 days postoperatively) initiation for thrombotic complications in neurosurgical patients undergoing cranial surgery to better understand the risks of catastrophic ICH. METHODS: Adult patients treated with early therapeutic anticoagulation following cranial surgery were considered. Anticoagulation indications were restricted to thrombotic or thromboembolic complications. Records were retrospectively reviewed for demographics, surgical details, and anticoagulation therapy start. The primary outcome was the incidence of catastrophic ICH, defined as ICH resulting in reoperation or death within 30 days of anticoagulation initiation. As a secondary outcome, post-anticoagulation cranial imaging was reviewed for new or worsening acute blood products. Fisher's exact and Wilcoxon rank-sum tests were used to compare cohorts. Cumulative outcome analyses were performed for primary and secondary outcomes according to anticoagulation start time. RESULTS: Seventy-one patients satisfied the inclusion criteria. Anticoagulation commenced on mean postoperative day (POD) 4.3 (SD 2.2). Catastrophic ICH was observed in 7 patients (9.9%) and was associated with earlier anticoagulation initiation (p = 0.02). Of patients with catastrophic ICH, 6 (85.7%) had intra-axial exploration during their index surgery. Patients with intra-axial exploration were more likely to experience a catastrophic ICH postoperatively compared to those with extra-axial exploration alone (OR 8.5, p = 0.04). Of the 58 patients with postoperative imaging, 15 (25.9%) experienced new or worsening blood products. Catastrophic ICH was 9 times more likely with anticoagulation initiation within 48 hours of surgery (OR 8.9, p = 0.01). The cumulative catastrophic ICH risk decreased with delay in initiation of anticoagulation, from 21.1% on POD 2 to 9.9% on POD 7. Concurrent antiplatelet medication was not associated with either outcome measure. CONCLUSIONS: The incidence of catastrophic ICH was significantly increased when anticoagulation was initiated within 48 hours of cranial surgery. Patients undergoing intra-axial exploration during their index surgery were at higher risk of a catastrophic ICH.

Cerebral blood flow regulation in hypobaric hypoxia: role of haemoconcentration.

During acute hypoxic exposure, cerebral blood flow (CBF) increases to compensate for the reduced arterial oxygen content (CaO2). Nevertheless, as exposure extends, both CaO2 and CBF progressively normalize. Haemoconcentration is the primary mechanism underlying the CaO2 restoration and may therefore explain, at least in part, the CBF normalization. Accordingly, we tested the hypothesis that reversing the haemoconcentration associated with extended hypoxic exposure returns CBF towards the values observed in acute hypoxia. Twenty-three healthy lowlanders (12 females) completed two identical 4-day sojourns in a hypobaric chamber, one in normoxia (NX) and one in hypobaric hypoxia (HH, 3500 m). CBF was measured by ultrasound after 1, 6, 12, 48 and 96 h and compared between sojourns to assess the time course of changes in CBF. In addition, CBF was measured at the end of the HH sojourn after hypervolaemic haemodilution. Compared with NX, CBF was increased in HH after 1 h (P = 0.001) but similar at all later time points (all P > 0.199). Haemoglobin concentration was higher in HH than NX from 12 h to 96 h (all P < 0.001). While haemodilution reduced haemoglobin concentration from 14.8 ± 1.0 to 13.9 ± 1.2 g·dl-1 (P < 0.001), it did not increase CBF (974 ± 282 to 872 ± 200 ml·min-1; P = 0.135). We thus conclude that, at least at this moderate altitude, haemoconcentration is not the primary mechanism underlying CBF normalization with acclimatization. These data ostensibly reflect the fact that CBF regulation at high altitude is a complex process that integrates physiological variables beyond CaO2. KEY POINTS: Acute hypoxia causes an increase in cerebral blood flow (CBF). However, as exposure extends, CBF progressively normalizes. We investigated whether hypoxia-induced haemoconcentration contributes to the normalization of CBF during extended hypoxia. Following 4 days of hypobaric hypoxic exposure (corresponding to 3500 m altitude), we measured CBF before and after abolishing hypoxia-induced haemoconcentration by hypervolaemic haemodilution. Contrary to our hypothesis, the haemodilution did not increase CBF in hypoxia. Our findings do not support haemoconcentration as a stimulus for the CBF normalization during extended hypoxia.

Prognostic factors for disease activity in newly diagnosed teriflunomide-treated patients with multiple sclerosis: a nationwide Danish study.

BACKGROUND: Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL). METHODS: We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex. RESULTS: In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations. CONCLUSION: A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment.

The Genetic Profile of Large B-Cell Lymphomas Presenting in the Ocular Adnexa.

