TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A.

Variants of UNC13A, a critical gene for synapse function, increase the risk of amyotrophic lateral sclerosis and frontotemporal dementia1-3, two related neurodegenerative diseases defined by mislocalization of the RNA-binding protein TDP-434,5. Here we show that TDP-43 depletion induces robust inclusion of a cryptic exon in UNC13A, resulting in nonsense-mediated decay and loss of UNC13A protein. Two common intronic UNC13A polymorphisms strongly associated with amyotrophic lateral sclerosis and frontotemporal dementia risk overlap with TDP-43 binding sites. These polymorphisms potentiate cryptic exon inclusion, both in cultured cells and in brains and spinal cords from patients with these conditions. Our findings, which demonstrate a genetic link between loss of nuclear TDP-43 function and disease, reveal the mechanism by which UNC13A variants exacerbate the effects of decreased TDP-43 function. They further provide a promising therapeutic target for TDP-43 proteinopathies.

IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Hereditary platelet disorders associated with germ line variants in RUNX1, ETV6, and ANKRD26.

Hereditary platelet disorders (HPDs) are a group of blood disorders with variable severity and clinical impact. Although phenotypically there is much overlap, known genetic causes are many, prompting the curation of multigene panels for clinical use, which are being deployed in increasingly large-scale populations to uncover missing heritability more efficiently. For some of these disorders, in particular RUNX1, ETV6, and ANKRD26, pathogenic germ line variants in these genes also come with a risk of developing hematological malignancy (HM). Although they may initially present as similarly mild-moderate thrombocytopenia, each of these 3 disorders have distinct penetrance of HM and a different range of somatic alterations associated with malignancy development. As our ability to diagnose HPDs has improved, we are now faced with the challenges of integrating these advances into routine clinical practice for patients and how to optimize management and surveillance of patients and carriers who have not developed malignancy. The volume of genetic information now being generated has created new challenges in how to accurately assess and report identified variants. The answers to all these questions involve international initiatives on rare diseases to better understand the biology of these disorders and design appropriate models and therapies for preclinical testing and clinical trials. Partnered with this are continued technological developments, including the rapid sharing of genetic variant information and automated integration with variant classification relevant data, such as high-throughput functional data. Collective progress in this area will drive timely diagnosis and, in time, leukemia preventive therapeutic interventions.

Discovery of novel predisposing coding and noncoding variants in familial Hodgkin lymphoma.

Familial aggregation of Hodgkin lymphoma (HL) has been demonstrated in large population studies, pointing to genetic predisposition to this hematological malignancy. To understand the genetic variants associated with the development of HL, we performed whole genome sequencing on 234 individuals with and without HL from 36 pedigrees that had 2 or more first-degree relatives with HL. Our pedigree selection criteria also required at least 1 affected individual aged <21 years, with the median age at diagnosis of 21.98 years (3-55 years). Family-based segregation analysis was performed for the identification of coding and noncoding variants using linkage and filtering approaches. Using our tiered variant prioritization algorithm, we identified 44 HL-risk variants in 28 pedigrees, of which 33 are coding and 11 are noncoding. The top 4 recurrent risk variants are a coding variant in KDR (rs56302315), a 5' untranslated region variant in KLHDC8B (rs387906223), a noncoding variant in an intron of PAX5 (rs147081110), and another noncoding variant in an intron of GATA3 (rs3824666). A newly identified splice variant in KDR (c.3849-2A>C) was observed for 1 pedigree, and high-confidence stop-gain variants affecting IRF7 (p.W238∗) and EEF2KMT (p.K116∗) were also observed. Multiple truncating variants in POLR1E were found in 3 independent pedigrees as well. Whereas KDR and KLHDC8B have previously been reported, PAX5, GATA3, IRF7, EEF2KMT, and POLR1E represent novel observations. Although there may be environmental factors influencing lymphomagenesis, we observed segregation of candidate germline variants likely to predispose HL in most of the pedigrees studied.

Consideration of factors associated with inequalities in interventions that support health-care professionals' interaction with patients to reduce inappropriate antimicrobial use: a systematic review.

