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1.
Am J Prev Med ; 2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39025248

ABSTRACT

INTRODUCTION: People with chronic pain are at increased risk of opioid-misuse. Less is known about the unique risk conferred by each pain management treatment, as treatments are typically implemented together, confounding their independent effects. This study estimated the extent to which pain management treatments were associated with risk of opioid use disorder (OUD) for those with chronic pain, controlling for baseline demographic and clinical confounding variables and holding other pain management treatments at their observed levels. METHODS: Data were analyzed in 2024 from two chronic pain subgroups within a cohort of non-pregnant Medicaid patients aged 35-64 years, 2016-2019, from 25 states: those with 1) chronic pain and physical disability (CPPD) (N=6,133) or 2) chronic pain without disability (CP) (N=67,438). Nine pain management treatments were considered: prescription opioid i) dose and ii) duration; iii) number of opioid prescribers; opioid co-prescription with iv) benzo- diazepines, v) muscle relaxants, and vi) gabapentinoids; vii) non-opioid pain prescription, viii) physical therapy, and ix) other pain treatment modality. The outcome was OUD risk. RESULTS: Having opioids co-prescribed with gabapentin or benzodiazepine was statistically significantly associated with a 37-45% increased OUD risk for the CP subgroup. Opioid dose and duration also were significantly associated with increased OUD risk in this subgroup. Physical therapy was significantly associated with an 18% decreased risk of OUD in the CP subgroup. CONCLUSIONS: Co-prescription of opioids with either gabapentin or benzodiazepines may substantially increase OUD risk. More positively, physical therapy may be a relatively accessible and safe pain management strategy.

2.
Am J Epidemiol ; 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38988255

ABSTRACT

Prior studies estimating longitudinal associations between nicotine vaping and subsequent initiation of cannabis and other substances (e.g., cocaine, heroin) have been limited by short follow-up periods, convenience sampling, and possibly inadequate confounding control. We sought to address some of these gaps using the nationally representative Population Assessment of Tobacco and Health Study (PATH) to estimate longitudinal associations between nicotine vaping and the initiation of cannabis or other substances among adolescents transitioning to adulthood from2013 to 2019, adjusting for treatment-confounder feedback. Estimands like the longitudinal average treatment effect were not identified because of extensive practical positivity violations. Therefore, we estimated longitudinal incremental propensity score effects, which were identified. We found that reduced odds of nicotine vaping were associated with decreased risks of cannabis or other substance initiation; these associations strengthened over time. For example, by the final wave (2018-19), cannabis and other substance initiation risks were 6.2 (95%CI:4.6-7.7) and 1.8 (95%CI:0.4-3.2) percentage points lower when odds of nicotine vaping were reduced to be 90% lower in all preceding waves (2013-14 to 2016-18), as compared with observed risks. Strategies to lower nicotine vaping prevalence during this period may have resulted in fewer young people initiating cannabis and other substances.

3.
JAMA Netw Open ; 7(7): e2420472, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38976269

ABSTRACT

Importance: The Palliative Performance Scale (PPS) is one of the most widely used prognostic tools for patients with serious illness. However, current prognostic estimates associated with PPS scores are based on data that are over a decade old. Objective: To generate updated prognostic estimates by PPS score, care setting, and illness category, and examine how well PPS predicts short- and longer-term survival. Design, Setting, and Participants: This prognostic study was conducted at a large academic medical center with robust inpatient and outpatient palliative care practices using electronic health record data linked with data from California Vital Records. Eligible participants included patients who received a palliative care consultation between January 1, 2018, and December 31, 2020. Data analysis was conducted from November 2022 to February 2024. Exposure: Palliative care consultation with a PPS score documented. Main Outcomes and Measures: The primary outcomes were predicted 1-, 6-, and 12-month mortality and median survival of patients by PPS score in the inpatient and outpatient settings, and performance of the PPS across a range of survival times. In subgroup analyses, mortality risk by PPS score was estimated in patients with cancer vs noncancer illnesses and those seen in-person vs by video telemedicine in the outpatient setting. Results: Overall, 4779 patients (mean [SD] age, 63.5 [14.8] years; 2437 female [51.0%] and 2342 male [49.0%]) had a palliative care consultation with a PPS score documented. Of these patients, 2276 were seen in the inpatient setting and 3080 were seen in the outpatient setting. In both the inpatient and outpatient settings, 1-, 6-, and 12-month mortality were higher and median survival was shorter for patients with lower PPS scores. Prognostic estimates associated with PPS scores were substantially longer (2.3- to 11.7-fold) than previous estimates commonly used by clinicians. The PPS had good ability to discriminate between patients who lived and those who died in the inpatient setting (integrated time-dependent area under the curve [iAUC], 0.74) but its discriminative ability was lower in the outpatient setting (iAUC, 0.67). The PPS better predicted 1-month survival than longer-term survival. Mortality rates were higher for patients with cancer than other serious illnesses at most PPS levels. Conclusions and Relevance: In this prognostic study, prognostic estimates associated with PPS scores were substantially longer than previous estimates commonly used by clinicians. Based on these findings, an online calculator was updated to assist clinicians in reaching prognostic estimates that are more consistent with modern palliative care practice and specific to the patient's setting and diagnosis group.