To provide insights into targetable oncogenic pathways, this retrospective cohort study investigated the genetic profile of 26 patients with diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), and two patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL) presenting in the ocular adnexa. Pathogenic variants and copy number variations in 128 B-cell lymphoma-relevant genes were analyzed by targeted next-generation sequencing. Genetic subtypes were determined with the LymphGen algorithm. Primary ocular adnexal DLBCL-NOS constituted 50% (n = 14) and was generally characterized by non-germinal center B-cell origin (non-GCB) (n = 8, 57%), and LymphGen MCD subtype (n = 5, 36%). Primary ocular adnexal DLBCL-NOS presented pathogenic variants in genes involved in NF-κB activation and genes which are recurrently mutated in other extranodal lymphomas of non-GCB origin, including MYD88 (n = 4, 29%), CD79B (n = 3, 21%), PIM1 (n = 3, 21%), and TBL1XR1 (n = 3, 21%). Relapsed DLBCL-NOS presenting in the ocular adnexa (n = 6) were all of non-GCB origin and frequently of MCD subtype (n = 3, 50%), presenting with a similar genetic profile as primary ocular adnexal DLBCL-NOS. These results provide valuable insights into genetic drivers in ocular adnexal DLBCL-NOS, offering potential applications in future precision medicine.

Lower Recurrence Rates of Atrial Fibrillation and MACE Events After Early Compared to Late Ablation: A Danish Nationwide Register Study.

BACKGROUND: Guidelines recommend prioritizing treatment with antiarrhythmic drugs before referral of patients with atrial fibrillation to ablation, delaying a potential subsequent ablation. However, delaying ablation may affect ablation outcomes. We sought to investigate the impact of duration from diagnosis to ablation on the risk of atrial fibrillation recurrence and adverse events. METHODS AND RESULTS: Using Danish nationwide registries, all patients with first-time ablation for atrial fibrillation were identified and included from 2010 to 2018. Patients were divided into 4 groups by diagnosis-to-ablation time: <1.0 year (early ablation), 1.0 to 1.9 years, 2.0 to 2.9 years, and >2.9 years (late ablation). The primary end point was atrial fibrillation recurrence after the 90-day blanking period, defined by admission for atrial fibrillation, cardioversions, use of antiarrhythmic drugs, or repeat atrial fibrillation ablations. The secondary end point was a composite end point of heart failure, ischemic stroke, or death, and each event individually. The study cohort consisted of 7705 patients. The 5-year cumulative incidence of atrial fibrillation recurrence in the 4 groups was 42.9%, 54.8%, 55.9%, and 58.4%, respectively. Hazard ratios were 1.20 (95% CI, 1.07-1.35), 1.29 (95% CI, 1.13-1.47), and 1.40 (95% CI, 1.28-1.53), respectively, with the early ablation group as reference. The hazard ratio for the combined secondary end point was 1.22 (95% CI, 1.04-1.44) in the late ablation group compared with the early ablation group. CONCLUSIONS: In patients undergoing ablation for atrial fibrillation, early ablation was associated with a significantly lower risk of atrial fibrillation recurrence. Furthermore, the associated risk of heart failure, ischemic stroke, or death was significantly lower in early-compared with late-ablation patients.

Cerebral Embolic Protection in Transcatheter Aortic Valve Implantation Using the Sentinel Cerebral Protection System: A Systematic Review and Meta-Analysis.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) plays a vital role in patients with symptomatic aortic stenosis. Despite the mortality benefit of TAVI, embolic stroke remains a feared complication. As a result, transcatheter cerebral embolic protection (TCEP) devices have been developed to reduce this risk. Given the ongoing debate of TCEP in TAVI, we performed a systematic review and meta-analysis of all randomized controlled trials to date to identify outcomes of periprocedural stroke using the Sentinel™ cerebral protection system (CPS). METHODS: MEDLINE, Cochrane, and Scopus databases were utilized from inception until 12/2023. PRISMA criteria was utilized. Keywords included "cerebral embolic protection", "sentinel cerebral protection system", "transcatheter aortic valve implantation", and "transcatheter aortic valve replacement". Primary outcome was periprocedural stroke. Secondary outcomes included periprocedural disabling and non-disabling stroke, all-cause mortality, transient ischemic attack, delirium, acute kidney injury, vascular complications, bleeding, and pacemaker implantation. Risk ratios (RR) were measured via Mantel-Haenszel method with fixed analysis. Heterogeneity was assessed via chi-squared and Higgin's I2 test. RESULTS: Four trials with 3528 patients were assessed. SAPIEN 3 was the most common bioprosthetic valve used. The average age was 79.4 years with 41.9% of the sample size being females. The most prevalent comorbidities were hypertension, diabetes mellitus, and coronary artery disease. There was no difference in periprocedural stroke in patients who underwent TAVI with the Sentinel™ CPS compared to no TCEP (RR 0.75, P = 0.12). Periprocedural disabling strokes were less likely in those who underwent TAVI with the Sentinel™ CPS compared to no TCEP (RR 0.41, P = 0.02) with a number needed to treat (NNT) of 123. All other outcomes did not reach statistical significance. CONCLUSIONS: In our analysis, there was no difference between TAVI with the Sentinel™ CPS compared to TAVI without TCEP in regard to risk of periprocedural stroke; however, it was associated with a decreased risk of periprocedural disabling stroke.

