Repression of developmental transcription factor networks triggers aging-associated gene expression in human glial progenitor cells.

Human glial progenitor cells (hGPCs) exhibit diminished expansion competence with age, as well as after recurrent demyelination. Using RNA-sequencing to compare the gene expression of fetal and adult hGPCs, we identify age-related changes in transcription consistent with the repression of genes enabling mitotic expansion, concurrent with the onset of aging-associated transcriptional programs. Adult hGPCs develop a repressive transcription factor network centered on MYC, and regulated by ZNF274, MAX, IKZF3, and E2F6. Individual over-expression of these factors in iPSC-derived hGPCs lead to a loss of proliferative gene expression and an induction of mitotic senescence, replicating the transcriptional changes incurred during glial aging. miRNA profiling identifies the appearance of an adult-selective miRNA signature, imposing further constraints on the expansion competence of aged GPCs. hGPC aging is thus associated with acquisition of a MYC-repressive environment, suggesting that suppression of these repressors of glial expansion may permit the rejuvenation of aged hGPCs.

Molecular markers of artemisinin resistance during falciparum malaria elimination in Eastern Myanmar.

BACKGROUND: Artemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized. METHODS: Throughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13-a molecular marker of artemisinin resistance. RESULT: The program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p < 0.001). In the MDA villages there was no significant change in the K13 proportions before and after MDA. The distribution of different K13 mutations changed substantially; F446I and P441L mutations increased in both MDA and non-MDA villages, while most other K13 mutations decreased. The proportion of C580Y mutations fell from 9.2% (43/467) before MDA to 2.3% (19/813) after MDA (p < 0.001). Similar changes occurred in the 487 villages where MDA was not conducted. CONCLUSION: The malaria elimination program in Kayin state, eastern Myanmar, led to a substantial reduction in falciparum malaria. Despite the intense use of artemisinin-based combination therapies, both in treatment and MDA, this did not select for artemisinin resistance.

Tandem lesions associate with angiographic progression of coronary artery stenoses.

Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined. Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses. Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses. Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56-73) and the median interval between angiograms was 2.1 years (IQR 1.2-3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04-4.63, p < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21-2.7, p = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity. Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes.

Saturn's F ring is intermittently shepherded by Prometheus.

One of the stranger planetary rings is Saturn's narrow, clumpy F ring, lying just outside the main rings, in a region disturbed by chaotic orbital dynamics. We show that the F ring has a stable "true core" that dominates its mass and is confined into discontinuous short arcs of particles larger than a few millimeters in radius. The more obvious micron-size particles seen in images, outlining and obscuring the true core, contribute only a small fraction of its mass. We found that these arcs of large particles orbit Saturn in a specific corotational resonance with the nearby 100-kilometer diameter ringmoon Prometheus, which stabilizes the F ring material and allows it to persist within the disturbed region for decades or longer. Toward the end of the observing period, a small chaotic glitch in the orbit of Prometheus temporarily disrupted the confinement, but the arcs seem to be able to adapt.

GAN Inversion for Data Augmentation to Improve Colonoscopy Lesion Classification.

A major challenge in applying deep learning to medical imaging is the paucity of annotated data. This study explores the use of synthetic images for data augmentation to address the challenge of limited annotated data in colonoscopy lesion classification. We demonstrate that synthetic colonoscopy images generated by Generative Adversarial Network (GAN) inversion can be used as training data to improve polyp classification performance by deep learning models. We invert pairs of images with the same label to a semantically rich and disentangled latent space and manipulate latent representations to produce new synthetic images. These synthetic images maintain the same label as the input pairs. We perform image modality translation (style transfer) between white light and narrow-band imaging (NBI). We also generate realistic synthetic lesion images by interpolating between original training images to increase the variety of lesion shapes in the training dataset. Our experiments show that GAN inversion can produce multiple colonoscopy data augmentations that improve the downstream polyp classification performance by 2.7% in F1-score and 4.9% in sensitivity over other methods, including state-of-the-art data augmentation. Testing on unseen out-of-domain data also showcased an improvement of 2.9% in F1-score and 2.7% in sensitivity. This approach outperforms other colonoscopy data augmentation techniques and does not require re-training multiple generative models. It also effectively uses information from diverse public datasets, even those not specifically designed for the targeted downstream task, resulting in strong domain generalizability. Project code and model: https://github.com/DurrLab/GAN-Inversion.