Subject(s)
Palliative Care , Humans , Palliative Care/methods , Male , Female , Prognosis , Aged , Middle Aged , Aged, 80 and over , California , Neoplasms/mortality , Neoplasms/therapy , Adult
4.
Methods Mol Biol ; 2805: 171-186, 2024.
Article in English | MEDLINE | ID: mdl-39008182

ABSTRACT

Biophysical factors, including changes in mechanical stiffness, have been shown to influence the morphogenesis of developing organs. There is a lack of experimental techniques, however, that can probe the mechanical properties of embryonic tissues-especially those which are not mechanically or optically accessible, such as the visceral organs of the developing mouse embryo. Here, using the embryonic kidney as a model system, we describe a method to use microindentation to quantify tissue-level regional differences in the mechanical properties of an embryonic organ. This technique is generalizable and can be used to quantify patterns of tissue stiffness within other developing organ systems. Going forward, these data will enable new experimental studies of the role of biophysical cues during organogenesis.


Subject(s)
Kidney , Animals , Mice , Kidney/embryology , Kidney/cytology , Biomechanical Phenomena , Organogenesis , Embryo, Mammalian/cytology , Embryo, Mammalian/physiology
5.
PLoS One ; 19(7): e0306614, 2024.
Article in English | MEDLINE | ID: mdl-38976656

ABSTRACT

Pigment patterns are incredibly diverse across vertebrates and are shaped by multiple selective pressures from predator avoidance to mate choice. A common pattern across fishes, but for which we know little about the underlying mechanisms, is repeated melanic vertical bars. To understand the genetic factors that modify the level or pattern of vertical barring, we generated a genetic cross of 322 F2 hybrids between two cichlid species with distinct barring patterns, Aulonocara koningsi and Metriaclima mbenjii. We identify 48 significant quantitative trait loci that underlie a series of seven phenotypes related to the relative pigmentation intensity, and four traits related to patterning of the vertical bars. We find that genomic regions that generate variation in the level of eumelanin produced are largely independent of those that control the spacing of vertical bars. Candidate genes within these intervals include novel genes and those newly-associated with vertical bars, which could affect melanophore survival, fate decisions, pigment biosynthesis, and pigment distribution. Together, this work provides insights into the regulation of pigment diversity, with direct implications for an animal's fitness and the speciation process.


Subject(s)
Cichlids , Melanins , Quantitative Trait Loci , Animals , Cichlids/genetics , Cichlids/metabolism , Melanins/metabolism , Melanins/genetics , Pigmentation/genetics , Phenotype , Male , Female
6.
Epidemiology ; 2024 Jul 05.
Article in English | MEDLINE | ID: mdl-38967975

