Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer.

BACKGROUND: Selpercatinib, a highly selective, potent RET inhibitor, has shown efficacy in advanced RET-mutant medullary thyroid cancer in a phase 1-2 trial, but its efficacy as compared with approved multikinase inhibitors is unclear. METHODS: We conducted a phase 3, randomized trial comparing selpercatinib as first-line therapy with the physician's choice of cabozantinib or vandetanib (control group). Eligible patients had progressive disease documented within 14 months before enrollment. The primary end point in the protocol-specified interim efficacy analysis was progression-free survival, assessed by blinded independent central review. Crossover to selpercatinib was permitted among patients in the control group after disease progression. Treatment failure-free survival, assessed by blinded independent central review, was a secondary, alpha-controlled end point that was to be tested only if progression-free survival was significant. Among the other secondary end points were overall response and safety. RESULTS: A total of 291 patients underwent randomization. At a median follow-up of 12 months, median progression-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 16.8 months (95% confidence interval [CI], 12.2 to 25.1) in the control group (hazard ratio for disease progression or death, 0.28; 95% CI, 0.16 to 0.48; P<0.001). Progression-free survival at 12 months was 86.8% (95% CI, 79.8 to 91.6) in the selpercatinib group and 65.7% (95% CI, 51.9 to 76.4) in the control group. Median treatment failure-free survival as assessed by blinded independent central review was not reached in the selpercatinib group and was 13.9 months in the control group (hazard ratio for disease progression, discontinuation due to treatment-related adverse events, or death, 0.25; 95% CI, 0.15 to 0.42; P<0.001). Treatment failure-free survival at 12 months was 86.2% (95% CI, 79.1 to 91.0) in the selpercatinib group and 62.1% (95% CI, 48.9 to 72.8) in the control group. The overall response was 69.4% (95% CI, 62.4 to 75.8) in the selpercatinib group and 38.8% (95% CI, 29.1 to 49.2) in the control group. Adverse events led to a dose reduction in 38.9% of the patients in the selpercatinib group, as compared with 77.3% in the control group, and to treatment discontinuation in 4.7% and 26.8%, respectively. CONCLUSIONS: Selpercatinib treatment resulted in superior progression-free survival and treatment failure-free survival as compared with cabozantinib or vandetanib in patients with RET-mutant medullary thyroid cancer. (Funded by Loxo Oncology, a subsidiary of Eli Lilly; LIBRETTO-531 ClinicalTrials.gov number, NCT04211337.).

From chasing funding to a funding body.

In this article, I discuss how my scientific career has evolved, starting in an immunology lab and ending up at the Medical Research Council of the UK.

Relationship between Urine Serotonin and Persistent Pulmonary Hypertension of the Newborn.

Urine serotonin (5-HT)/creatinine was lower at day of life 3 in newborns with pulmonary hypertension compared with controls, while the percent change in the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA)/creatinine increased. We speculate that the changes in 5-HT and 5-HIAA reflect enhanced pulmonary 5-HT uptake and/or metabolism.

A systematic review of 454 randomized controlled trials using the Dermatology Life Quality Index: experience in 69 diseases and 43 countries.