Population pharmacokinetic modelling of primaquine exposures in lactating women and breastfed infants.

Current guidelines advise against primaquine treatment for breastfeeding mothers to avoid the potential for haemolysis in infants with G6PD deficiency. To predict the haemolytic risk, the amount of drug received from the breast milk and the resulting infant drug exposure need to be characterised. Here, we develop a pharmacokinetic model to describe the drug concentrations in breastfeeding women using venous, capillary, and breast milk data. A mother-to-infant model is developed to mimic the infant feeding pattern and used to predict their drug exposures. Primaquine and carboxyprimaquine exposures in infants are <1% of the exposure in mothers. Therefore, even in infants with the most severe G6PD deficiency variants, it is highly unlikely that standard doses of primaquine (0.25-1 mg base/kg once daily given to the mother for 1-14 days) would cause significant haemolysis. After the neonatal period, primaquine should not be restricted for breastfeeding women (Clinical Trials Registration: NCT01780753).

Rapid expansion and international spread of M1UK in the post-pandemic UK upsurge of Streptococcus pyogenes.

The UK observed a marked increase in scarlet fever and invasive group A streptococcal infection in 2022 with severe outcomes in children and similar trends worldwide. Here we report lineage M1UK to be the dominant source of invasive infections in this upsurge. Compared with ancestral M1global strains, invasive M1UK strains exhibit reduced genomic diversity and fewer mutations in two-component regulator genes covRS. The emergence of M1UK is dated to 2008. Following a bottleneck coinciding with the COVID-19 pandemic, three emergent M1UK clades underwent rapid nationwide expansion, despite lack of detection in previous years. All M1UK isolates thus-far sequenced globally have a phylogenetic origin in the UK, with dispersal of the new clades in Europe. While waning immunity may promote streptococcal epidemics, the genetic features of M1UK point to a fitness advantage in pathogenicity, and a striking ability to persist through population bottlenecks.

Seven-Year Revision Rates for Cochlear Implants in Pediatric and Adult Populations of an Integrated Healthcare System.

OBJECTIVE: We assessed three cochlear implant (CI) suppliers: Advanced Bionics, Cochlear Limited, and MED-EL, for implant revision requiring reoperation after CI placement. STUDY DESIGN: Retrospective cohort study of integrated-health-system database between 2010 and 2021. Separate models were created for pediatric (age <18) and adult (age ≥18) cohorts. PATIENTS: Pediatric (age <18) and adult (age ≥18) patients undergoing cochlear implantation within our integrated healthcare system. MAIN OUTCOME MEASURE: Revision after CI placement. Cox proportional hazard regression was used to evaluate revision risk and adjust for confounding factors. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented. RESULTS: A total of 2,347 patients underwent a primary CI placement, and Cochlear Limited was most implanted (51.5%), followed by Advanced Bionics (35.2%) and MED-EL (13.3%). In the pediatric cohort, the 7-year crude revision rate was 10.9% for Advanced Bionics and 4.8% for Cochlear Limited, whereas MED-EL had insufficient cases. In adults, the rates were 9.1%, 4.5%, and 3.3% for Advanced Bionics, MED-EL, and Cochlear Limited, respectively. After 2 years of postoperative follow-up, Advanced Bionics had a significantly higher revision risk (HR = 8.25, 95% CI = 2.91-23.46); MED-EL had no difference (HR = 2.07, 95% CI = 0.46-9.25). CONCLUSION: We found an increased revision risk after 2 years of follow-up for adults with Advanced Bionics CI devices. Although we found no statistical difference between manufacturers in the pediatric cohort, after 2 years of follow-up, there were increasing trends in the revision probability for Advanced Bionics. Further research may determine whether patients are better suited for some CI devices.