ABSTRACT

Lifecourse epidemiology is hampered by the absence of large studies with exposures and outcomes measured at different life stages on the same individuals. We describe when the effect of an exposure (A) on an outcome (Y) in a target population is identifiable in a combined ("synthetic") cohort created by pooling an early-life cohort including measures of A with a late-life cohort including measures of Y. We enumerate causal assumptions needed for unbiased effect estimation in the synthetic cohort and illustrate by simulating target populations under four causal models. From each target population, we randomly sampled early- and late-life cohorts and created a synthetic cohort by matching individuals from the two cohorts based on mediators and confounders. We estimated the effect of A on Y in the synthetic cohort, varying matching variables, the match ratio, and the strength of association between matching variables and A. Finally, we compared bias in the synthetic cohort estimates when matching variables did not d-separate A and Y to the bias expected in the original cohort. When the set of matching variables includes all variables d-connecting exposure and outcome (i.e., variables blocking all back- and front-door pathways), the synthetic cohort yields unbiased effect estimates. Even when matching variables did not fully account for confounders, the synthetic cohort estimate was sometimes less biased than comparable estimates in the original cohort. Methods based on merging cohorts may hasten the evaluation of early- and mid-life determinants of late-life health but rely on available measures of both confounders and mediators.

7.
Am J Epidemiol ; 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38879744

ABSTRACT

Studies often report estimates of the average treatment effect (ATE). While the ATE summarizes the effect of a treatment on average, it does not provide any information about the effect of treatment within any individual. A treatment strategy that uses an individual's information to tailor treatment to maximize benefit is known as an optimal dynamic treatment rule (ODTR). Treatment, however, is typically not limited to a single point in time; consequently, learning an optimal rule for a time-varying treatment may involve not just learning the extent to which the comparative treatments' benefits vary across the characteristics of individuals, but also learning the extent to which the comparative treatments' benefits vary as relevant circumstances evolve within an individual. The goal of this paper is to provide a tutorial for estimating ODTR from longitudinal observational and clinical trial data for applied researchers. We describe an approach that uses a doubly-robust unbiased transformation of the conditional average treatment effect. We then learn a time-varying ODTR for when to increase buprenorphine-naloxone (BUP-NX) dose to minimize return-to-regular-opioid-use among patients with opioid use disorder. Our analysis highlights the utility of ODTRs in the context of sequential decision making: the learned ODTR outperforms a clinically defined strategy.

8.
Curr Biol ; 34(12): 2773-2781.e3, 2024 Jun 17.
Article in English | MEDLINE | ID: mdl-38843829

ABSTRACT

Across vertebrates, live bearing evolved at least 150 times from ancestral egg laying into diverse forms and degrees of prepartum maternal investment.1,2 A key question is how reproductive diversity arose and whether reproductive diversification underlies species diversification.3,4,5,6,7,8,9,10,11 To test this, we evaluate the most basal jawed vertebrates: the sharks, rays, and chimaeras, which have one of the greatest ranges of reproductive and ecological diversity among vertebrates.2,12 We reconstruct the sequence of reproductive mode evolution across a phylogeny of 610 chondrichthyans.13 We reveal egg laying as ancestral, with live bearing evolving at least seven times. Matrotrophy evolved at least 15 times, with evidence of one reversal. In sharks, transitions to live bearing and matrotrophy are more prevalent in larger-bodied tropical species. Further, the evolution of live bearing is associated with a near doubling of the diversification rate, but there is only a small increase associated with the appearance of matrotrophy. Although pre-copulatory sexual selection is associated with increased rates of speciation in teleosts,3 sexual size dimorphism in chondrichthyans does not appear to be related to sexual selection,14,15 and instead we find increased rates of speciation associated with the colonization of novel habitats. This highlights a potential key difference between chondrichthyans and other fishes, specifically a slower rate of evolution of reproductive isolation following speciation, suggesting different rate-limiting mechanisms for diversification between these clades.16 The chondrichthyan diversification and radiation, particularly throughout shallow tropical shelf seas and oceanic pelagic habitats, appear to be associated with the evolution of live bearing and proliferation of a wide range of maternal investment in developing offspring.


Subject(s)
Biological Evolution , Body Size , Phylogeny , Sharks , Skates, Fish , Animals , Sharks/physiology , Sharks/anatomy & histology , Sharks/genetics , Skates, Fish/physiology , Skates, Fish/genetics , Skates, Fish/anatomy & histology , Female , Reproduction , Male
10.
Sci Rep ; 14(1): 10538, 2024 05 08.
Article in English | MEDLINE | ID: mdl-38719874