100 ancient genomes show repeated population turnovers in Neolithic Denmark.

Major migration events in Holocene Eurasia have been characterized genetically at broad regional scales1-4. However, insights into the population dynamics in the contact zones are hampered by a lack of ancient genomic data sampled at high spatiotemporal resolution5-7. Here, to address this, we analysed shotgun-sequenced genomes from 100 skeletons spanning 7,300 years of the Mesolithic period, Neolithic period and Early Bronze Age in Denmark and integrated these with proxies for diet (13C and 15N content), mobility (87Sr/86Sr ratio) and vegetation cover (pollen). We observe that Danish Mesolithic individuals of the Maglemose, Kongemose and Ertebølle cultures form a distinct genetic cluster related to other Western European hunter-gatherers. Despite shifts in material culture they displayed genetic homogeneity from around 10,500 to 5,900 calibrated years before present, when Neolithic farmers with Anatolian-derived ancestry arrived. Although the Neolithic transition was delayed by more than a millennium relative to Central Europe, it was very abrupt and resulted in a population turnover with limited genetic contribution from local hunter-gatherers. The succeeding Neolithic population, associated with the Funnel Beaker culture, persisted for only about 1,000 years before immigrants with eastern Steppe-derived ancestry arrived. This second and equally rapid population replacement gave rise to the Single Grave culture with an ancestry profile more similar to present-day Danes. In our multiproxy dataset, these major demographic events are manifested as parallel shifts in genotype, phenotype, diet and land use.

Population genomics of post-glacial western Eurasia.

Western Eurasia witnessed several large-scale human migrations during the Holocene1-5. Here, to investigate the cross-continental effects of these migrations, we shotgun-sequenced 317 genomes-mainly from the Mesolithic and Neolithic periods-from across northern and western Eurasia. These were imputed alongside published data to obtain diploid genotypes from more than 1,600 ancient humans. Our analyses revealed a 'great divide' genomic boundary extending from the Black Sea to the Baltic. Mesolithic hunter-gatherers were highly genetically differentiated east and west of this zone, and the effect of the neolithization was equally disparate. Large-scale ancestry shifts occurred in the west as farming was introduced, including near-total replacement of hunter-gatherers in many areas, whereas no substantial ancestry shifts happened east of the zone during the same period. Similarly, relatedness decreased in the west from the Neolithic transition onwards, whereas, east of the Urals, relatedness remained high until around 4,000 BP, consistent with the persistence of localized groups of hunter-gatherers. The boundary dissolved when Yamnaya-related ancestry spread across western Eurasia around 5,000 BP, resulting in a second major turnover that reached most parts of Europe within a 1,000-year span. The genetic origin and fate of the Yamnaya have remained elusive, but we show that hunter-gatherers from the Middle Don region contributed ancestry to them. Yamnaya groups later admixed with individuals associated with the Globular Amphora culture before expanding into Europe. Similar turnovers occurred in western Siberia, where we report new genomic data from a 'Neolithic steppe' cline spanning the Siberian forest steppe to Lake Baikal. These prehistoric migrations had profound and lasting effects on the genetic diversity of Eurasian populations.

Cannabis for chronic pain: cardiovascular safety in a nationwide Danish study.