BACKGROUND: Over 29 years of clinical application, the Dermatology Life Quality Index (DLQI) has remained the most used patient-reported outcome (PRO) in dermatology due to its robustness, simplicity and ease of use. OBJECTIVES: To generate further evidence of the DLQI's utility in randomized controlled trials (RCTs) and to cover all diseases and interventions. METHODS: The methodology followed PRISMA guidelines and included seven bibliographical databases, searching articles published from 1 January 1994 until 16 November 2021. Articles were reviewed independently by two assessors, and an adjudicator resolved any opinion differences. RESULTS: Of 3220 screened publications, 454 articles meeting the eligibility criteria for inclusion, describing research on 198 190 patients, were analysed. DLQI scores were primary endpoints in 24 (5.3%) of studies. Most studies were of psoriasis (54.1%), although 69 different diseases were studied. Most study drugs were systemic (85.1%), with biologics comprising 55.9% of all pharmacological interventions. Topical treatments comprised 17.0% of total pharmacological interventions. Nonpharmacological interventions, mainly laser therapy and ultraviolet radiation treatment, comprised 12.2% of the total number of interventions. The majority of studies (63.7%) were multicentric, with trials conducted in at least 42 different countries; 40.2% were conducted in multiple countries. The minimal clinically importance difference (MCID) was reported in the analysis of 15.0% of studies, but only 1.3% considered full score meaning banding of the DLQI. Forty-seven (10.4%) of the studies investigated statistical correlation of the DLQI with clinical severity assessment or other PRO/quality of life tools; and 61-86% of studies had within-group scores differences greater than the MCID in 'active treatment arms'. The Jadad risk-of-bias scale showed that bias was generally low, as 91.8% of the studies had Jadad scores of ≥ 3; only 0.4% of studies showed a high risk of bias from randomization. Thirteen per cent had a high risk of bias from blinding and 10.1% had a high risk of bias from unknown outcomes of all participants in the studies. In 18.5% of the studies the authors declared that they followed an intention-to-treat protocol; imputation for missing DLQI data was used in 34.4% of studies. CONCLUSIONS: This systematic review provides a wealth of evidence of the use of the DLQI in clinical trials to inform researchers' and -clinicians' decisions for its further use. Recommendations are also made for improving the reporting of data from future RCTs using the DLQI.

Development of a Clinical Risk Score to Risk Stratify for a Serious Cause of Vertigo in Patients Presenting to the Emergency Department.

STUDY OBJECTIVE: Identify high-risk clinical characteristics for a serious cause of vertigo in patients presenting to the emergency department (ED). METHODS: Multicentre prospective cohort study over 3 years at three university-affiliated tertiary care EDs. Participants were patients presenting with vertigo, dizziness or imbalance. Main outcome measurement was an adjudicated serious diagnosis defined as stroke, transient ischemic attack, vertebral artery dissection or brain tumour. RESULTS: A total of 2,078 of 2,618 potentially eligible patients (79.4%) were enrolled (mean age 77.1 years; 59% women). Serious events occurred in 111 (5.3%) patients. We used logistic regression to create a 7-item prediction model: male, age over 65, hypertension, diabetes, motor/sensory deficits, cerebellar signs/symptoms and benign paroxysmal positional vertigo diagnosis (C-statistic 0.96, 95% confidence interval [CI] 0.92 to 0.98). The risk of a serious diagnosis ranged from 0% for a score of <5, 2.1% for a score of 5 to 8, and 41% for a score >8. Sensitivity for a serious diagnosis was 100% (95% CI, 97.1% to 100%) and specificity 72.1% (95% CI, 70.1% to 74%) for a score <5. CONCLUSION: The Sudbury Vertigo Risk Score identifies the risk of a serious diagnosis as a cause of a patient's vertigo and if validated could assist physicians in guiding further investigation, consultation, and treatment decisions, improving resource utilization and reducing missed diagnoses.

Physician Approaches to Antithrombotic Therapies for Recently Symptomatic Carotid Stenosis.

BACKGROUND: Whereas the beneficial effect of antiplatelet therapy for recurrent stroke prevention has been well established, uncertainties remain regarding the optimal antithrombotic regimen for recently symptomatic carotid stenosis. We sought to explore the approaches of stroke physicians to antithrombotic management of patients with symptomatic carotid stenosis. METHODS: We employed a qualitative descriptive methodology to explore the decision-making approaches and opinions of physicians regarding antithrombotic regimens for symptomatic carotid stenosis. We conducted semi-structured interviews with a purposive sample of 22 stroke physicians (11 neurologists, 3 geriatricians, 5 interventional-neuroradiologists, and 3 neurosurgeons) from 16 centers on four continents to discuss symptomatic carotid stenosis management. We then conducted thematic analysis on the transcripts. RESULTS: Important themes revealed from our analysis included limitations of existing clinical trial evidence, competing surgeon versus neurologist/internist preferences, and the choice of antiplatelet therapy while awaiting revascularization. There was a greater concern for adverse events while using multiple antiplatelet agents (e.g., dual-antiplatelet therapy (DAPT)) in patients undergoing carotid endarterectomy compared to carotid artery stenting. Regional variations included more frequent use of single antiplatelet agents among European participants. Areas of uncertainty included antithrombotic management if already on an antiplatelet agent, implications of nonstenotic features of carotid disease, the role of newer antiplatelet agents or anticoagulants, platelet aggregation testing, and timing of DAPT. CONCLUSION: Our qualitative findings can help physicians critically examine the rationale underlying their own antithrombotic approaches to symptomatic carotid stenosis. Future clinical trials may wish to accommodate identified variations in practice patterns and areas of uncertainty to better inform clinical practice.

