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The Journal of Prevention of... 2023Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to...
Lecanemab (Leqembi®) is approved in the United States for the treatment of Alzheimer's disease (AD) to be initiated in early AD (mild cognitive impairment [MCI] due to AD or mild AD dementia) with confirmed brain amyloid pathology. Appropriate Use Recommendations (AURs) are intended to help guide the introduction of new therapies into real-world clinical practice. Community dwelling patients with AD differ from those participating in clinical trials. Administration of lecanemab at clinical trial sites by individuals experienced with monoclonal antibody therapy also differs from the community clinic-based administration of lecanemab. These AURs use clinical trial data as well as research and care information regarding AD to help clinicians administer lecanemab with optimal safety and opportunity for effectiveness. Safety and efficacy of lecanemab are known only for patients like those participating in the phase 2 and phase 3 lecanemab trials, and these AURs adhere closely to the inclusion and exclusion criteria of the trials. Adverse events may occur with lecanemab including amyloid related imaging abnormalities (ARIA) and infusion reactions. Monitoring guidelines for these events are detailed in this AUR. Most ARIA with lecanemab is asymptomatic, but a few cases are serious or, very rarely, fatal. Microhemorrhages and rare macrohemorrhages may occur in patients receiving lecanemab. Anticoagulation increases the risk of hemorrhage, and the AUR recommends that patients requiring anticoagulants not receive lecanemab until more data regarding this interaction are available. Patients who are apolipoprotein E ε4 (APOE4) gene carriers, especially APOE4 homozygotes, are at higher risk for ARIA, and the AUR recommends APOE genotyping to better inform risk discussions with patients who are lecanemab candidates. Clinician and institutional preparedness are mandatory for use of lecanemab, and protocols for management of serious events should be developed and implemented. Communication between clinicians and therapy candidates or those on therapy is a key element of good clinical practice for the use of lecanemab. Patients and their care partners must understand the potential benefits, the potential harms, and the monitoring requirements for treatment with this agent. Culture-specific communication and building of trust between clinicians and patients are the foundation for successful use of lecanemab.
Topics: Humans; Apolipoprotein E4; Alzheimer Disease; Antibodies, Monoclonal; Amyloid
PubMed: 37357276
DOI: 10.14283/jpad.2023.30 -
JAMA Jul 2023Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a...
IMPORTANCE
Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression.
OBJECTIVE
To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022).
INTERVENTIONS
Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos.
MAIN OUTCOMES AND MEASURES
The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome.
RESULTS
Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%).
CONCLUSION AND RELEVANCE
Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.
Topics: Adult; Male; Humans; Middle Aged; Female; Antiviral Agents; Valganciclovir; Cytomegalovirus; Kidney Transplantation; Cytomegalovirus Infections; Neutropenia
PubMed: 37279999
DOI: 10.1001/jama.2023.9106 -
Nature Genetics Feb 2019Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types...
Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in selected cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI. To examine this association more broadly, we analyzed the clinical and genomic data of 1,662 advanced cancer patients treated with ICI, and 5,371 non-ICI-treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better overall survival. For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.
Topics: Antineoplastic Agents; High-Throughput Nucleotide Sequencing; Humans; Immunotherapy; Mutation; Neoplasms; Tumor Burden
PubMed: 30643254
DOI: 10.1038/s41588-018-0312-8 -
EuroIntervention : Journal of EuroPCR... Nov 2021Approximately 4% of subjects aged 75 years or more have clinically relevant tricuspid regurgitation (TR). Primary TR results from anatomical abnormality of the tricuspid...
Approximately 4% of subjects aged 75 years or more have clinically relevant tricuspid regurgitation (TR). Primary TR results from anatomical abnormality of the tricuspid valve apparatus and is observed in only 8-10% of the patients with tricuspid valve disease. Secondary TR is more common and arises as a result of annular dilation caused by right ventricular enlargement and dysfunction as a consequence of pulmonary hypertension, often caused by left-sided heart disease or atrial fibrillation. Irrespective of its aetiology, TR leads to volume overload and increased wall stress, both of which negatively contribute to detrimental remodelling and worsening TR. This vicious circle translates into impaired survival and increased heart failure symptoms in patients with and without reduced left ventricular ejection fraction. Interventions to correct TR are underutilised in daily clinical practice owing to increased surgical risk and late patient presentation. The recently introduced transcatheter tricuspid valve interventions aim to address this unmet need. Dedicated expertise and an interdisciplinary Heart Team evaluation are essential to integrate these new techniques successfully and select patients. The present article proposes a standardised approach to evaluate patients with TR who may be candidates for transcatheter interventions. In addition, a state-of-the-art review of the available transcatheter therapies, the main criteria for patient and device selection, and information concerning the remaining uncertainties are provided.
Topics: Heart Valve Diseases; Heart Valve Prosthesis Implantation; Humans; Stroke Volume; Treatment Outcome; Tricuspid Valve; Tricuspid Valve Insufficiency; Ventricular Function, Left
PubMed: 34796878
DOI: 10.4244/EIJ-D-21-00695 -
The Journal of Adolescent Health :... Apr 2022There are no large-scale studies examining mental health among transgender and nonbinary youth who receive gender-affirming hormone therapy (GAHT). The purpose of this...
