Disease types and pathogenic mechanisms induced by PM2.5 in five human systems: An analysis using omics and human disease databases.

Atmospheric fine particulate matter (PM2.5) can harm various systems in the human body. Due to limitations in the current understanding of epidemiology and toxicology, the disease types and pathogenic mechanisms induced by PM2.5 in various human systems remain unclear. In this study, the disease types induced by PM2.5 in the respiratory, circulatory, endocrine, and female and male urogenital systems have been investigated and the pathogenic mechanisms identified at molecular level. The results reveal that PM2.5 is highly likely to induce pulmonary emphysema, reperfusion injury, malignant thyroid neoplasm, ovarian endometriosis, and nephritis in each of the above systems respectively. The most important co-existing gene, cellular component, biological process, molecular function, and pathway in the five systems targeted by PM2.5 are Fos proto-oncogene (FOS), extracellular matrix, urogenital system development, extracellular matrix structural constituent conferring tensile strength, and ferroptosis respectively. Differentially expressed genes that are significantly and uniquely targeted by PM2.5 in each system are BTG2 (respiratory), BIRC5 (circulatory), NFE2L2 (endocrine), TBK1 (female urogenital) and STAT1 (male urogenital). Important disease-related cellular components, biological processes, and molecular functions are specifically induced by PM2.5. For example, response to wounding, blood vessel morphogenesis, body morphogenesis, negative regulation of response to endoplasmic reticulum stress, and response to type I interferon are the top uniquely existing biological processes in each system respectively. PM2.5 mainly acts on key disease-related pathways such as the PD-L1 expression and PD-1 checkpoint pathway in cancer (respiratory), cell cycle (circulatory), apoptosis (endocrine), antigen processing and presentation (female urogenital), and neuroactive ligand-receptor interaction (male urogenital). This study provides a novel analysis strategy for elucidating PM2.5-related disease types and is an important supplement to epidemiological investigation. It clarifies the risks of PM2.5 exposure, elucidates the pathogenic mechanisms, and provides scientific support for promoting the precise prevention and treatment of PM2.5-related diseases.

Arterial Leg Ulcers in the Octogenarian.

Arterial leg ulcers are a debilitating sequela of chronic ischemia, and their management, particularly in the octogenarian, is an immense challenge. ALUs are frequently a manifestation of end-stage peripheral arterial disease, and their presence portends a high morbidity and mortality. Management primarily relies on restoration of flow, but in the geriatric population, interventions may carry undue risk and pathologies may not be amenable. Adjunctive therapies that improve quality of life and decrease morbidity and mortality are therefore essential, and understanding their benefits and limitations is crucial in developing a multimodal treatment algorithm of care for the uniquely challenging octogenarian population.

Transcatheter Axial Pump Use in Pediatric Patients on Veno-Arterial Extracorporeal Membrane Oxygenation: An ACTION Collaborative Experience.

We report the largest pediatric multicenter experience with Impella pump use and peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support. Utilizing the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) collaborative database, we conducted a retrospective, multicenter study of all patients with cardiogenic shock requiring VA-ECMO support with subsequent Impella implant between October 2014 and December 2021. The primary outcome was defined as death while on Impella support. Secondary outcomes were recovery, transplantation, and transition to durable ventricular assist device (VAD) at the time of Impella explantation. Adverse events were defined according to the ACTION registry criteria. Twenty subjects were supported with Impella; Impella 2.5 (n = 3), CP (n = 12), 5.0/5.5 (n = 5). The median Interquartile range (IQR) age, weight, and body surface area at implantation were 15.6 years (IQR = 13.9-17.2), 65.7 kg (IQR = 53.1-80.7), and 1.74 m2 (IQR = 1.58-1.98). Primary cardiac diagnoses were dilated cardiomyopathy/myocarditis in nine (45%), congenital heart disease in four (20%), graft failure/rejection in four (20%), and three (15%) others. Most common adverse events included hemolysis (50%) and bleeding (20%). There were two deaths (10%) in the cohort. Nine patients (45%) were explanted for recovery, eight (40%) were transitioned to a durable VAD, and one (5%) underwent heart transplantation. Impella percutaneous pump support should be considered in the older pediatric population supported with peripheral VA-ECMO, as a means of left heart decompression, and a strategy to come off ECMO to achieve endpoints of myocardial recovery, transition to a durable VAD, or transplantation.