De novo formation of a carotid web in an adult: A longitudinal observation.

BACKGROUND: Carotid web is a thin shelf-like fibrointimal membrane arising from the posterior or posterolateral wall of the carotid bulb. Webs cause stroke, especially in younger adults with high risk of recurrence. METHODS: To report the first case of de-novo formation of an asymptomatic carotid web and describe longitudinal clinical-angiographic follow-up. RESULTS: A previously healthy 50-year-old White female presented with acute vestibular syndrome. Brain MRI showed no brain infarction. An arch-to-vertex CT angiogram showed normal posterior circulation, however, the left internal carotid artery bulb had a thin shelf-like projection into the lumen arising from the posterior wall of the artery - an incidental carotid web. A CT angiogram performed seven years earlier showed normal carotid arteries. The three-year angiographic follow-up showed an unchanged angiographic appearance of the carotid web. The patient preferred staying on aspirin and suffered no retinal or cerebral ischemic event during the 5-year clinic follow-up. CONCLUSION: Our case suggests de novo (acquired) formation of a carotid web in an adult. This challenges the prevailing theory that carotid web is a congenital/developmental lesion.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Impact on Quality of Life (QoL) of Persons with ME/CFS.

Background and Objectives: We previously reported on the impact of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) on the QoL of persons with ME/CFS and their family members. Here, we present the findings of the impact on the QoL of individuals with ME/CFS whose family members did not participate in the survey. Materials and Methods: A prospective multinational online survey was disseminated via patient charities, support groups and social media. Persons with ME/CFS completed the EuroQoL questionnaire (EQ-5D-3L). Results: Data were analysed from 876 participants from 26 countries who reported a health care professional diagnosis of ME/CFS. In total, 742 participants identified as female, 124 male and 10 preferred not to say. The mean age of the participants was 47 years (range 18-82), and the mean time to diagnosis was 14 years. The mean overall health status on a visual analogue scale for people with ME/CFS was 36.4 (100 = best health). People with ME/CFS were most often affected by inability to perform usual activities (n = 852, 97%), followed by pain (n = 809, 92%), impaired mobility (n = 724, 83%), difficulty in self-care (n = 561, 64%) and least often affected by anxiety and depression (n = 540, 62%). Conclusions: The QoL of people with ME/CFS is significantly affected globally. There was no significant difference in quality of life compared with previously published data on those with ME/CFS who did have a family member complete the family member quality of life questionnaire (FROM16). Contrary to popular misconception, anxiety and depression are the least often affected areas in persons with ME/CFS who are most impacted by their inability to perform usual activities.

Efficacy and outcome of indocyanine green-based intraoperative cholangiography using near-infrared fluorescence imaging: A prospective study.

INTRODUCTION: The most dreaded complication during laparoscopic cholecystectomy still remains to be injury to the common bile duct. The primary cause for bile duct injury during LC is misinterpretation of the biliary anatomy. Intra-operative cholangiography was introduced as a means of reducing the chances of biliary injury, done using Fluoroscopic imaging or Near-infrared fluorescence imaging method. NIRF is one of the most popular imaging methods in biomedical sciences. Indocyanine Green is sterile and water soluble which completely binds to albumin and is excreted in bile. PATIENTS AND METHODS: This prospective study was conducted among 70 patients between July 2020 and December 2021. Subjects were administered 5mg of ICG dye pre-operatively and procedure performed using Karl Storz HD image S1 system with a D-light P light source for NIRF imaging. RESULTS: The average duration of surgery was 58.10 minutes. After calot's dissection, the CBD was visualized in 88.71 % patients, with a mean time to visualization at 26.33 minutes. The cystic duct was visualized in 87.3% cases with a mean time of visualization of 32.10 minutes. The hepatic duct was visualized in 28.57% and the hepatic duct-CBD confluence was visualized in 34.28% patients. CONCLUSION: Near infrared imaging based intra-operative cholangiography, using Indocyanine Green dye, during Lap. Cholecystectomy is an easy, useful and inexpensive method of visualizing the biliary ductal anatomy.