BACKGROUND: Tackling the public health challenge of antimicrobial resistance (AMR) requires promotion of appropriate antimicrobial use by health-care professionals. The objective of this review was to identify interventions that facilitate appropriate antimicrobial behaviours when health-care professionals interact with patients and any considerations for factors associated with health inequalities. METHODS: For this systematic review, we searched electronic databases (MEDLINE, EMBASE, Web of Science and Google Scholar) from Jan 31, 2023, to Feb 8, 2023. We included search terms such as antimicrobial use/prescribing, health-care professionals, and AMR programmes. We included any relevant primary study published from year 2010 and in English. We conducted forward and backward citation searching from included studies on March 27, 2023. We extracted information on the interventions following the Template for Intervention Description and Replication (TIDieR) guideline and examined reports on how the interventions might impact on inequalities. We performed quality assessment using the Mixed Methods Appraisal Tool (MMAT). We conducted descriptive synthesis. The protocol is registered with PROSPERO (CRD42023395642). FINDINGS: After screening 4979 records, we included 59 studies. Most studies were randomised trials (n=25) and qualitative/mixed methods studies (n=16). Included studies covered 16 countries, particularly the UK (n=16) and the USA (n=13). Most studies (n=34) fulfilled at least 80% of the relevant quality criteria, but 12 studies fulfilled less than 50%. Many interventions were established strategies (eg, TARGET: Treat Antibiotics Responsibly, Guidance, Education and Tools). Patient interaction elements of the interventions often involved using education materials (eg, digital/paper leaflets, and videos) and point-of-care testing. While many studies (n=49) included participants from disadvantaged groups, only three examined how outcomes differ between groups. In those studies, antimicrobial prescription was not associated with age, sex, and level of learning disability. Some other studies reported issues with language barriers and potential digital exclusion, especially for older people. INTERPRETATION: We might have missed some relevant studies due to publication year and language restrictions. Notwithstanding, this review showed that the potential impact of factors associated with health inequalities are not routinely considered during the implementation and evaluation of interventions to improve health-care professionals' interaction with patients. Future work should routinely consider this to help mitigate potential inequalities. FUNDING: UK Health Security Agency.

Ceramide-induced integrated stress response overcomes Bcl-2 inhibitor resistance in acute myeloid leukemia.

Inducing cell death by the sphingolipid ceramide is a potential anticancer strategy, but the underlying mechanisms remain poorly defined. In this study, triggering an accumulation of ceramide in acute myeloid leukemia (AML) cells by inhibition of sphingosine kinase induced an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This effect led to transcription of the BH3-only protein Noxa and degradation of the prosurvival Mcl-1 protein on which AML cells are highly dependent for survival. Targeting this novel ISR pathway, in combination with the Bcl-2 inhibitor venetoclax, synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as immunophenotypic leukemic stem cells, and reduced leukemic engraftment in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anticancer effects of ceramide and preclinical evidence for new approaches to augment Bcl-2 inhibition in the therapy of AML and other cancers with high Mcl-1 dependency.

Genomic profiling for clinical decision making in myeloid neoplasms and acute leukemia.

Myeloid neoplasms and acute leukemias derive from the clonal expansion of hematopoietic cells driven by somatic gene mutations. Although assessment of morphology plays a crucial role in the diagnostic evaluation of patients with these malignancies, genomic characterization has become increasingly important for accurate diagnosis, risk assessment, and therapeutic decision making. Conventional cytogenetics, a comprehensive and unbiased method for assessing chromosomal abnormalities, has been the mainstay of genomic testing over the past several decades and remains relevant today. However, more recent advances in sequencing technology have increased our ability to detect somatic mutations through the use of targeted gene panels, whole-exome sequencing, whole-genome sequencing, and whole-transcriptome sequencing or RNA sequencing. In patients with myeloid neoplasms, whole-genome sequencing represents a potential replacement for both conventional cytogenetic and sequencing approaches, providing rapid and accurate comprehensive genomic profiling. DNA sequencing methods are used not only for detecting somatically acquired gene mutations but also for identifying germline gene mutations associated with inherited predisposition to hematologic neoplasms. The 2022 International Consensus Classification of myeloid neoplasms and acute leukemias makes extensive use of genomic data. The aim of this report is to help physicians and laboratorians implement genomic testing for diagnosis, risk stratification, and clinical decision making and illustrates the potential of genomic profiling for enabling personalized medicine in patients with hematologic neoplasms.