The brain-specific kinase LMTK3 regulates neuronal excitability by decreasing KCC2-dependent neuronal Cl- extrusion.

LMTK3 is a brain-specific transmembrane serine/threonine protein kinase that acts as a scaffold for protein phosphatase-1 (PP1). Although LMKT3 has been identified as a risk factor for autism and epilepsy, its physiological significance is unknown. Here, we demonstrate that LMTK3 copurifies and binds to KCC2, a neuron-specific K+/Cl- transporter. KCC2 activity is essential for Cl--mediated hyperpolarizing GABAAR receptor currents, the unitary events that underpin fast synaptic inhibition. LMTK3 acts to promote the association of KCC2 with PP1 to promote the dephosphorylation of S940 within its C-terminal cytoplasmic domain, a process the diminishes KCC2 activity. Accordingly, acute inhibition of LMTK3 increases KCC2 activity dependent upon S940 and increases neuronal Cl- extrusion. Consistent with this, LMTK3 inhibition reduced intrinsic neuronal excitability and the severity of seizure-like events in vitro. Thus, LMTK3 may have profound effects on neuronal excitability as an endogenous modulator of KCC2 activity.

Cholera rages in Africa and the Middle East: A narrative review on challenges and solutions.

Background and Aim: Cholera is a life-threatening infectious disease that is still one of the most common acute watery diarrheal diseases in the world today. Acute diarrhea and severe dehydration brought on by cholera can cause hypovolemic shock, which can be fatal in minutes. Without competent clinical therapy, the rate of case fatality surpasses 50%. The purpose of this review was to highlight cholera challenges in Africa and the Middle East and explain the reasons for why this region is currently a fertile environment for cholera. We investigated cholera serology, epidemiology, and the geographical distribution of cholera in Africa and the Middle East in 2022 and 2023. We reviewed detection methods, such as rapid diagnostic tests (RDTs), and treatments, such as antibiotics and phage therapy. Finally, this review explored oral cholera vaccines (OCVs), and the vaccine shortage crisis. Methods: We carried out a systematic search in multiple databases, including PubMed, Web of Science, Google Scholar, Scopus, MEDLINE, and Embase, for studies on cholera using the following keywords: ((Cholera) OR (Vibrio cholera) and (Coronavirus) OR (COVID-19) OR (SARS-CoV2) OR (The Middle East) OR (Africa)). Results and Conclusions: Cholera outbreaks have increased dramatically, mainly in Africa and many Middle Eastern countries. The COVID-19 pandemic has reduced the attention devoted to cholera and disrupted diagnosis and treatment services, as well as vaccination initiatives. Most of the cholera cases in Africa and the Middle East were reported in Malawi and Syria, respectively, in 2022. RDTs are effective in the early detection of cholera epidemics, especially with limited advanced resources, which is the case in much of Africa. By offering both direct and indirect protection, expanding the use of OCV will significantly reduce the burden of current cholera outbreaks in Africa and the Middle East.

Microplastics in different tissues of historical and live samples of endangered mega-fish (Acipenser sinensis) and their potential relevance to exposure pathways.

The Chinese sturgeon (Acipenser sinensis) is an endangered freshwater mega-fish (IUCN-red listed) that survives in the Yangtze River Basin, but the population of which has declined significantly in response to environmental pressures generated by human activities. In order to evaluate the interaction between Chinese sturgeon and microplastics (MPs) for the first time, we examined the gut and gills of historical samples (n = 27), in conjunction with the blood and mucus of live samples (n = 10), to explore the potential pathways involved in MP uptake. We detected MPs in 62.9 % of the field fish, with no significant difference between guts (mean=0.9 items/individual) and gills (mean=0.8 items/individual). The abundance of MPs in fish from 2017 was significantly higher than that from 2015 to 2016 with regards to both gills and gut samples. The size of MPs in gills was significantly smaller than those in guts, yet both contained mostly fibers (90.2 %). No MPs were confirmed in blood, however 62.5 % of mucus samples contained MPs. The MPs in mucus indicated the possibility of MPs entering Chinese sturgeons if their skins were damaged. The body size of Chinese sturgeons affected their MPs uptake by ingestion and inhalation, as less MPs were detected in the gut and gills of smaller individuals. Combining the evidence from historical and live samples, we revealed the presence of MPs in different tissues of Chinese sturgeon and their potential relevance to exposure pathways. Our work expands the understanding of multiple exposure pathways between MPs and long-lived mega-fish, while emphasizing the potential risks of long-term exposure in the field.