Identification, Measurement, and Assessment of the Clinical Utility of Human Pancreatic Polypeptide by Liquid Chromatography-Tandem Mass Spectrometry.

Human pancreatic polypeptide (HPP) is a 36 amino acid peptide hormone that plays a role in the bidirectional communication between the digestive system and the brain. HPP measurements are used to assess vagal nerve function following sham feeding and to detect gastroenteropancreatic-neuroendocrine tumors. These tests have historically been conducted by radioimmunoassays, but liquid chromatography-tandem mass spectrometry (LC-MS/MS) has several advantages such as improved specificity and elimination of radioactive molecules. Here, we present our LC-MS/MS method. Initially, samples were immunopurified and subjected to LC-high resolution accurate mass tandem mass spectrometry (HRAM-MS/MS) to identify circulating forms of the peptide in human plasma. We identified 23 forms of HPP, including several glycosylated forms. The most abundant peptides then were used for targeted LC-MS/MS measurements. LC-MS/MS performance for precision, accuracy, linearity, recovery, limit of detection, and carryover met our acceptance criteria based on CLIA regulations. Additionally, we observed the expected physiological rise in HPP in response to sham feeding. Our results indicate that HPP measurement by LC-MS/MS produces clinically equivalent results to our established immunoassay when several peptides are monitored, making it a suitable replacement. The measurement of peptide fragments, including modified species, might have additional clinical value.

Changes in serum cortisol levels after 10 days of overfeeding and fasting.

Chronic caloric deprivation and obesity are complicated by hypercortisolemia. The effects of acute overfeeding and fasting on circulating free cortisol levels and conversion of cortisone to free cortisol are unknown. We hypothesized that serum-free cortisol and free cortisol-to-cortisone ratio would increase after both overfeeding and fasting. This is a prospective study of 22 healthy volunteers who completed a 10-day high-calorie protocol followed by a 10-day fast, separated by a 2-wk washout. Morning free and total cortisol and free cortisone levels (LC/MS) were measured at baseline and after 10 days of each intervention. Both high-calorie feeding and fasting increased total and free cortisol and the free cortisol-to-free cortisone ratio (P = 0.001 to P = 0.046). There were sex interactions, with significant effects in men (P < 0.001), but not in women (P = 0.898 and 1.000, respectively) in subset analyses examining the effects of fasting on free cortisol and the free-to-total cortisol ratio. Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. Further study is warranted to determine whether elevated cortisol levels contribute to complications of starvation and obesity, such as bone fragility.NEW & NOTEWORTHY Overfeeding and fasting both increase circulating free cortisol levels and appear to alter the balance between cortisol and its inactive metabolite, cortisone. The effect of fasting on free cortisol levels is modified by sex. Further study is needed to determine the mechanisms driving the increases in cortisol.

Persistence and Recurrence of Hypercalcemia After Parathyroidectomy Over 5 Decades (1965-2010) in a Community-based Cohort.

BACKGROUND: There is limited long-term follow-up of patients undergoing parathyroidectomy. Recurrence is described as 4% to 10%. This study evaluated persistence and recurrence of hypercalcemia in primary hyperparathyroidism after parathyroidectomy. METHODS: Single-institution retrospective (1965-2010) population-based cohort from Olmsted County (MN) of patients undergoing surgery for primary hyperparathyroidism. Patients' demographic data, preoperative and postoperative laboratory values, clinical characteristics, surgical treatment, and follow-up were noted. RESULTS: A total of 345 patients were identified, 75.7% female, and median age 58.4 years [interquartile range (IQR): 17.6]. In all, 68% of patients were asymptomatic and the most common symptoms were musculoskeletal complaints (28.4%) and nephrolithiasis (25.6%). Preoperative median serum calcium was 11 mg/dL (IQR: 10.8-11.4 mg/dL), and median parathyroid hormone was 90 pg/mL (IQR: 61-169 pg/dL). Bilateral cervical exploration was performed in 38% and single gland resection in 79% of cases. Median postoperative serum calcium was 9.2 mg/dL (IQR: 5.5-11.3). Nine percent of patients presented persistence of hypercalcemia, and recurrence was found in 14% of patients. Highest postoperative median serum calcium was 10 mg/dL (IQR: 6-12.4), and median number of postoperative calcium measurements was 10 (IQR: 0-102). Postoperative hypercalcemia was identified in 37% of patient. Fifty-three percent were attributed to secondary causes, most commonly medications, 22%. Three percent of patients required treatment for postoperative hypercalcemia. Median time to recurrence and death were 12.2 and 16.7 years, respectively. CONCLUSION: Recurrent hypercalcemia after successful parathyroidectomy is higher than previously reported. Most cases are transient and often associated to other factors with only the minority requiring treatment. Long-term follow-up of serum calcium should be considered in patients after successful parathyroidectomy.