Baseline levels and longitudinal changes in plasma Aß42/40 among Black and white individuals.

Blood-based biomarkers of Alzheimer disease (AD) may facilitate testing of historically under-represented groups. The Study of Race to Understand Alzheimer Biomarkers (SORTOUT-AB) is a multi-center longitudinal study to compare AD biomarkers in participants who identify their race as either Black or white. Plasma samples from 324 Black and 1,547 white participants underwent analysis with C2N Diagnostics' PrecivityAD test for Aß42 and Aß40. Compared to white individuals, Black individuals had higher average plasma Aß42/40 levels at baseline, consistent with a lower average level of amyloid pathology. Interestingly, this difference resulted from lower average levels of plasma Aß40 in Black participants. Despite the differences, Black and white individuals had similar longitudinal rates of change in Aß42/40, consistent with a similar rate of amyloid accumulation. Our results agree with multiple recent studies demonstrating a lower prevalence of amyloid pathology in Black individuals, and additionally suggest that amyloid accumulates consistently across both groups.

The association between primary care appointment lengths and opioid prescribing for common pain conditions.

BACKGROUND: While brief duration primary care appointments may improve access, they also limit the time clinicians spend evaluating painful conditions. This study aimed to evaluate whether 15-minute primary care appointments resulted in higher rates of opioid prescribing when compared to ≥ 30-minute appointments. METHODS: We performed a retrospective cohort study using electronic health record (EHR), pharmacy, and administrative scheduling data from five primary care practices in Minnesota. Adult patients seen for acute Evaluation & Management visits between 10/1/2015 and 9/30/2017 scheduled for 15-minute appointments were propensity score matched to those scheduled for ≥ 30-minutes. Sub-groups were analyzed to include patients with acute and chronic pain conditions and prior opioid exposure. Multivariate logistic regression was performed to examine the effects of appointment length on the likelihood of an opioid being prescribed, adjusting for covariates including ethnicity, race, sex, marital status, and prior ED visits and hospitalizations for all conditions. RESULTS: We identified 45,471 eligible acute primary care visits during the study period with 2.7% (N = 1233) of the visits scheduled for 15 min and 98.2% (N = 44,238) scheduled for 30 min or longer. Rates of opioid prescribing were significantly lower for opioid naive patients with acute pain scheduled in 15-minute appointments when compared to appointments of 30 min of longer (OR 0.55, 95% CI 0.35-0.84). There were no significant differences in opioid prescribing among other sub-groups. CONCLUSIONS: For selected indications and for selected patients, shorter duration appointments may not result in greater rates of opioid prescribing for common painful conditions.

Shear wave elastography of transverse carpal ligament increased with simulated carpal tunnel pressure.

BACKGROUND: Elevation of carpal tunnel pressure is known to be associated with carpal tunnel syndrome. This study aimed to correlate the shear wave elastography in the transverse carpal ligament (TCL) with carpal tunnel pressures using a cadaveric model. METHODS: Eight human cadaveric hands were dissected to evacuate the tunnels. A medical balloon was inserted into each tunnel and connected to a pressure regulator to simulate tunnel pressure in the range of 0-210 mmHg with an increment of 30 mmHg. Shear wave velocity and modulus was measure in the middle of TCL. RESULTS: SWV and SWE were significantly dependent on the pressure levels (p < 0.001), and positively correlated to the tunnel pressure (SWV: R = 0.997, p < 0.001; SWE: R = 0.996, p < 0.001). Regression analyses showed linear relationship SWV and pressure (SWV = 4.359 + 0.0263 * Pressure, R2 = 0.994) and between SWE and pressure (SWE = 48.927 + 1.248 * Pressure, R2 = 0.996). CONCLUSION: The study indicated that SWV and SWE in the TCL increased linearly as the tunnel pressure increased within the current pressure range. The findings suggested that SWV/SWE in the TCL has the potential for prediction of tunnel pressure and diagnosis of carpal tunnel syndrome.