PURPOSE
There are no large-scale studies examining mental health among transgender and nonbinary youth who receive gender-affirming hormone therapy (GAHT). The purpose of this study is to examine associations among access to GAHT with depression, thoughts of suicide, and attempted suicide among a large sample of transgender and nonbinary youth.
METHODS
Data were collected as part of a 2020 survey of 34,759 lesbian, gay, bisexual, transgender, queer, and questioning youth aged 13-24, including 11,914 transgender or nonbinary youth. Adjusted logistic regression assessed whether receipt of GAHT was associated with lower levels of depression, thoughts of suicide, and attempted suicide among those who wanted to receive GAHT.
RESULTS
Half of transgender and nonbinary youth said they were not using GAHT but would like to, 36% were not interested in receiving GAHT, and 14% were receiving GAHT. Parent support for their child's gender identity had a strong relationship with receipt of GAHT, with nearly 80% of those who received GAHT reporting they had at least one parent who supported their gender identity. Use of GAHT was associated with lower odds of recent depression (adjusted odds ratio [aOR] = .73, p < .001) and seriously considering suicide (aOR = .74, p < .001) compared to those who wanted GAHT but did not receive it. For youth under age 18, GAHT was associated with lower odds of recent depression (aOR = .61, p < .01) and of a past-year suicide attempt (aOR = .62, p < .05).
CONCLUSIONS
Findings support a relationship between access to GAHT and lower rates of depression and suicidality among transgender and nonbinary youth.
Topics: Adolescent; Child; Depression; Female; Gender Identity; Hormones; Humans; Male; Suicide, Attempted; Transgender Persons
PubMed: 34920935
DOI: 10.1016/j.jadohealth.2021.10.036 -
Journal of Internal Medicine Oct 2022Vitamin D, when activated to 1,25-dihydroxyvitamin D, is a steroid hormone that induces responses in several hundred genes, including many involved in immune responses... (Review)
Review
Vitamin D, when activated to 1,25-dihydroxyvitamin D, is a steroid hormone that induces responses in several hundred genes, including many involved in immune responses to infection. Without supplementation, people living in temperate zones commonly become deficient in the precursor form of vitamin D, 25-hydroxyvitamin D, during winter, as do people who receive less sunlight exposure or those with darker skin pigmentation. Studies performed pre-COVID-19 have shown significant but modest reduction in upper respiratory infections in people receiving regular daily vitamin D supplementation. Vitamin D deficiency, like the risk of severe COVID-19, is linked with darker skin colour and also with obesity. Greater risk from COVID-19 has been associated with reduced ultraviolet exposure. Various studies have examined serum 25-hydroxyvitamin D levels, either historical or current, in patients with COVID-19. The results of these studies have varied but the majority have shown an association between vitamin D deficiency and increased risk of COVID-19 illness or severity. Interventional studies of vitamin D supplementation have so far been inconclusive. Trial protocols commonly allow control groups to receive low-dose supplementation that may be adequate for many. The effects of vitamin D supplementation on disease severity in patients with existing COVID-19 are further complicated by the frequent use of large bolus dose vitamin D to achieve rapid effects, even though this approach has been shown to be ineffective in other settings. As the pandemic passes into its third year, a substantial role of vitamin D deficiency in determining the risk from COVID-19 remains possible but unproven.
Topics: COVID-19; Dietary Supplements; Hormones; Humans; Sunlight; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 35798564
DOI: 10.1111/joim.13536 -
Cancers Jan 2021Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune... (Review)
Review
Groundbreaking research in immunology and cancer biology in the last few decades has led to the discovery and development of novel therapeutics, such as immune checkpoint inhibitors and targeted therapies, which have revolutionized the clinical care of patients with metastatic melanoma. Updated data from the largest clinical trials continue to support the use of these treatment modalities, both in the metastatic and in adjuvant settings, with studies showing the predicted plateau effect on survival curves. However, with growing evidence that neoadjuvant therapy is also associated with high rates of recurrence-free survival, the question about whether patients should receive adjuvant or neoadjuvant treatment raises new questions about therapeutic options. Finally, management after resistance and intervention with novel immunotherapies are newer challenges, particularly in the field of non-cutaneous melanoma.
PubMed: 33435389
DOI: 10.3390/cancers13020221 -
Journal of the American Academy of... Jul 2023Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular... (Randomized Controlled Trial)
Randomized Controlled Trial
Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study.
BACKGROUND
Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare.
OBJECTIVE
To assess the effects of spesolimab over the 12-week study.
METHODS
The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8.
RESULTS
Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics.
LIMITATIONS
The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab.
CONCLUSION
Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients.
Topics: Humans; Treatment Outcome; Psoriasis; Antibodies, Monoclonal, Humanized; Double-Blind Method
PubMed: 36870370
DOI: 10.1016/j.jaad.2023.02.040 -
British Journal of Sports Medicine May 2022
PubMed: 35523538
DOI: 10.1136/bjsports-2022-105673