Metabolic alterations unravel the maternofetal immune responses with disease severity in pregnant women infected with SARS-CoV-2.

Pregnancy being an immune compromised state, coronavirus disease of 2019 (COVID-19) disease poses high risk of premature delivery and threat to fetus. Plasma metabolome regulates immune cellular responses, therefore we aimed to analyze the change in plasma secretome, metabolome, and immune cells with disease severity in COVID-19 positive pregnant females and their cord blood. COVID-19 reverse transcriptase-polymerase chain reaction positive pregnant females (n = 112) with asymptomatic (Asy) (n = 82), mild (n = 21), or moderate (n = 9) disease, healthy pregnant (n = 18), COVID-19 positive nonpregnant females (n = 7) were included. Eighty-two cord blood from COVID-19 positive and seven healthy cord blood were also analyzed. Mother's peripheral blood and cord blood were analyzed for untargeted metabolome profiling and cytokines by using high-resolution mass spectrometry and cytokine bead array. Immune scan was performed only in mothers' blood by flow cytometry. In Asy severe acute respiratory syndrome coronavirus 2 infection, the amino acid metabolic pathways such as glycine, serine, l-lactate, and threonine metabolism were upregulated with downregulation of riboflavin and tyrosine metabolism. However, with mild-to-moderate disease, the pyruvate and nicotinamide adenine dinucleotide (NAD+ ) metabolism were mostly altered. Cord blood mimicked the mother's metabolomic profiles by showing altered valine, leucine, isoleucine, glycine, serine, threonine in Asy and NAD+ , riboflavin metabolism in mild and moderate. Additionally, with disease severity tumor necrosis factor-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-6 cytokine storm, IL-9 was raised in both mothers and neonates. Pyruvate, NAD metabolism and increase in IL-9 and IFN-γ had an impact on nonclassical monocytes, exhausted T and B cells. Our results demonstrated that immune-metabolic interplay in mother and fetus is influenced with increase in IL-9 and IFN-γ regulated pyruvate, lactate tricarboxylic acid, and riboflavin metabolism with context to disease severity.

Genomics assisted characterization of plant growth-promoting and metabolite producing psychrotolerant Himalayan Chryseobacterium cucumeris PCH239.

Here, we report the first complete genome of a psychrotolerant and yellow-pigmented rhizobacteria Chryseobacterium cucumeris PCH239. It was obtained from the rhizospheric soil of the Himalayan plant Bergenia ciliata. The genome consists of a single contig (5.098 Mb), 36.3% G + C content, and 4899 genes. The cold adaptation, stress response, and DNA repair genes promote survivability in a high-altitude environment. PCH239 grows in temperature (10-37 °C), pH (6.0-8.0), and NaCl (2.0%). The genome derived plant growth-promoting activities of siderophore production (siderophore units 53 ± 0.6), phosphate metabolism (PSI 5.0 ± 0.8), protease, indole acetic acid production (17.3 ± 0.5 µg/ml), and ammonia (2.89 ± 0.4 µmoles) were experimentally validated. Interestingly, PCH239 treatment of Arabidopsis seeds significantly enhances germination, primary, and hairy root growth. In contrast, Vigna radiata and Cicer arietinum seeds had healthy radicle and plumule elongation, suggesting varied plant growth-promotion effects. Our findings suggested the potential of PCH239 as a bio-fertilizer and biocontrol agent in the challenging conditions of cold and hilly regions.