RNA aptamer reveals nuclear TDP-43 pathology is an early aggregation event that coincides with STMN-2 cryptic splicing and precedes clinical manifestation in ALS.

TDP-43 is an aggregation-prone protein which accumulates in the hallmark pathological inclusions of amyotrophic lateral sclerosis (ALS). However, the analysis of deeply phenotyped human post-mortem samples has shown that TDP-43 aggregation, revealed by standard antibody methods, correlates poorly with symptom manifestation. Recent identification of cryptic-splicing events, such as the detection of Stathmin-2 (STMN-2) cryptic exons, are providing evidence implicating TDP-43 loss-of-function as a potential driving pathomechanism but the temporal nature of TDP-43 loss and its relation to the disease process and clinical phenotype is not known. To address these outstanding questions, we used a novel RNA aptamer, TDP-43APT, to detect TDP-43 pathology and used single molecule in situ hybridization to sensitively reveal TDP-43 loss-of-function and applied these in a deeply phenotyped human post-mortem tissue cohort. We demonstrate that TDP-43APT identifies pathological TDP-43, detecting aggregation events that cannot be detected by classical antibody stains. We show that nuclear TDP-43 pathology is an early event, occurring prior to cytoplasmic accumulation and is associated with loss-of-function measured by coincident STMN-2 cryptic splicing pathology. Crucially, we show that these pathological features of TDP-43 loss-of-function precede the clinical inflection point and are not required for region specific clinical manifestation. Furthermore, we demonstrate that gain-of-function in the form of extensive cytoplasmic accumulation, but not loss-of-function, is the primary molecular correlate of clinical manifestation. Taken together, our findings demonstrate implications for early diagnostics as the presence of STMN-2 cryptic exons and early TDP-43 aggregation events could be detected prior to symptom onset, holding promise for early intervention in ALS.

Immunological Drug-Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies.

With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.

Novel endoscopic scoring system for immune mediated colitis: a multicenter retrospective study of 674 patients.

BACKGROUND AND AIMS: No endoscopic scoring system has been established for immune-mediated colitis (IMC). This study aimed to establish such a system for IMC and explore its utility in guiding future selective immunosuppressive therapy (SIT) use compared to clinical symptoms. METHODS: This retrospective, international, 14-center study included 674 patients who developed IMC after immunotherapy and underwent endoscopic evaluation. Ten endoscopic features were selected by group consensus and assigned 1 point each to calculate an IMC endoscopic score (IMCES). IMCES cutoffs were chosen to maximize specificity for SIT use. This specificity was compared between IMCESs, and clinical symptoms were graded according to a standardized instrument. RESULTS: A total of 309 (45.8%) patients received SIT. IMCES specificity for SIT use was 82.8% with a cutoff of 4. The inclusion of ulceration as a mandatory criterion resulted in higher specificity (85.0% for a cutoff of 4). In comparison, the specificity of a Mayo endoscopic subscore of 3 was 74.6%, and the specificity of clinical symptom grading was much lower at 27.4% and 12.3%, respectively. Early endoscopy was associated with timely SIT use (P < .001; r = 0.4084). CONCLUSIONS: This is the largest multicenter study to devise an endoscopic scoring system to guide IMC management. An IMCES cutoff of 4 has a higher specificity for SIT use than clinical symptoms, supporting early endoscopic evaluation for IMC.

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population.

CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of approximately 1:30 000 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74 277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% [95% confidence interval (CI) 90.8-100%], specificity of 99% (95% CI 94.2-99.7%), and a positive predictive value of 97.4% (95% CI 84.4-99.6%). We found the mutation frequency to be 1:3182 (95% CI 1:2309-1:4386, n = 117 734) X chromosomes-10 times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced penetrance, and/or pleomorphic clinical manifestations.

Anaerobic Soil Disinfestation and Vermicompost to Manage Bottom Rot in Organic Lettuce.