The phosphorylation landscape of infection-related development by the rice blast fungus.

Many of the world's most devastating crop diseases are caused by fungal pathogens that elaborate specialized infection structures to invade plant tissue. Here, we present a quantitative mass-spectrometry-based phosphoproteomic analysis of infection-related development by the rice blast fungus Magnaporthe oryzae, which threatens global food security. We mapped 8,005 phosphosites on 2,062 fungal proteins following germination on a hydrophobic surface, revealing major re-wiring of phosphorylation-based signaling cascades during appressorium development. Comparing phosphosite conservation across 41 fungal species reveals phosphorylation signatures specifically associated with biotrophic and hemibiotrophic fungal infection. We then used parallel reaction monitoring (PRM) to identify phosphoproteins regulated by the fungal Pmk1 MAPK that controls plant infection by M. oryzae. We define 32 substrates of Pmk1 and show that Pmk1-dependent phosphorylation of regulator Vts1 is required for rice blast disease. Defining the phosphorylation landscape of infection therefore identifies potential therapeutic interventions for the control of plant diseases.

Postprandial symptoms in disorders of gut-brain interaction and their potential as a treatment target.

Postprandial, or meal-related, symptoms, such as abdominal pain, early satiation, fullness or bloating, are often reported by patients with disorders of gut-brain interaction, including functional dyspepsia (FD) or irritable bowel syndrome (IBS). We propose that postprandial symptoms arise via a distinct pathophysiological process. A physiological or psychological insult, for example, acute enteric infection, leads to loss of tolerance to a previously tolerated oral food antigen. This enables interaction of both the microbiota and the food antigen itself with the immune system, causing a localised immunological response, with activation of eosinophils and mast cells, and release of inflammatory mediators, including histamine and cytokines. These have more widespread systemic effects, including triggering nociceptive nerves and altering mood. Dietary interventions, including a diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols, elimination of potential food antigens or gluten, IgG food sensitivity diets or salicylate restriction may benefit some patients with IBS or FD. This could be because the restriction of these foods or dietary components modulates this pathophysiological process. Similarly, drugs including proton pump inhibitors, histamine-receptor antagonists, mast cell stabilisers or even tricyclic or tetracyclic antidepressants, which have anti-histaminergic actions, all of which are potential treatments for FD and IBS, act on one or more of these mechanisms. It seems unlikely that food antigens driving intestinal immune activation are the entire explanation for postprandial symptoms in FD and IBS. In others, fermentation of intestinal carbohydrates, with gas release altering reflex responses, adverse reactions to food chemicals, central mechanisms or nocebo effects may dominate. However, if the concept that postprandial symptoms arise from food antigens driving an immune response in the gastrointestinal tract in a subset of patients is correct, it is paradigm-shifting, because if the choice of treatment were based on one or more of these therapeutic targets, patient outcomes may be improved.

Geographic Access to Pediatric Orthopedic Surgeons in the United States: An Analysis of Sociodemographic Factors.