Unexpected Low Rate of Amyloid-ß Pathology in Multiple Sclerosis Patients.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024.

Assessing the Fractional Curve for Proper Management of Adult Degenerative Scoliosis.

Adult degenerative scoliosis (ADS) is a coronal plane deformity often accompanied by sagittal plane malalignment. Surgical correction may involve the major and/or distally-located fractional curves (FCs). Correction of the FC has been increasingly recognized as key to ameliorating radicular pain localized to the FC levels. The present study aims to summarize the literature on the rationale for FC correction in ADS. Three databases were systematically reviewed to identify all primary studies reporting the rationale for correcting the FC in ADS. Articles were included if they were English full-text studies with primary data from ADS ( ≥ 18 years old) patients. Seventy-four articles were identified, of which 12 were included after full-text review. Findings suggest FC correction with long-segment fusion terminating at L5 increases the risk of distal junctional degeneration as compared to constructs instrumenting the sacrum. Additionally, circumferential fusion offers greater FC correction, lower reoperation risk, and shorter construct length. Minimally invasive surgery (MIS) techniques may offer effective radiographic correction and improve leg pain associated with foraminal stenosis on the FC concavity, though experiences are limited. Open surgery may be necessary to achieve adequate correction of severe, highly rigid deformities. Current data support major curve correction in ASD where the FC concavity and truncal shift are concordant, suggesting that the FC contributes to the patient's overall deformity. Circumferential fusion and the use of kickstand rods can improve correction and enhance the stability and durability of long constructs. Last, MIS techniques show promise for milder deformities but require further investigation.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

Characterization of Turner Syndrome-associated diabetes mellitus.

CONTEXT: Diabetes mellitus (DM) risk factors in Turner Syndrome (TS) may include autoimmunity, obesity, beta-cell dysfunction, genetic predisposition and insulin resistance (IR). OBJECTIVE: Evaluate glucose tolerance and DM risk factors in adults with TS. DESIGN: A single centre study with two phases. To determine the prevalence of DM and to assess diabetes risk markers comparing women with TS with and without impaired glucose tolerance (IGT). SETTING: Tertiary referral center, University College Hospitals. PATIENTS: 106 Women with TS (age range 18-70 years) undergoing annual health surveillance. INTERVENTIONS: Participants underwent oral glucose tolerance tests (OGTT), with additional samples for autoimmunity and genetic analysis. MAIN OUTCOME MEASURE: Glucose tolerance, insulin, autoimmune and single nucleotide polymorphism (SNP) profile. RESULTS: OGTT screening showed that those without a previous DM diagnosis, 72.7% had normal glucose tolerance, 19.5% had IGT, and 7.6% were newly diagnosed with DM. OGTT identified more cases of DM than HbAc1 sampling alone. Women with IGT or DM were older, with higher body mass index and IR. No association was found between autoimmune markers GAD, IA-2 and ZnT8, risk karyotypes or selected SNPs and DM. In DM cases, GAD positivity was associated with requirement for insulin therapy. The median age of onset of the diagnosis of DM was 36 years (range 11-56). CONCLUSIONS: In the spectrum of DM subtypes, TS-associated DM lies between type 1 and type 2 DM with features of both. Key factors include weight and IR. Assessing C-peptide or GAD antibodies may aid future insulin requirement.

[18F]F-AraG imaging reveals association between neuroinflammation and brown- and bone marrow adipose tissue.

Brown and brown-like adipose tissues have attracted significant attention for their role in metabolism and therapeutic potential in diabetes and obesity. Despite compelling evidence of an interplay between adipocytes and lymphocytes, the involvement of these tissues in immune responses remains largely unexplored. This study explicates a newfound connection between neuroinflammation and brown- and bone marrow adipose tissue. Leveraging the use of [18F]F-AraG, a mitochondrial metabolic tracer capable of tracking activated lymphocytes and adipocytes simultaneously, we demonstrate, in models of glioblastoma and multiple sclerosis, the correlation between intracerebral immune infiltration and changes in brown- and bone marrow adipose tissue. Significantly, we show initial evidence that a neuroinflammation-adipose tissue link may also exist in humans. This study proposes the concept of an intricate immuno-neuro-adipose circuit, and highlights brown- and bone marrow adipose tissue as an intermediary in the communication between the immune and nervous systems. Understanding the interconnectedness within this circuitry may lead to advancements in the treatment and management of various conditions, including cancer, neurodegenerative diseases and metabolic disorders.