High real-world effectiveness of 12-week elbasvir/grazoprevir without resistance testing in the treatment of patients with HCV genotype 1a infection in Norway.

BACKGROUND AND AIMS: The recommended treatment duration of hepatitis C virus (HCV) genotype 1a (GT1a) infection with elbasvir/grazoprevir (EBR/GZR) in the presence of a high baseline viral load and resistance associated substitutions (RAS) is 16 weeks with ribavirin added. The objective of this study was to evaluate the real-world effectiveness of 12 weeks of EBR/GZR without ribavirin and regardless of baseline viral load and RAS testing. METHOD: This retrospective, observational cohort study was performed at five Norwegian hospitals that did not systematically utilize RAS testing. All adult patients with chronic HCV GT1a and compensated liver disease who had received 12 weeks of EBR/GZR without ribavirin and baseline RAS testing, were included. The primary endpoint was sustained virologic response at week 12 (SVR12), or if not available, at week 4 (SVR4). RESULTS: We included 433 patients and attained SVR data on 388. The mean age was 45.7 years (22-73 years). 67.2% were male. HIV co-infection was present in 3.8% (16/424) and cirrhosis in 4% (17/424). The viral load was >800 000 IU/mL in 55.0% (235/427) of patients. Overall SVR was achieved in 97.2% (377/388). SVR was achieved in 98.3% (169/172) of those with viral load ≤800 000 IU/mL and in 96.2% (202/210) of those with viral load >800 000 IU/mL. CONCLUSION: We observed high SVR rates among patients with HCV GT1a infection treated with EBR/GZR for 12 weeks without ribavirin, with no regard to baseline viral load and no RAS testing.

Correlation of angiogenic growth factors and inflammatory cytokines with the clinical phenotype of ocular tuberculosis.

PURPOSE: To determine the correlation of angiogenic growth factors and inflammatory cytokines with the clinical phenotype of ocular tuberculosis (OTB). METHODS: Vitreous fluid was analysed for cytokines in patients with OTB and non-OTB uveitis using multiplex fluorescent bead-based flow cytometric assay. The clinical phenotypes were recorded and correlated with vitreous biomarkers. RESULTS: Vitreous humour from OTB patients had elevated levels of interleukin-10 (IL-10), IL-17-A, interferon-gamma (IFN-γ), and tumour necrosis factor-alpha (TNF-α). Angiopoietin (Ang-2) levels were higher in the panuveitis phenotype. OTB posterior uveitis phenotype had relatively higher vascular endothelial growth factor (VEGF) levels and lower fibroblast growth factor (FGF) levels. Additionally, eyes with choroiditis and vasculitis had elevated levels of VEGF and Ang-2 with FGF downregulation. Both IFN-γ and IL-10 were upregulated in the choroiditis phenotype of OTB. CONCLUSION: Angiogenic growth factors and inflammatory cytokines were altered in the vitreous humour of OTB patients. IFN-γ, VEGF, and IL-10 levels are increased in choroiditis and vasculitis phenotypes. Receiver operating characteristic (ROC) curve analysis further emphasized the importance of the IFN-γ assay in the diagnosis of OTB.

The Exploration of Cannabis and Cannabinoid Therapies for Migraine.

PURPOSE OF REVIEW: There is increasing interest in the use of cannabis and cannabinoid therapies (CCT) by the general population and among people with headache disorders, which results in a need for healthcare professionals to be well versed with the efficacy and safety data. In this manuscript, we review cannabis and cannabinoid terminology, the endocannabinoid system and its role in the central nervous system (CNS), the data on efficacy, safety, tolerability, and potential pitfalls associated with use in people with migraine and headache disorders. We also propose possible mechanisms of action in headache disorders and debunk commonly held myths about its use. RECENT FINDINGS: Preliminary studies show that CCT have evidence for the management of migraine. While this evidence exists, further randomized, controlled studies are needed to better support its clinical use. CCT can be considered an integrative treatment added to mainstream medicine for people with migraine who are refractory to treatment and/or exhibit disability and/or interest in trying these therapies. Further studies are warranted to specify appropriate formulation, dosage, and indication(s). Although not included in guidelines or the AHS 2021 Consensus Statement on migraine therapies, with the legalization of CCT for medical or unrestricted use across the USA, recent systematic reviews highlighting the preliminary evidence for its use in migraine, it is vital for clinicians to be well versed in the efficacy, safety, and clinical considerations for their use. This review provides information which can help people with migraine and clinicians who care for them make mutual, well-informed decisions on the use of cannabis and cannabinoid therapies for migraine based on the existing data.