Rhizoctonia solani Kühn (teleomorph: Thanatephorus cucumeris [Frank] Donk) is an aggressive soilborne pathogen with a wide host range that survives saprophytically between crops, presenting a challenge for organic vegetable farmers who lack effective management tools. A 2-year field experiment was conducted at two organic farms to compare anaerobic soil disinfestation (ASD) and worm-cured compost (vermicompost) to manage bottom rot caused by R. solani subspecies AG1-IB in field-grown organic lettuce (Lactuca sativa). At each farm, four replicate plots of seven treatments were arranged in a randomized complete block design. Randomization was restricted by grouping treatments to evaluate ASD, and treatments to evaluate vermicompost in starter plugs. ASD experiment treatments were three different ASD carbon sources that are commonly used and widely available to local farmers in Vermont: compost, cover crop residues, and poultry manure fertilizer, as well as a tarped control. Vermicompost experimental treatments were vermicompost compared with two types of controls: a commercial biocontrol product (RootShield PLUS + G), and unamended (untarped control). This study demonstrated that the ASD method is achievable in a field setting on Vermont farms. However, neither ASD nor vermicompost produced significant disease suppression or resulted in higher marketable yields than standard growing practices. Given the laborious nature of ASD, it is likely more appropriate in a greenhouse setting with high-value crops that could especially benefit from being grown in plastic tarped beds (e.g., tomatoes and strawberries). This study is the first known attempt of field-implemented ASD for soil pathogen control in the northeastern United States.

Are expectations of labour and birth fulfilled? A qualitative investigation of first-time parents.

AIM: To describe if first-time parents' expectations of labour and birth, explored during the third trimester of pregnancy, were fulfilled or not when investigated 1 year following birth. DESIGN: Qualitative Husserlian phenomenological approach. METHODS: The sample comprises 10 parents (five couples), who participated in an online semi-structured audio-recorded individual interview conducted 1 year after birth, between September 2020 and October 2020. Parents' expectations of labour and birth, described throughout a focus group discussion on pregnancy, were compared with their experience explored 1 year after birth. A thematic analysis was adopted and member checking was used to validate participants' thoughts. RESULTS: Participants gave birth in a II level maternity unit and one-to-one midwifery care was provided. Although during the focus group conducted in pregnancy, women reported being aware of the unpredictable nature of childbirth, they expressed sadness and failure after experiencing some unexpected interventions. The midwife was a reassuring guide, as expected; however, sometimes, the communication was not effective, and women perceived lack of support. Some women partly blame themselves for not being prepared to manage labour pain, which hurt more than expected. Feeling of uncertainty about events were experienced in relation to seeking care at an early stage of labour, which confirmed the fears expressed during pregnancy. During the antenatal focus group discussion, fathers doubted they could be helpful for the labouring women. This negative emotion was confirmed after birth. However, they understood the importance to be present and to support their partner. CONCLUSIONS: One year after birth, participants had consistent memories of their birth experience. Professionals might identify fundamental components of quality maternity care that are meaningful for parents, with the potential to generate a long-term positive health impact on them. Respectful maternity care should be ensured through a family-centred approach, with the aim to promote satisfaction. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: The study highlights the importance of taking parents' expectations into account when providing antenatal care to tailor individualized support that addresses their distinct needs and preferences. Healthcare professionals might consider initiating a post-natal discussion with parents to assess whether their needs and perspectives have been addressed. This perspective may present valuable insights to achieve long-term positive outcomes, provide high-quality maternity care, address issues and make improvements. IMPACT: The study showed that 1 year after birth, parents can accurately recall their birth. They might also give significant insights into fundamental components of care that they value as crucial to shape a positive birthing experience. Professionals should use this information to build solutions, promoting long-term well-being for parents. Respectful interactions and trusting relationships emerged as key elements in parents' experience. A midwifery care focused on parents' needs may contribute to the achievement of positive birth memories. REPORTING METHOD: This study used the Standards for Reporting Qualitative Research checklist. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Intelligent Millimeter-Wave System for Human Activity Monitoring for Telemedicine.