ABSTRACT

We estimated the effect of community-level natural hazard exposure during prior developmental stages on later anxiety and depression symptoms among young adults and potential differences stratified by gender. We analyzed longitudinal data (2002-2020) on 5585 young adults between 19 and 26 years in Ethiopia, India, Peru, and Vietnam. A binary question identified community-level exposure, and psychometrically validated scales measured recent anxiety and depression symptoms. Young adults with three exposure histories ("time point 1," "time point 2," and "both time points") were contrasted with their unexposed peers. We applied a longitudinal targeted minimum loss-based estimator with an ensemble of machine learning algorithms for estimation. Young adults living in exposed communities did not exhibit substantially different anxiety or depression symptoms from their unexposed peers, except for young women in Ethiopia who exhibited less anxiety symptoms (average causal effect [ACE] estimate = - 8.86 [95% CI: - 17.04, - 0.68] anxiety score). In this study, singular and repeated natural hazard exposures generally were not associated with later anxiety and depression symptoms. Further examination is needed to understand how distal natural hazard exposures affect lifelong mental health, which aspects of natural hazards are most salient, how disaster relief may modify symptoms, and gendered, age-specific, and contextual differences.


Subject(s)
Anxiety , Depression , Humans , Female , Male , Depression/epidemiology , Depression/etiology , Anxiety/epidemiology , Young Adult , Adult , Ethiopia/epidemiology , Longitudinal Studies , Vietnam/epidemiology , Peru/epidemiology , India/epidemiology , Developing Countries
11.
JAMA Netw Open ; 7(5): e2410696, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38722632

ABSTRACT

This cohort study assesses population-level associations of COVID-19 with birth parent and infant health, distinguishing the COVID-19 pandemic period from individual SARS-CoV-2 infection.


Subject(s)
COVID-19 , Pregnancy Complications, Infectious , SARS-CoV-2 , Humans , COVID-19/epidemiology , Pregnancy , Female , Pregnancy Complications, Infectious/epidemiology , Infant, Newborn , Pandemics , Infectious Disease Transmission, Vertical/prevention & control , Perinatal Care , Adult
12.
J Biomed Mater Res A ; 2024 May 16.
Article in English | MEDLINE | ID: mdl-38752415

ABSTRACT

Tissue engineering can provide in vitro models for drug testing, disease modeling, and perhaps someday, tissue/organ replacements. For building 3D heart tissue, the alignment of cardiac cells or cardiomyocytes (CMs) is important in generating a synchronously contracting tissue. To that end, researchers have generated several fabrication methods for building heart tissue, but direct comparisons of pros and cons using the same cell source is lacking. Here, we derived cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) and compare the assembly of these cells using three fabrication methods: cardiospheres, muscle rings, and muscle strips. All three protocols successfully generated compacted tissue comprised of hiPSC-derived CMs stable for at least 2 weeks. The percentage of aligned cells was greatest in the muscle strip (55%) and the muscle ring (50%) compared with the relatively unaligned cardiospheres (35%). The iPSC-derived CMs within the muscle strip also exhibited the greatest elongation, with elongation factor at 2.0 compared with 1.5 for the muscle ring and 1.2 for the cardiospheres. This is the first direct comparison of various fabrication techniques using the same cell source.

13.
Front Public Health ; 12: 1369777, 2024.
Article in English | MEDLINE | ID: mdl-38774043

ABSTRACT

Background: The COVID-19 pandemic has disproportionately impacted rural and under-resourced urban communities in Kansas. The state's response to COVID-19 has relied on a highly decentralized and underfunded public health system, with 100 local health departments in the state, few of which had prior experience engaging local community coalitions in a coordinated response to a public health crisis. Methods: To improve the capacity for local community-driven responses to COVID-19 and other public health needs, the University of Kansas Medical Center, in partnership with the Kansas Department of Health and Environment, will launch Communities Organizing to Promote Equity (COPE) in 20 counties across Kansas. COPE will establish Local Health Equity Action Teams (LHEATs), coalitions comprised of community members and service providers, who work with COPE-hired community health workers (CHWs) recruited to represent the diversity of the communities they serve. CHWs in each county are tasked with addressing unmet social needs of residents and supporting their county's LHEAT. LHEATs are charged with implementing strategies to improve social determinants of health in their county. Monthly, LHEATs and CHWs from all 20 counties will come together as part of a learning collaborative to share strategies, foster innovation, and engage in peer problem-solving. These efforts will be supported by a multilevel communications strategy that will increase awareness of COPE activities and resources at the local level and successes across the state. Our mixed methods evaluation design will assess the processes and impact of COPE activities as well as barriers and facilitators to implementation using aspects of both the Consolidated Framework for Implementation Research (CFIR) and Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) models. Discussion: This protocol is designed to expand community capacity to strategically partner with local public health and social service partners to prioritize and implement health equity efforts. COPE intentionally engages historically resilient communities and those living in underserved rural areas to inform pragmatic strategies to improve health equity.


