Citations

PURPOSE Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in various malignancies. However, the high cost of these therapies limits access for much of the global population. This systematic review aims to evaluate the efficacy of low-dose ICIs compared with standard doses in different malignancies, addressing financial and access barriers in global cancer care. METHODS We conducted a systematic review of studies comparing the efficacy of low-dose versus standard-dose ICI regimens in advanced solid tumors. A comprehensive search was performed across multiple electronic databases, including retrospective and prospective studies. Excluded were animal studies, editorials, conference papers, book chapters, and other immunotherapy modalities. Outcomes assessed included overall survival (OS), progression-free survival, and objective response rate. Results were summarized descriptively due to study heterogeneity. RESULTS From 1,010 screened articles, four studies with 435 Asian patients were included, covering a variety of solid tumors. All included studies were with a low quality of evidence and a high risk of bias due to retrospective design. Two studies used weight-based dosing (pembrolizumab <2 mg/kg and nivolumab <2.15 mg/kg), showing similar OS to standard dosing in non–small cell lung cancer (NSCLC) and renal cell carcinoma, respectively. Flat dose regimens in two studies (nivolumab 20 mg or 100 mg once every 3 weeks and pembrolizumab 100 mg once every 3 weeks) also demonstrated comparable OS in NSCLC. CONCLUSION Low-dose ICIs may offer equivalent clinical benefits to standard dosing, potentially reducing costs and expanding access in developing countries. Although awaiting more representative randomized clinical trials, weight-based ICI regimens could be a viable alternative in low- and middle-income countries.

ABSTRACT Disruptions in the metabolism of cholesterol and other lipids are strongly implicated in the pathogenesis of neurological disease. The CNS is highly enriched in cholesterol, which is primarily synthesized de novo . Cholesterol synthesis is also rate limiting for myelin regeneration. Given that knockout of the thrombin receptor (Protease Activated Receptor 1 (PAR1)) accelerates myelin regeneration, here we sought to determine the potential regulatory actions of PAR1 in CNS cholesterol and lipid metabolism in the intact adult CNS and during myelin regeneration. We present quantitative PCR and RNAseq evidence from murine spinal cords at the peak of myelination and in adulthood showing PAR1 knockout is associated with increased gene expression for cholesterol biosynthesis (Hmgcs1, Hmgcr, Sqle, and Dhcr7), lipid transport (ApoE, Abca1, and Ldlr), and intracellular processing (Lcat, Npc1, and Npc2) at one or more time points examined. An upregulation of genes involved in the synthesis of other lipids enriched in the myelin membrane, specifically Fa2h, Ugt8a, and Gal3st1, was also observed in PAR1 knockouts. Transcription factors essential for lipid and cholesterol production (Srebf1 and Srebf2) were also increased in PAR1 knockout spinal cords at the postnatal day 21 peak of myelination and at day 45. GC–MS and LC–MS quantification of lipids demonstrated coordinate increases in the abundance of select cholesterol and lipid species in the spinal cords of PAR1 knockout mice, including enrichment of esterified cholesterol, together with sphingomyelins and sphingolipids. Co‐localization of the SREBP1 and SREBP2 transcription factors, as well as HMGCS1, a rate‐limiting enzyme in cholesterol biosynthesis, to glia during remyelination post‐lysolecithin or cuprizone‐mediated demyelination showed a prominent regulatory role for PAR1 in Olig2+ oligodendrocytes. PAR1 knockouts also demonstrated elevated levels of SREBP2 in more mature GST3+ oligodendrocytes and SREBP1 in GFAP+ astrocytes during remyelination post‐lysolecithin. These findings demonstrate novel roles for PAR1 as a regulator of CNS cholesterol and lipid metabolism and its potential as a therapeutic target to increase cholesterol availability to improve myelin regeneration. image

Advanced heart failure (HF) significantly diminishes quality of life (QoL) due to severe symptom burden and psychological distress. This meta-analysis investigates the impact of palliative care interventions on QoL, psychological well-being, symptom burden, and mortality in adults with advanced HF. A systematic search of major databases through August 2024 identified 13 randomized controlled trials involving 1541 participants from the USA, China, Iran, and Sweden. Palliative care significantly improved QoL scores compared with usual care [mean difference (MD) = 1.36; 95% confidence interval (CI), 0.89–1.83; P < 0.00001], with notable improvements using the Kansas City Cardiomyopathy Questionnaire. Palliative care significantly reduced anxiety scores (MD = −0.39; 95% CI, −0.66 to −0.11), P = 0.006), especially when assessed with the Edmonton Symptom Assessment Scale. While no significant differences were observed for dyspnea or depression ( P =0.56, P = 0.23, respectively). Mortality rates did not differ significantly between groups ( P = 0.61). These findings highlight the potential of palliative care, particularly interventions incorporating symptom management and psychological support, to enhance QoL and reduce anxiety in advanced HF patients. However, further research is required to standardize these interventions and evaluate their long-term outcomes.