High-Resolution Mass Spectrometry for the Measurement of PTH and PTH Fragments: Insights into PTH Physiology and Bioactivity.

Full-length parathyroid hormone (PTH 1-84) is crucial for the regulation of calcium and phosphate homeostasis and bone remodeling. PTH 1-84 is metabolized into various PTH fragments, which are measured with varying levels of efficiency by PTH immunoassays. These PTH fragments, which increase in serum as CKD progresses, could potentially modulate the effects of PTH 1-84 and contribute to CKD-associated bone disorders. To obtain a true biologic representation of total PTH bioactivity, it is necessary to measure not only PTH 1-84 but also PTH fragments that are present in circulation. Traditional second-generation PTH immunoassays collectively measure PTH 1-84, PTH fragments, and post-translationally modified PTH 1-84, making it difficult to accurately predict the character of underlying renal osteodystrophy. This review highlights current advances in methods available for PTH measurement and the clinical relevance of PTH fragments in CKD. We emphasize the usefulness of mass spectrometry as a potential reference method for PTH measurement.

A mentored hands-on training model for scaling up implementation and intervention research in India: "connecting the dots".

Despite the high burden of mental disorders in low- and middle-income countries (LMICs), less than 25% of those in need have access to appropriate services, in part due to a scarcity of locally relevant, evidence-based interventions and models of care. To address this gap, researchers from India and the United States and the Indian Council of Medical Research (ICMR) collaboratively developed a "Grantathon" model to provide mentored research training to 24 new principal investigators (PIs). This included a week-long didactic training, a customized web-based data entry/analysis system and a National Coordination Unit (NCU) to support PIs and track process objectives. Outcome objectives were assessed via scholarly output including publications, awards received and subsequent grants that were leveraged. Multiple mentorship strategies including collaborative problem-solving approaches were used to foster single-centre and multicentre research. Flexible, approachable and engaged support from mentors helped PIs overcome research barriers, and the NCU addressed local policy and day-to-day challenges through informal monthly review meetings. Bi-annual formal review presentations by all PIs continued through the COVID-19 pandemic, enabling interim results reporting and scientific review, also serving to reinforce accountability. To date, more than 33 publications, 47 scientific presentations, 12 awards, two measurement tools, five intervention manuals and eight research grants have been generated in an open-access environment. The Grantathon is a successful model for building research capacity and improving mental health research in India that could be adopted for use in other LMICs.

Venous spot sign: Indicator of rapid hematoma expansion in venous thrombosis type of submission: Case reports.

BACKGROUND: The term "spot sign" was coined by Wada et al in 2007 and thought to be due to ongoing arterial bleeding in primary intraparenchymal haemorrhage (IPH).1 Spot sign has also been described in the context of intraventricular haemorrhage (IVH).2 Over the years arterial spot signs have been found to correlate with intraparenchymal hematoma expansion, worse clinical outcomes and increased risk of surgical intervention.3 We are describing a unique instance of a spot sign in venous sinus thrombosis that initially misled the clinical diagnosis. CASE PRESENTATION: An 83-year-old woman on dual antiplatelet therapy, with a history of minor stroke, presented with sudden right-sided weakness and dysarthria. Serial CT brain imaging revealed rapidly enlarging intraparenchymal haemorrhage (IPH). Contrast enhanced CT displayed multiple spot signs typically associated with arterial bleeding pattern. Initially possibility of antithrombotic related IPH was kept, however venogram confirmed venous pathology with focal superior sagittal sinus thrombosis (SSS). Unfortunately, the patient deteriorated and eventually succumbed to the illness before the diagnosis could be made. CONCLUSION: The case exemplifies the potential of venous sinus thrombosis to manifest as a spot sign, thereby emphasizing the need for a broader differential diagnosis. The rarity of venous spot signs may be attributed to patient-specific venous anatomy and poor collateralization in the occluded sinus territory.