Subject(s)
COVID-19 , Health Equity , Public Health , Humans , Kansas , SARS-CoV-2 , Health Status Disparities , Community Health Workers
14.
PLoS One ; 19(5): e0302622, 2024.
Article in English | MEDLINE | ID: mdl-38768138

ABSTRACT

BACKGROUND: Most U.S. K-12 schools have adopted safety tactics and policies like arming teachers and installing metal detectors, to address intentional school gun violence. However, there is minimal research on their effectiveness. Furthermore, sociodemographic factors may influence their implementation. Controlled studies are necessary to investigate their impact on gun violence and related disciplinary outcomes. OBJECTIVE: The paper outlines the protocol for a case-control study examining gun violence prevention policies in U.S. K-12 schools. The study aims to investigate if there is an association between the total number and type of specific safety tactics and policies and the occurrence of intentional shootings in K-12 public schools, student disciplinary outcomes, and if urbanicity, economic, and racial factors modify these associations. METHODS: We will create a nationally representative dataset for this study and ascertain a full census of case schools (schools that experienced intentional gunfire on the campus during school hours since 2015) through national school shooting databases. Matched control schools will be randomly selected from U.S. Department of Education's national database of all public schools. We will analyze 27 school safety strategies organized into seven key exposure groupings. RESULTS: Supported by the National Institutes for Child Health and Development (R01HD108027-01) and having received Institutional Review Board approval, our study is currently in the data collection phase. Our analytical plan will determine the association between the number and type of school safety tactics and policies with the occurrence of intentional shootings and suspensions and expulsions in a national sample of approximately 650 K-12 public schools. Additional analyses will investigate the effect modification of specific covariates. CONCLUSION: As the first national, controlled study, its results will provide novel and needed data on the effectiveness of school safety tactics and policies in preventing intentional shootings at K-12 public schools.


Subject(s)
Firearms , Gun Violence , Schools , Humans , Case-Control Studies , Gun Violence/prevention & control , Gun Violence/statistics & numerical data , United States/epidemiology , Child , Adolescent , Male , Students/statistics & numerical data , Violence/prevention & control , Violence/statistics & numerical data
15.
Article in English | MEDLINE | ID: mdl-38589636

ABSTRACT

In population neuroscience, samples are not often selected with equal or known probability from an underlying population of interest; in other words, samples are not often formally representative of a specified underlying population. This chapter provides an overview of an epidemiological approach to considering the implications of selective participation on the value of our results for population health. We discuss definitions of generalizability and transportability, given the growing recognition that generalizability and transportability are central for interpreting data that are aiming to be population-based. We provide evidence that differences in the prevalence of effect measure modifiers between a study sample and a target population will lead to a lack of generalizability and transportability. We provide an example of an association between a poly-genetic risk score and depression, showing how an internally valid association can differ based on the prevalence of effect measure modifiers. We show that when estimating associations, inferences from a study sample to a population can depend on clearly defining a target population. Given that representative sampling from explicitly defined target populations may not be feasible or realistic in many situations, especially given the sample sizes needed for statistical power for many exposures of interest (and especially when interactions are being tested), researchers should be well versed in tools available to enhance the interpretability of samples regarding target populations.