Hypertension is the leading modifiable risk factor for atrial fibrillation (AF) and is estimated to be present in >70% of AF patients. This Frontiers Review was prepared by 29 expert members of the AF-SCREEN International Collaboration to summarize existing evidence and knowledge gaps on links between hypertension, AF, and their cardiovascular sequelae; simultaneous screening for hypertension and AF; and the prevention of AF through antihypertensive therapy. Hypertension and AF are inextricably connected. Both are easily diagnosed, often silent, and frequently treated inadequately. Together, they additively increase the risk of ischemic stroke, heart failure, and many types of dementia, resulting in greater all-cause mortality, considerable disease burden, and increased health care expenditures. Automated upper arm cuff blood pressure devices with implemented technology can be used to simultaneously detect both hypertension and AF. However, positive screening for AF with an oscillometric blood pressure monitor still requires ECG confirmation. The current evidence suggests that high-risk individuals aged ≥65 years or with treatment-resistant hypertension could benefit from AF screening. Since antihypertensive therapy effectively lowers AF risk, particularly in individuals with left ventricular dysfunction, hypertension should be the key target for AF prediction and prevention rather than merely a comorbidity of AF. Nevertheless, several important gaps in knowledge need to be filled over the next years, including the ideal method and selection of patients for simultaneous screening of hypertension and AF and the optimal antihypertensive drug class and blood pressure targets for AF prevention.

Introduction: Online self-scheduling of medical appointments is increasingly common. An automated waitlist can be used for patients who desire an earlier appointment time if one becomes available after they are scheduled. Our study examines outcomes of an automated waitlist and self-rescheduling process. Methods: We studied outcomes of an automated waitlist self-rescheduling process in which patients with existing appointments elected to be placed on an automated waitlist for an earlier appointment offer. When software found earlier dates for the same visit type, patients were then notified through an automated process and could self-reschedule. We reviewed appointments for which patients were sent new offers when earlier appointment slots were found. We compared the accepted appointment offers with the original scheduled appointments and determined the number of days that the appointment had been moved up. Results: Spanning the calendar year 2023 there were 1 019 698 appointment offers generated by an automated waitlist process for 229 998 appointments and sent to 164 248 patients. The waitlist process automatically found open appointments as they became available and sent the first new appointment offer within 2 days after being placed on the waitlist for 74 736 (32.5%) of the 229 998 waitlisted appointments. Patients sent back at least 1 response for 104 554 (45.4%) of the waitlisted appointments. Of the responses, 56 636 accepted one of the sent offers for an accept rate of 24.6% (56 636/229 998). For accepted, moved-up visits, appointments were self-rescheduled earlier by a mean of 22.6 days (95%CI; 22.2, 22.9, P < .0001). Conclusion: New appointments can be successfully self-rescheduled using an automated waitlist process that allows patients to accept or decline new appointment offers. This process can increase the efficiency of scheduling and decrease appointment wait time for patients desiring more timely access to healthcare. In addition, this process can be successfully applied across several different appointment type categories.

Importance Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive development of kidney cysts and is the most common inherited kidney disorder worldwide. ADPKD accounts for 5% to 10% of kidney failure in the US and Europe, and its prevalence in the US is 9.3 per 10 000 individuals. Observations ADPKD is typically diagnosed in individuals aged 27 to 42 years and is primarily caused by pathogenic variants in the PKD1 (78%) or PKD2 (15%) genes. Most persons with ADPKD have an affected parent, but de novo disease is suggested in 10% to 25% of families. More than 90% of patients older than 35 years have hepatic cysts, which may cause abdominal discomfort and occasionally require medical or surgical intervention. Hypertension affects 70% to 80% of patients with ADPKD, and approximately 9% to 14% develop intracranial aneurysms, which have a rupture rate of 0.57 per 1000 patient-years. Approximately 50% of individuals with ADPKD require kidney replacement therapy by 62 years of age. The severity of kidney disease can be quantified using the Mayo Imaging Classification (MIC), which stratifies patients based on total kidney volume adjusted for height and age and ranges from 1A to 1E. Patients with MIC 1C to MIC 1E have larger kidneys because of more rapid growth (6%-10% per year) compared with those with MIC 1A and 1B (1%-5% per year) and have earlier progression to kidney replacement therapy, which occurs at a mean age of 58.4 years for MIC 1C, 52.5 years for MIC 1D, and 43.4 years for MIC 1E. Optimal management of ADPKD includes systolic blood pressure lower than 120 mm Hg for most patients, but lower than 110/75 mm Hg for patients with MIC 1C to 1E who have an estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 and are younger than 50 years, dietary sodium restriction (&amp;lt;2000 mg/d), weight management, and adequate hydration (&amp;gt;2.5 L daily). The vasopressin type 2 receptor antagonist tolvaptan reduces the annual rate of eGFR decline by 0.98 to 1.27 mL/min/1.73 m 2 and is indicated for patients with MIC 1C to 1E or an eGFR decline greater than 3 mL/min/1.73 m 2 per year to slow disease progression and delay the onset of kidney failure. Conclusion ADPKD is the most common genetic kidney disease worldwide and is characterized by progressive development of kidney cysts. Patients typically have hypertension and liver cysts, and 9% to 14% develop intracranial aneurysms. First-line treatment includes blood pressure control, dietary and weight management, and adequate hydration. Tolvaptan reduces the rate of eGFR decline for those at high risk of rapid progression to kidney failure.