BACKGROUND AND AIMS: A rising number of countries allow physicians to treat chronic pain with medical cannabis. However, recreational cannabis use has been linked with cardiovascular side effects, necessitating investigations concerning the safety of prescribed medical cannabis. METHODS: Using nationwide Danish registers, patients with chronic pain initiating first-time treatment with medical cannabis during 2018-21 were identified and matched 1:5 to corresponding control patients on age, sex, chronic pain diagnosis, and concomitant use of other pain medication. The absolute risks of first-time arrhythmia (atrial fibrillation/flutter, conduction disorders, paroxysmal tachycardias, and ventricular arrhythmias) and acute coronary syndrome were reported comparing medical cannabis use with no use. RESULTS: Among 1.88 million patients with chronic pain (46% musculoskeletal, 11% cancer, 13% neurological, and 30% unspecified pain), 5391 patients claimed a prescription of medical cannabis [63.2% women, median age: 59 (inter-quartile range 48-70) years] and were compared with 26 941 control patients of equal sex- and age composition. Arrhythmia was observed in 42 and 107 individuals, respectively, within 180 days. Medical cannabis use was associated with an elevated risk of new-onset arrhythmia {180-day absolute risk: 0.8% [95% confidence interval (CI) 0.6%-1.1%]} compared with no use [180-day absolute risk: 0.4% (95% CI 0.3%-0.5%)]: a risk ratio of 2.07 (95% CI 1.34-2.80) and a 1-year risk ratio of 1.36 (95% CI 1.00-1.73). No significant association was found for acute coronary syndrome [180-day risk ratio: 1.20 (95% CI 0.35-2.04)]. CONCLUSIONS: In patients with chronic pain, the use of prescribed medical cannabis was associated with an elevated risk of new-onset arrhythmia compared with no use-most pronounced in the 180 days following the initiation of treatment.

The obesity paradox and ventriculoperitoneal shunting in aneurysmal subarachnoid hemorrhage patients undergoing microsurgical clipping.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) can be devastating. Identifying predisposing factors is paramount in reducing aSAH-related mortality. Obesity's negative impact on health is well-established. However, the controversial "obesity paradox" in neurosurgery suggests that obesity may confer a survival advantage in SAH. We hypothesized that obesity would have a negative impact on outcomes following surgical clipping in aSAH. METHODS: A single-institution retrospective review was performed of aSAH patients undergoing surgical clipping from 2017 to 2021. Demographics and clinically relevant variables were collected. Obesity was defined as body mass index >30. Primary outcome was death or severe disability (mRS 4-6) at last follow-up. Secondary outcome was VPS placement. Multivariable Cox proportional-hazards model identified predictors of poor outcome. Kaplan-Meier curves identified survivorship differences between obese and non-obese patients. RESULTS: Poor outcome occurred in 11 of 52 total patients (21.2 %). There were no differences in demographics or distribution of Hunt Hess (HH), modified Fisher Grade (mFG), or external ventricular drain (EVD) placement between obese and non-obese patients. On univariate analysis, hypertension, older age, and non-obesity were predictive of poor outcome. On multivariable analysis, only obesity remained significant, suggesting a protective effect from poor outcome (HR 0.45 [0.21-0.95], p = 0.037). VPS placement occurred in 6 (11.5 %) patients for which obesity was not a significant predictor. CONCLUSIONS: Obesity may have a protective effect against poor outcome following surgical clipping in aSAH. Additionally, obesity does not appear to increase rate of EVD conversion to VPS. Thus, our study suggests that obesity should not preclude patients from open surgical intervention when clinically appropriate.

Treatment outcomes for ARUBA-eligible brain arteriovenous malformations: a comparison of real-world data from the NVQI-QOD AVM registry with the ARUBA trial.

BACKGROUND: Significant controversy exists about the management of unruptured cerebral arteriovenous malformations (AVMs). Results from A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) suggested that intervention increases the risk of stroke/death compared with medical management. However, numerous study limitations raised concerns about the trial's generalizability. OBJECTIVE: To assess the rate of stroke/death and functional outcomes in ARUBA-eligible patients from a multicenter database, the Neurovascular Quality Initiative-Quality Outcomes Database (NVQI-QOD). METHODS: We performed a retrospective analysis of prospectively collected data of ARUBA-eligible patients who underwent intervention at 18 participating centers. The primary endpoint was stroke/death from any cause. Secondary endpoints included neurologic, systemic, radiographic, and functional outcomes. RESULTS: 173 ARUBA-eligible patients underwent intervention with median follow-up of 269 (25-722.5) days. Seventy-five patients received microsurgery±embolization, 37 received radiosurgery, and 61 received embolization. Baseline demographics, risk factors, and general AVM characteristics were similar between groups. A total of 15 (8.7%) patients experienced stroke/death with no significant difference in primary outcome between treatment modalities. Microsurgery±embolization was more likely to achieve AVM obliteration (P<0.001). Kaplan-Meier survival curves demonstrated no difference in overall death/stroke outcomes between the different treatment modalities' 5-year period (P=0.087). Additionally, when compared with the ARUBA interventional arm, our patients were significantly less likely to experience death/stroke (8.7% vs 30.7%; P<0.001) and functional impairment (mRS score ≥2 25.4% vs 46.2%; P<0.01). CONCLUSION: Our results suggest that intervention for unruptured brain AVMs at comprehensive stroke centers across the United States is safe.