Resource pulses shape seasonal and individual variation in the diet of an omnivorous carnivore.

Resource pulses are ecologically important phenomenon that occur in most ecosystems globally. Following optimal foraging theory, many consumers switch to pulsatile foods when available, examples of which include fruit mast and vulnerable young prey. Yet how the availability of resource pulses shapes the ecology of predators is still an emerging area of research; and how much individual variation there is in response to pulses is not well understood. We hypothesized that resource pulses would lead to dietary convergence in our population, which we tested by tracking both population-level and individual coyote diets for 3 years in South Carolina, USA. We (1) described seasonal dietary shifts in relation to resource pulses; (2) compared male and female diets across seasons; and (3) tested this dietary convergence hypothesis by quantifying individual dietary variation both across and within periods when resource pulses were available. We found that pulses of white-tailed deer fawns and blackberries composed over half of coyote diet in summer, and persimmon fruits were an important component in fall. Male and female coyotes generally had similar diets, but males consumed more deer in fall, perhaps driven by scavenging more. We found support for our dietary convergence hypothesis, where individuals had more similar diets during resource pulses compared to a non-pulse period. We also found that this convergence happened before peak availability, suggesting a non-symmetric response to pulse availability. We show that nearly all coyotes eat fawns, suggesting that targeted efforts to remove "fawn killers" would be in vain. Instead, given how quickly coyotes collectively converge on resource pulses, our findings show that resource pulses could potentially be used by managers to alter the behavior of apex predators. More broadly, we open a new line of inquiry into how variation in individual foraging decisions scales up to shape the effects of resource pulses on ecological communities.

The OHStat Guidelines for Reporting Observational Studies and Clinical Trials in Oral Health Research: manuscript checklist.

Adequate and transparent reporting is necessary for critically appraising published research. Yet, ample evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research-statisticians and trialists from academia and industry-identified the minimum information needed to report and evaluate observational studies and clinical trials in oral health: the OHStat Guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The guidelines were subsequently revised by the Task Force's writing group. The guidelines draw heavily from the Consolidated Standards for Reporting Trials (CONSORT), Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), and CONSORT harms guidelines and incorporate the SAMPL guidelines for reporting statistics, the CLIP principles for documenting images, and the GRADE indicating the quality of evidence. The guidelines also recommend reporting estimates in clinically meaningful units using confidence intervals, rather than relying on P values. In addition, OHStat introduces 7 new guidelines that concern the text itself, such as checking the congruence between abstract and text, structuring the discussion, and listing conclusions to make them more specific. OHStat does not replace other reporting guidelines; it incorporates those most relevant to dental research into a single document. Manuscripts using the OHStat guidelines will provide more information specific to oral health research.

The OHStat Guidelines for Reporting Observational Studies and Clinical Trials in Oral Health Research: explanation and elaboration.

Adequate and transparent reporting is necessary for critically appraising research. Yet, evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research-statisticians and trialists from academia and industry-empaneled a group of authors to develop methodological and statistical reporting guidelines identifying the minimum information needed to document and evaluate observational studies and clinical trials in oral health: the OHstat Guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The final version was subsequently approved by the Task Force in September 2021, submitted for journal review in 2022, and revised in 2023. The checklist consists of 48 guidelines: 5 for introductory information, 17 for methods, 13 for statistical analysis, 6 for results, and 7 for interpretation; 7 are specific to clinical trials. Each of these guidelines identifies relevant information, explains its importance, and often describes best practices. The checklist was published in multiple journals. The article was published simultaneously in JDR Clinical and Translational Research, the Journal of the American Dental Association, and the Journal of Oral and Maxillofacial Surgery. Completed checklists should accompany manuscripts submitted for publication to these and other oral health journals to help authors, journal editors, and reviewers verify that the manuscript provides the information necessary to adequately document and evaluate the research.

Sex and aging signatures of proteomics in human cerebrospinal fluid identify distinct clusters linked to neurodegeneration.