Abstract Emphysema’s significant morbidity and mortality underscore the need for reliable outcome metrics in clinical trials. However, commonly accepted chronic obstructive pulmonary disease outcome measures do not adequately capture emphysema severity or progression. Computed tomography (CT) metrics have been validated as accurate indicators of pathological emphysema and predictors of chronic obstructive pulmonary disease progression, exacerbations, and mortality. This position paper reviews the evidence supporting CT densitometry as a biomarker for emphysema, establishes implementation standards, and highlights areas for future research. A systematic literature review addressed three key questions: whether CT densitometry can be used as a diagnostic biomarker of emphysema, whether CT densitometry can be used as a prognostic biomarker, and whether longitudinal change in densitometry can be used as a disease progression monitoring biomarker. Emphysema metrics, such as the percentage of low attenuation areas below −950 Hounsfield units, are validated, highly reproducible diagnostic and prognostic biomarkers. Volume-adjusted lung density is recommended for disease monitoring. Both metrics demonstrate a scan–rescan intraclass correlation coefficient of 0.99 with proper technique. The paper also discusses relevant CT physics, techniques, and sources of variation, including technical factors, physiological changes, and software analysis. Key recommendations for clinical trials include using standardized CT techniques, proper subject selection, and longitudinal evaluation with volume-adjusted lung density.

Context.— In 2018, an evidence-based guideline was published by the College of American Pathologists to develop recommendations for the testing, application, interpretation, and reporting of high-risk human papillomavirus and surrogate marker tests in head and neck carcinomas. Substantial new evidence has prompted a review, including data on human papillomavirus (HPV) in nonoropharyngeal anatomic sites, HPV global rates, p16 immunohistochemistry, and HPV testing performance in cytology specimens, and performance of p16 immunohistochemistry as a surrogate marker. Objective.— To assess research published since the release of the original 2018 guideline and to update evidence-based recommendations for HPV testing in head and neck carcinomas. Design.— The College of American Pathologists convened a panel of experts to update the guideline following the standards established by the National Academy of Medicine for developing trustworthy clinical practice guidelines. The expert panel defined the key questions and performed a systematic review of the literature. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, recommendations were updated on the basis of available evidence, certainty of that evidence, and key judgments. Results.— Seven strong recommendations, 4 conditional recommendations, and 5 good practice statements are offered in the guideline update. Conclusions.— The updated guideline statements provide direction on the nature of HPV testing in various head and neck specimens (including key updates based on new research on sinonasal squamous cell carcinoma) and expanded guidance on specific scenarios and practice settings. The goal is to improve and standardize, where possible, HPV testing across diverse pathology practice settings and different countries.

The heat shock protein B8 (HSPB8) is one of the small heat shock proteins (sHSP or HSPB) and is a ubiquitous protein in various organisms, including humans. It is highly expressed in skeletal muscle, heart, and neurons. It plays a crucial role in identifying misfolding proteins and participating in chaperone-assisted selective autophagy (CASA) for the removal of misfolded and damaged, potentially cytotoxic proteins. Mutations in HSPB8 can cause distal hereditary motor neuropathy (dHMN), Charcot–Marie–Tooth (CMT) disease type 2L, or myopathy. The disease can manifest from childhood to mid-adulthood. Most missense mutations in the N-terminal and α-crystallin domains of HSPB8 lead to dHMN or CMT2L. Frameshift mutations in the C-terminal domain (CTD), resulting in elongation of the HSPB8 C-terminal, cause myopathy with myofibrillar pathology and rimmed vacuoles. Myopathy and motor neuropathy can coexist. HSPB8 frameshift mutations in the CTD result in HSPB8 mutant aggregation, which weakens the CASA ability to direct misfolded proteins to autophagic degradation. Cellular and animal models indicate that HSPB8 mutations drive pathogenesis through a toxic gain-of-function mechanism. Currently, no cure is available for HSPB8-associated neuromuscular disorders, but numerous therapeutic strategies are under investigation spanning from small molecules to RNA interference to exogenous HSPB8 delivery.