BACKGROUND: It is unclear how pediatric orthopedic surgeons are geographically distributed relative to their patients. The purpose of this study was to evaluate the geographic distribution of pediatric orthopedic surgeons in the United States. MATERIALS AND METHODS: County-level data of actively practicing pediatric orthopedic surgeons were identified by matching several registries and membership logs. Data were used to calculate the distance between counties and nearest surgeon. Counties were categorized as "surgeon clusters" or "surgeon deserts" if the distance to the nearest surgeon was less than or greater than the national average and the average of all neighboring counties, respectively. Cohorts were then compared for differences in population characteristics using data obtained from the 2020 American Community Survey. RESULTS: A total of 1197 unique pediatric orthopedic surgeons were identified. The mean distance to the nearest pediatric orthopedic surgeon for a patient residing in a surgeon desert or a surgeon cluster was 141.9±53.8 miles and 30.9±16.0 miles, respectively. Surgeon deserts were found to have lower median household incomes (P<.001) and greater rates of children without health insurance (P<.001). Multivariate analyses showed that higher Rural-Urban Continuum codes (P<.001), Area Deprivation Index scores (P<.001), and percentage of patients without health insurance (P<.001) all independently required significantly greater travel distances to see a pediatric orthopedic surgeon. CONCLUSION: Pediatric orthopedic surgeons are not equally distributed in the United States, and many counties are not optimally served. Additional studies are needed to identify the relationship between travel distances and patient outcomes and how geographic inequalities can be minimized. [Orthopedics. 202x;4x(x):xx-xx.].

Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder.

Bipolar disorder is a highly heritable brain disorder which affects an estimated 50 million people worldwide. Due to recent advances in genotyping technology and bioinformatics methodology, as well as the increase in the overall amount of available data, our understanding of the genetic underpinnings of BD has improved. A growing consensus is that BD is polygenic and heterogeneous, but the specifics of that heterogeneity are not yet well understood. Here we use a recently developed technique to investigate the genetic heterogeneity of bipolar disorder. We find strong statistical evidence for a `bicluster': a subset of bipolar subjects that exhibits a disease-specific genetic pattern. The structure illuminated by this bicluster replicates in several other data-sets and can be used to improve BD risk-prediction algorithms. We believe that this bicluster is likely to correspond to a genetically-distinct subtype of BD. More generally, we believe that our biclustering approach is a promising means of untangling the underlying heterogeneity of complex disease without the need for reliable subphenotypic data.

Plasma p-tau217 in Alzheimer's disease: Lumipulse and ALZpath SIMOA head-to-head comparison.

Background: Plasma phosphorylated-tau217 (p-tau217) has been shown to be one of the most accurate diagnostic markers for Alzheimer's disease (AD). No studies have compared the clinical performance of p-tau217 as assessed by the fully automated Lumipulse and SIMOA ALZpath p-tau217. Aim: To evaluate the diagnostic accuracy of Lumipulse and SIMOA plasma p-tau217 assays for AD. Methods: The study included 392 participants, 162 with AD, 70 with other neurodegenerative diseases (NDD) with CSF biomarkers and 160 healthy controls. Plasma p-tau217 levels were measured using the Lumipulse and ALZpath SIMOA assays. The ability of p-tau217 assessed by both techniques to discriminate AD from NDD and controls was investigated using ROC analyses. Results: Both techniques showed high internal consistency of p-tau217 with similar correlation with CSF p-tau181 levels. In head-to-head comparison, Lumipulse and SIMOA showed similar diagnostic accuracy for differentiating AD from NDD (area under the curve [AUC] 0.952, 95%CI 0.927-0.978 vs 0.955, 95%CI 0.928-0.982, respectively) and HC (AUC 0.938, 95%CI 0.910-0.966 and 0.937, 95% CI0.907-0.967 for both assays). Conclusions: This study demonstrated the high precision and diagnostic accuracy of p-tau217 for the clinical diagnosis of Alzheimer's disease using either fully automated or semi-automated techniques.

Structure of a human monoclonal antibody in complex with Outer surface protein C (OspC) of the Lyme disease spirochete, Borreliella burgdorferi.