Sex and age are major risk factors for chronic diseases. Recent studies examining age-related molecular changes in plasma provided insights into age-related disease biology. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and neurodegeneration. By comprehensively examining 7,006 aptamers targeting 6,139 proteins in CSF obtained from 660 healthy individuals aged from 43 to 91 years old, we subsequently identified significant sex and aging effects on 5,097 aptamers in CSF. Many of these effects on CSF proteins had different magnitude or even opposite direction as those on plasma proteins, indicating distinctive CSF-specific signatures. Network analysis of these CSF proteins revealed not only modules associated with healthy aging but also modules showing sex differences. Through subsequent analyses, several modules were highlighted for their proteins implicated in specific diseases. Module 2 and 6 were enriched for many aging diseases including those in the circulatory systems, immune mechanisms, and neurodegeneration. Together, our findings fill a gap of current aging research and provide mechanistic understanding of proteomic changes in CSF during a healthy lifespan and insights for brain aging and diseases.

Benchmarking of a multi-biomarker low-volume panel for Alzheimer's Disease and related dementia research.

Alzheimer's Disease (AD) biomarker measurement is key to aid in the diagnosis and prognosis of the disease. In the research setting, participant recruitment and retention and optimization of sample use, is one of the main challenges that observational studies face. Thus, obtaining accurate established biomarker measurements for stratification and maximizing use of the precious samples is key. Accurate technologies are currently available for established biomarkers, mainly immunoassays and immunoprecipitation liquid chromatography-mass spectrometry (IP-MS), and some of them are already being used in clinical settings. Although some immunoassays- and IP-MS based platforms provide multiplexing for several different coding proteins there is not a current platform that can measure all the stablished and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) is a mid-throughput platform with antibody-based measurements with a sequencing output that requires 15µL of sample volume to measure more than 100 analytes, including those typically assayed for AD. Here we benchmarked and compared the AD-relevant biomarkers including in the NULISA against validated assays, in both CSF and plasma. Overall, we have found that CSF measures of Aß42/40, NfL, GFAP, and p-tau217 are highly correlated and have similar predictive performance when measured by immunoassay, mass-spectrometry or NULISA. In plasma, p-tau217 shows a performance similar to that reported with other technologies when predicting amyloidosis. Other established and exploratory biomarkers (total tau, p-tau181, NRGN, YKL40, sTREM2, VILIP1 among other) show a wide range of correlation values depending on the fluid and the platform. Our results indicate that the multiplexed immunoassay platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional novel biomarkers using minimal sample volume.

Transfection of a Molecular Clone of Naegleria gruberi rDNA into N. gruberi Trophozoites.

All ribosomal genes of Naegleria trophozoites are maintained in a closed circular extrachromosomal ribosomal DNA (rDNA) containing element (CERE). While little is known about the CERE, a complete genome sequence analysis of three Naegleria species clearly demonstrates that there are no rDNA cistrons in the nuclear genome. Furthermore, a single DNA origin of replication has been mapped in the N. gruberi CERE, supporting the hypothesis that CERE replicates independently of the nuclear genome. This CERE characteristic suggests that it may be possible to use engineered CERE to introduce foreign proteins into Naegleria trophozoites. As the first step in exploring the use of a CERE as a vector in Naegleria, we developed a protocol to transfect N. gruberi with a molecular clone of the N. gruberi CERE cloned into pGEM7zf+ (pGRUB). Following transfection, pGRUB was readily detected in N. gruberi trophozoites for at least seven passages, as well as through encystment and excystment. As a control, trophozoites were transfected with the backbone vector, pGEM7zf+, without the N. gruberi sequences (pGEM). pGEM was not detected after the first passage following transfection into N. gruberi, indicating its inability to replicate in a eukaryotic organism. These studies describe a transfection protocol for Naegleria trophozoites and demonstrate that the bacterial plasmid sequence in pGRUB does not inhibit successful transfection and replication of the transfected CERE clone. Furthermore, this transfection protocol will be critical in understanding the minimal sequence of the CERE that drives its replication in trophozoites, as well as identifying regulatory regions in the non-ribosomal sequence (NRS).