Telemedicine has the potential to improve access and delivery of healthcare to diverse and aging populations. Recent advances in technology allow for remote monitoring of physiological measures such as heart rate, oxygen saturation, blood glucose, and blood pressure. However, the ability to accurately detect falls and monitor physical activity remotely without invading privacy or remembering to wear a costly device remains an ongoing concern. Our proposed system utilizes a millimeter-wave (mmwave) radar sensor (IWR6843ISK-ODS) connected to an NVIDIA Jetson Nano board for continuous monitoring of human activity. We developed a PointNet neural network for real-time human activity monitoring that can provide activity data reports, tracking maps, and fall alerts. Using radar helps to safeguard patients' privacy by abstaining from recording camera images. We evaluated our system for real-time operation and achieved an inference accuracy of 99.5% when recognizing five types of activities: standing, walking, sitting, lying, and falling. Our system would facilitate the ability to detect falls and monitor physical activity in home and institutional settings to improve telemedicine by providing objective data for more timely and targeted interventions. This work demonstrates the potential of artificial intelligence algorithms and mmwave sensors for HAR.

Multiparametric prostate magnetic resonance imaging in the evaluation of prostate cancer.

Imaging has traditionally played a minor role in the diagnosis and staging of prostate cancer. However, recent controversies generated by the use of prostate-specific antigen (PSA) screening followed by random biopsy have encouraged the development of new imaging methods for prostate cancer. Multiparametric magnetic resonance imaging (mpMRI) has emerged as the imaging method best able to detect clinically significant prostate cancers and to guide biopsies. Here, the authors explain what mpMRI is and how it is used clinically, especially with regard to high-risk populations, and we discuss the impact of mpMRI on treatment decisions for men with prostate cancer. CA Cancer J Clin 2016;66:326-336. © 2015 American Cancer Society.

The physical exam's role in determining dose-limiting toxicity prior to immunochemotherapy administration in lymphoma.

INTRODUCTION: The COVID-19 pandemic has introduced new challenges to healthcare access and delivery. It is critical to identify areas for innovation within oncologic clinical practice to maintain high quality care. We evaluated the potential utility of telemedicine initiatives for patients with lymphoma undergoing immunochemotherapy. We conducted a retrospective review of adult lymphoma patients receiving R-CHOP + /- R, R-ICE, R-GEMOX, and R-DHAP at our institution in the last three years (2017-2019) and identified cycles for which dose modifications were required. METHODS: We reviewed 1290 total treatment cycles in 301 unique patients, 1102 cycles (85.4%) were R-CHOP + /- R, 105 (8.1%) were R-ICE, 71 (5.5%) were R-GEMOX, and 12 (0.9%) were R-DHAP. We identified that 144 cycles (11.2%) were subject to dosing adjustments. We retrospectively reviewed laboratory results, patient history, and/or physical exam findings that informed dose modifications. RESULTS: Of the 144 dose adjustments, 11% of cycles contained dose increases due to a well-tolerated previous dose noted in the clinical assessment. The remaining 128 modified cycles were dose reductions. Notably, only 7/128 dose reductions were based on physical exam findings alone, due solely to a change in patient body weight. As patients are routinely weighed immediately prior to chemotherapy administration, effectively no dose modifications (0/144) were exclusively based on abnormal physical exam finding during a pre-infusion assessment. CONCLUSION: These findings suggest that pre-infusion assessments may be amenable to virtual visits for lymphoma patients undergoing immunochemotherapy.

Investigating the Normativity of Trait Estimates from Multidimensional Forced-Choice Data.

The Thurstonian item response model (Thurstonian IRT model) allows deriving normative trait estimates from multidimensional forced-choice (MFC) data. In the MFC format, persons must rank-order items that measure different attributes according to how well the items describe them. This study evaluated the normativity of Thurstonian IRT trait estimates both in a simulation and empirically. The simulation investigated normativity and compared Thurstonian IRT trait estimates to those using classical partially ipsative scoring, from dichotomous true-false (TF) data and rating scale data. The results showed that, with blocks of opposite keyed items, Thurstonian IRT trait estimates were normative in contrast to classical partially ipsative estimates. Unbalanced numbers of items per trait, few opposite keyed items, traits correlated positively or assessing fewer traits did not decrease measurement precision markedly. Measurement precision was lower than that of rating scale data. The empirical study investigated whether relative MFC responses provide a better differentiation of behaviors within persons than absolute TF responses. However, criterion validity was equal and construct validity (with constructs measured by rating scales) lower in MFC. Thus, Thurstonian IRT modeling of MFC data overcomes the drawbacks of classical scoring, but gains in validity may depend on eliminating common method biases from the comparison.