Lyme disease is a tick-borne, multisystem infection caused by the spirochete, Borreliella burgdorferi . Although antibodies have been implicated in the resolution of Lyme disease, the specific B cell epitopes targeted during human infections remain largely unknown. In this study, we characterized and defined the structural epitope of a patient-derived bactericidal monoclonal IgG ("B11") against Outer surface protein C (OspC), a homodimeric lipoprotein necessary for B. burgdorferi tick-mediated transmission and early-stage colonization of vertebrate hosts. High-resolution epitope mapping was accomplished through hydrogen deuterium exchange-mass spectrometry (HDX-MS) and X-ray crystallography. Structural analysis of B11 Fab-OspC A complexes revealed the B11 Fabs associated in a 1:1 stoichiometry with the lateral faces of OspC A homodimers such that the antibodies are essentially positioned perpendicular to the spirochete's outer surface. B11's primary contacts reside within the membrane proximal regions of α-helices 1 and 6 and adjacent loops 5 and 6 in one OspC A monomer. In addition, B11 spans the OspC A dimer interface, engaging opposing α-helix 1', α-helix 2', and loop 2-3' in the second OspC A monomer. The B11-OspC A structure is reminiscent of the recently solved mouse transmission blocking monoclonal IgG B5 in complex with OspC A , indicating a mode of engagement with OspC that is conserved across species. In conclusion, we provide the first detailed insight into the interaction between a functional human antibody and an immunodominant Lyme disease antigen long considered an important vaccine target.

Classics in Chemical Neuroscience: Xylazine.

Xylazine (also known as "tranq") is a potent nonopioid veterinary sedative that has recently experienced a surge in use as a drug adulterant, most often combined with illicitly manufactured fentanyl. This combination may heighten the risk of fatal overdose. Xylazine has no known antidote approved for use in humans, and age-adjusted overdose deaths involving xylazine were 35 times higher in 2021 than 2018. In April 2023, the Biden Administration declared xylazine-laced fentanyl an emerging drug threat in the United States. In 2022, the Drug Enforcement Agency (DEA) reported nearly a quarter of seized fentanyl powder contained xylazine. This dramatic increase in prevalence has solidified the status of xylazine as an emerging drug of abuse and an evolving threat to public health. The following narrative review outlines the synthesis, pharmacokinetics, pharmacodynamics, and adverse effects of xylazine, as well as the role it may play in the ongoing opioid epidemic.

Outcome of 3q26.2/MECOM rearrangements in chronic myeloid leukemia.

STUDY AIMS: To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML). METHODS: We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015. RESULTS: We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89 months, median survival was 14 months. The 5-year survival rate was 19% overall, 23% in CML-CP/AP, and 15% in CML-BP. In the 6-month landmark analysis, the 5-year survival rate was 41% for allogeneic stem cell transplantation (allo-SCT) recipients versus 17% for non-recipients (P = 0.050). Multivariate analysis showed that the percentage of marrow blasts and achievement of MCyR or deeper could predict survival. CONCLUSION: Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.

Revised Recommendations on Methods for Assessing Multimorbidity Changes over Time: Aligning the Method to the Purpose.

BACKGROUND: The rapidly growing field of multimorbidity research demonstrates that changes in multimorbidity in mid- and late-life have far reaching effects on important person-centered outcomes, such as health-related quality of life. However, there are few organizing frameworks and comparatively little work weighing the merits and limitations of various quantitative methods applied to the longitudinal study of multimorbidity. METHODS: We identify and discuss methods aligned to specific research objectives with the goals of 1) establishing a common language for assessing longitudinal changes in multimorbidity, 2) illuminating gaps in our knowledge regarding multimorbidity progression and critical periods of change, and 3) informing research to identify groups that experience different rates and divergent etiological pathways of disease progression linked to deterioration in important health-related outcomes. RESULTS: We review practical issues in the measurement of multimorbidity, longitudinal analysis of health-related data, operationalizing change over time, and discuss methods that align with four general typologies for research objectives in the longitudinal study of multimorbidity: 1) examine individual change in multimorbidity, 2) identify sub-groups that follow similar trajectories of multimorbidity progression, 3) understand when, how, and why individuals or groups shift to more advanced stages of multimorbidity, and 4) examine the co-progression of multimorbidity with key health domains. CONCLUSION: This work encourages a systematic approach to the quantitative study of change in multimorbidity and provides a valuable resource for researchers working to measure and minimize the deleterious effects of multimorbidity on aging populations.