16.
Environ Epidemiol ; 8(2): e300, 2024 Apr.
Article in English | MEDLINE | ID: mdl-38617421

ABSTRACT

Background: Direct potable reuse (DPR) involves adding purified wastewater that has not passed through an environmental buffer into a water distribution system. DPR may help address water shortages and is approved or is under consideration as a source of drinking water for several water-stressed population centers in the United States, however, there are no studies of health outcomes in populations who receive DPR drinking water. Our objective was to determine whether the introduction of DPR for certain public water systems in Texas was associated with changes in birth defect prevalence. Methods: We obtained data on maternal characteristics for all live births and birth defects cases regardless of pregnancy outcome in Texas from 2003 to 2017 from the Texas Birth Defects Registry and birth and fetal death records. The ridge augmented synthetic control method was used to model changes in birth defect prevalence (per 10,000 live births) following the adoption of DPR by four Texas counties in mid-2013, with county-level data on maternal age, percent women without a high school diploma, percent who identified as Hispanic/Latina or non-Hispanic/Latina Black, and rural-urban continuum code as covariates. Results: There were nonstatistically significant increases in prevalence of all birth defects collectively (average treatment effect in the treated = 53.6) and congenital heart disease (average treatment effect in the treated = 287.3) since June 2013. The estimated prevalence of neural tube defects was unchanged. Conclusions: We estimated nonstatistically significant increases in birth defect prevalence following the implementation of DPR in four West Texas counties. Further research is warranted to inform water policy decisions.

17.
Int J Equity Health ; 23(1): 74, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38622612

ABSTRACT

BACKGROUND: Adverse childhood experiences (ACE) are important predictors of mental health outcomes in adulthood. However, commonly used ACE measures such as the Behavioural Risk Factor Surveillance System (BRFSS) have not been validated among Black sexually minoritized men (SMM) nor transgender women (TW), whom are known to have higher rates of ACE and poorer mental health outcomes. Assessing the psychometric properties of the measure is important for health equity research, as measurements that are not valid for some populations will render uninterpretable results. METHODS: Data are drawn from the Neighborhoods and Networks (N2) study, a longitudinal cohort of Black SMM and TW living in Southern Chicago. We conducted confirmatory factor analysis, correlation analysis and a two-parameter Item Response Theory (IRT) on the BRFSS ACE measure, an 11-item measure with 8 domains of ACE. RESULTS: One hundred forty seven participants (85% cisgender male) completed the BRFSS ACE measurement in the N2 study with age ranges from 16-34. The cohort were from a low socioeconomic background: about 40% of the cohort were housing insecure and made than $10,000 or less annually. They also have a high number of ACEs; 34% had endorsed 4 or more ACE domains. The three-factor structure fit the BRFSS ACE measure best; the measurement consisted of three subscales: of "Household Dysfunction", "Emotional / Physical", and "Sexual Abuse" (CFI = 0.975, TLI = 0.967, and RMSEA = 0.051). When the 8 domains of ACE were summed to one score, the total score was is correlated with depressive symptoms and anxiety scores, establishing concurrent validity. Item Response Theory model indicated that the "parental separation" domain had a low discrimination (slope) parameter, suggesting that this domain does not distinguish well between those with and without high ACE. CONCLUSIONS: The BRFFS ACE measure had adequate reliability, a well-replicated structure and some moderate evidence of concurrent validity among Black SMM and TW. The parental separation domain does not discriminate between those with high and low ACE experiences in this population. With changing population demographics and trends in marriage, further examination of this item beyond the current study is warranted to improve health equity research for all.


Subject(s)
Adverse Childhood Experiences , Transgender Persons , Humans , Male , Female , Reproducibility of Results , Chicago , Risk Factors
18.
Cereb Cortex ; 34(4)2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38679479

ABSTRACT

Normative ferret brain development was characterized using magnetic resonance imaging. Brain growth was longitudinally monitored in 10 ferrets (equal numbers of males and females) from postnatal day 8 (P8) through P38 in 6-d increments. Template T2-weighted images were constructed at each age, and these were manually segmented into 12 to 14 brain regions. A logistic growth model was used to fit data from whole brain volumes and 8 of the individual regions in both males and females. More protracted growth was found in males, which results in larger brains; however, sex differences were not apparent when results were corrected for body weight. Additionally, surface models of the developing cortical plate were registered to one another using the anatomically-constrained Multimodal Surface Matching algorithm. This, in turn, enabled local logistic growth parameters to be mapped across the cortical surface. A close similarity was observed between surface area expansion timing and previous reports of the transverse neurogenic gradient in ferrets. Regional variation in the extent of surface area expansion and the maximum expansion rate was also revealed. This characterization of normative brain growth over the period of cerebral cortex folding may serve as a reference for ferret studies of brain development.