Statewide availability of acute stroke treatment, services, and programs: A survey of North Carolina Hospitals.

INTRODUCTION: We conducted a statewide assessment of the availability of stroke treatment, services, and programs in North Carolina (NC) hospitals. We also examined differences in stroke care capabilities between urban, suburban, and rural hospitals and trends over the past 2 decades. METHODS: An electronic survey was distributed to all 111 licensed hospitals in NC. Survey questions asked about stroke center certification status (i.e., standardized levels of stroke care capabilities), diagnostic testing, acute treatments and protocols, and post-acute management. Responses were collected from October 2020-April 2021. Select characteristics were compared to those from prior NC surveys in 1998, 2003, and 2008. RESULTS: All 111 hospitals responded to the survey (100% response rate). Among 108 hospitals providing acute stroke care, 12 (11%) were Comprehensive Stroke Centers or Thrombectomy-Capable Stroke Centers, which were all located in urban or suburban areas. While 38% of urban/suburban hospitals were non-certified, 48% of rural hospitals were non-certified. Non-contrast computed tomography (CT), CT angiography, and alteplase treatment were widely available (100%, 95%, and 99%, respectively). Endovascular thrombectomy was solely available in urban/suburban hospitals (29%). Of non-tertiary hospitals, 81% were using telestroke for treatment and transfer decisions. Compared to prior survey results, the availability of CT angiography (76% in 2008 to 95% in 2020-2021), alteplase treatment (69% in 2008 to 99% in 2020-2021), and acute stroke clinical pathways (47% in 2008 to 90% in 2020-2021) increased. However, having an in-house neurologist on staff dropped from approximately 55% in prior surveys to 21% in the current survey. CONCLUSIONS: Rural NC hospitals were less likely to have advanced diagnostic imaging and treatment capabilities for acute stroke. Temporal trends in staffing with an in-house neurologist and use of telestroke services should be further examined.

Clinical effectiveness of pharmacological interventions for managing chronic migraine in adults: a systematic review and network meta-analysis.

BACKGROUND: Chronic migraine can be a profoundly disabling disorder that may be treated with preventive medications. However, uncertainty remains as to which preventive medication is the most effective. We present a network meta-analysis to determine the effectiveness and rank of preventive drugs for chronic migraine in adults. METHODS: We identified, reviewed, and extracted data from randomised controlled trials (RCTs) of preventive drugs for chronic migraine with at least 200 participants. Data were analysed using network meta-analysis. FINDINGS: We included 12 RCTs of six medications (Eptinezumab, Erenumab, Fremanezumab, Galcanezumab, Onabotulinumtoxin A, and Topiramate) compared to placebo or each other. All drugs effectively reduced monthly headache and migraine days compared with placebo. The most effective drug for monthly headache days was Eptinezumab 300mg, with a mean difference of -2.46 days, 95% Credible Interval (CrI): -3.23 to -1.69. On the Surface Under the Cumulative Ranking Area (SUCRA) analysis, the probability that Eptinezumab 300mg was ranked highest was 0.82. For monthly migraine days, the most effective medication was Fremanezumab-monthly, with a mean difference: -2.77 days, 95% CrI: -3.36 to -2.17, and 0.98 probability of being ranked the highest. All included drugs, except Topiramate, improved headache-related quality of life. No eligible studies were identified for the other common preventive oral medications such as Amitriptyline, Candesartan, and Propranolol. The main reasons were that the studies did not define chronic migraine, were undertaken before the definition of chronic migraine, or were too small. INTERPRETATION: All six medications were more effective than the placebo on monthly headache and migraine days. The absolute differences in the number of headache/migraine days are, at best, modest. No evidence was found to determine the relative effectiveness of the six included drugs with other oral preventive medications. REGISTRATION: PROSPERO (number CRD42021265990).