Subject(s)
Brain , Ferrets , Magnetic Resonance Imaging , Animals , Ferrets/growth & development , Magnetic Resonance Imaging/methods , Male , Female , Brain/growth & development , Brain/diagnostic imaging , Brain/anatomy & histology , Longitudinal Studies , Sex Characteristics
19.
J Neuromuscul Dis ; 11(3): 687-699, 2024.
Article in English | MEDLINE | ID: mdl-38607761

ABSTRACT

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare, degenerative, recessive X-linked neuromuscular disease. Mutations in the gene encoding dystrophin lead to the absence of functional dystrophin protein. Individuals living with DMD exhibit progressive muscle weakness resulting in loss of ambulation and limb function, respiratory insufficiency, and cardiomyopathy, with multiorgan involvement. Adeno-associated virus vector-mediated gene therapy designed to enable production of functional dystrophin protein is a new therapeutic strategy. Delandistrogene moxeparvovec (Sarepta Therapeutics, Cambridge, MA) is indicated for treatment of ambulatory pediatric patients aged 4 through 5 years with DMD who have an indicated mutation in the DMD gene. OBJECTIVE: Evidence-based considerations for management of potential adverse events following gene therapy treatment for DMD are lacking in clinical literature. Our goal was to provide interdisciplinary consensus considerations for selected treatment-related adverse events (TRAEs) (vomiting, acute liver injury, myocarditis, and immune-mediated myositis) that may arise following gene therapy dosing with delandistrogene moxeparvovec. METHODS: An interdisciplinary panel of 12 specialists utilized a modified Delphi process to develop consensus considerations for the evaluation and management of TRAEs reported in delandistrogene moxeparvovec clinical studies. Panelists completed 2 Questionnaires prior to gathering for an in-person discussion. Consensus was defined as a majority (≥58% ; 7/12) of panelists either agreeing or disagreeing. RESULTS: Panelists agreed that the choice of baseline assessments should be informed by individual clinical indications, the treating provider's judgment, and prescribing information. Corticosteroid dosing for treatment of TRAEs should be optimized by considering individual risk versus benefit for each indication. In all cases involving patients with a confirmed TRAE, consultations with appropriate specialists were suggested. CONCLUSIONS: The Delphi Panel established consensus considerations for the evaluation and management of potential TRAEs for patients receiving delandistrogene moxeparvovec, including vomiting, acute liver injury, myocarditis, and immune-mediated myositis.


Subject(s)
Biological Products , Genetic Therapy , Muscular Dystrophy, Duchenne , Recombinant Fusion Proteins , Humans , Muscular Dystrophy, Duchenne/therapy , Muscular Dystrophy, Duchenne/genetics , Genetic Therapy/methods , Delphi Technique , Myocarditis/therapy , Child, Preschool
20.
J Morphol ; 285(5): e21698, 2024 May.
Article in English | MEDLINE | ID: mdl-38669130

ABSTRACT

The glycosylation of macromolecules can vary both among tissue structural components and by adverse conditions, potentially providing an alternative marker of stress in organisms. Lectins are proteins that bind carbohydrate moieties and lectin histochemistry is a common method to visualize microstructures in biological specimens and diagnose pathophysiological states in human tissues known to alter glycan profiles. However, this technique is not commonly used to assess broad-spectrum changes in cellular glycosylation in response to environmental stressors. In addition, the binding of various lectins has not been studied in elasmobranchs (sharks, skates, and rays). We surveyed the binding tissue structure specificity of 14 plant-derived lectins, using both immunoblotting and immunofluorescence, in the pectoral fins of neonate little skates (Leucoraja erinacea). Skates were reared under present-day or elevated (+5°C above ambient) temperature regimes and evaluated for lectin binding as an indicator of changing cellular glycosylation and tissue structure. Lectin labeling was highly tissue and microstructure specific. Dot blots revealed no significant changes in lectin binding between temperature regimes. In addition, lectins only detected in the elevated temperature treatment were Canavalia ensiformis lectin (Concanavalin A) in spindle cells of muscle and Ricinus communis agglutinin in muscle capillaries. These results provide a reference for lectin labeling in elasmobranch tissue that may aid future investigations.


Subject(s)
Lectins , Temperature , Animals , Lectins/metabolism , Animal Fins , Skates, Fish , Glycosylation , Animals, Newborn , Protein Binding
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