Category: Statistics

J Physiol. 2024 Jun 25. doi: 10.1113/JP286032. Online ahead of print.

ABSTRACT

Persistent inward currents (PICs) and persistent outward currents (POCs) regulate the excitability and firing behaviours of spinal motoneurons (MNs). Given their potential role in MN excitability dysfunction in amyotrophic lateral sclerosis (ALS), PICs have been previously studied in superoxide dismutase 1 (SOD1)-G93A mice (the standard animal model of ALS); however, conflicting results have been reported on how the net PIC changes during disease progression. Also, individual PICs and POCs have never been examined before in symptomatic ALS. To fill this gap, we measured the net and individual PIC and POC components of wild-type (WT) and SOD MNs in current clamp and voltage clamp during disease progression (assessed by neuroscores). We show that SOD MNs of symptomatic mice experience a much larger net PIC, relative to WT cells from age-matched littermates. Specifically, the Na⁺ and Ca²⁺ PICs are larger, whereas the lasting SK-mediated (SK_L) POC is smaller than WT (Na⁺ PIC is the largest and SK_L POC is the smallest components in SOD MNs). We also show that PIC dysregulation is present at symptom onset, is sustained throughout advanced disease stages and is proportional to SOD MN cell size (largest dysregulation is in the largest SOD cells, the most vulnerable in ALS). Additionally, we show that studying disease progression using neuroscores is more accurate than using SOD mouse age, which could lead to misleading statistics and age-based trends. Collectively, this study contributes novel PIC and POC data, reveals ionic mechanisms contributing to the vulnerability differential among MN types/sizes, and provides insights on the roles PIC and POC mechanisms play in MN excitability dysfunction in ALS. KEY POINTS: Individual persistent inward currents (PICs) and persistent outward currents (POCs) have never been examined before in spinal motoneurons (MNs) of symptomatic amyotrophic lateral sclerosis (ALS) mice. Thus, we contribute novel PIC and POC data to the ALS literature. Male SOD MNs of symptomatic mice have elevated net PIC, with larger Na⁺ and Ca²⁺ PICs but reduced SK_L POC vs. wild-type littermates. Na⁺ PIC is the largest and SK_L POC is the smallest current in SOD cells. The PIC/POC dysregulation is present at symptom onset. PIC dysregulation is sustained throughout advanced disease, and is proportional to SOD MN size (largest dysregulation is in the largest cells, the most vulnerable in ALS). Thus, we reveal ionic mechanisms contributing to the vulnerability differential among MN types/sizes in ALS. Studying disease progression using SOD mice neuroscores is more accurate than using age, which could distort the statistical differences between SOD and WT PIC/POC data and the trends during disease progression.

PMID:38924530 | DOI:10.1113/JP286032

Australas J Dermatol. 2024 Jun 25. doi: 10.1111/ajd.14315. Online ahead of print.

ABSTRACT

BACKGROUND/OBJECTIVES: Royal Darwin Hospital (RDH) is the sole public dermatology service in the Northern Territory (NT). Prescription of biologic therapies (BT) in the NT is uniquely challenging, with remote populations carrying a high tropical disease burden. The aim of this audit is to examine the demographics and outcomes of patients on BT for dermatologic conditions.

METHODS: Retrospective case note review of patients receiving BT through the RDH Dermatology department between August 2021 and October 2023. Data analysed were demographics, location, dermatological diagnosis and serology status.

RESULTS: In this audit, 115 patients were included. Age range of 13-91 years, mean of 51.1 years (±14.7), 52 (45.2%) patients were female and 8 (7.8%) identified as First Nations Australian. A large geographical area was serviced, with a primary address between 1 and 1496 km from RDH. Eighteen patients (15.7%) have discontinued BT completely. There was a statistically significant relationship between cessation of BT and increased distance of primary residence from RDH (p < 0.0007). Eighteen patients (15.7%) required management of infections identified in opportunistic infection screening. These infections were strongyloidiasis, tuberculosis, melioidosis and hepatitis B.

CONCLUSIONS: There is significant anxiety surrounding BT and tropical infections, including in returning travellers in southern Australian states. There has been particular interest in strongyloidiasis infection, as dupilumab acts on the Th2 immunity mechanism critical to parasitic infection response. This audit exhibits the unique experience of dermatological care in a tropical setting, demonstrating how BT can be used safely and how, when identified, these tropical infections can be successfully managed.

PMID:38924521 | DOI:10.1111/ajd.14315

Eur J Cardiothorac Surg. 2024 Jun 26:ezae242. doi: 10.1093/ejcts/ezae242. Online ahead of print.

ABSTRACT

OBJECTIVES: Gender difference in the outcome after type A aortic dissection surgery remains an issue of ongoing debate. In this study we aimed to evaluate the impact of gender on the short- and long-term outcome after surgery for type A aortic dissection.

METHODS: A multicentre European registry retrospectively included all consecutive type A aortic dissection surgery patients between 2005 and 2021 from 18 hospitals across eight European countries. Early and late mortality, and cumulative incidence of aortic reoperation were compared between genders.

RESULTS: A total of 3902 patients underwent type A aortic dissection surgery, with 1185 (30.4%) being females. After propensity score matching, 766 pairs of males and females were compared. No statistical differences were detected in the early postoperative outcome between genders. Ten-year survival was comparable between genders (47.8% vs 47.1%; Log-rank test, p = 0.679), as well as cumulative incidences of distal or proximal aortic reoperations. Ten-year relative survival compared to country-, year-, age-, and sex-matched general population was higher among males (0.65) compared to females (0.58). The time-period subanalysis revealed advancements in surgical techniques in both genders over the years. However, an increase of stroke was observed over time for both populations, particularly among females.

CONCLUSIONS: The past sixteen years have witnessed marked advancements in surgical techniques for TAAD in both males and females, achieving comparable early and late mortality rates. Despite these findings, late relative survival was still in favour of males.

PMID:38924518 | DOI:10.1093/ejcts/ezae242

Bioinformatics. 2024 Jun 26:btae421. doi: 10.1093/bioinformatics/btae421. Online ahead of print.

ABSTRACT

MOTIVATION: The annotation of cell types from single-cell transcriptomics is essential for understanding the biological identity and functionality of cellular populations. Although manual annotation remains the gold standard, the advent of automatic pipelines has become crucial for scalable, unbiased, and cost-effective annotations. Nonetheless, the effectiveness of these automatic methods, particularly those employing deep learning, significantly depends on the architecture of the classifier and the quality and diversity of the training datasets.

RESULTS: To address these limitations, we present a Pruning-enabled Gene-Cell Net (PredGCN) incorporating a Coupled Gene-Cell Net (CGCN) to enable representation learning and information storage. PredGCN integrates a Gene Splicing Net (GSN) and a Cell Stratification Net (CSN), employing a pruning operation (PrO) to dynamically tackle the complexity of heterogeneous cell identification. Among them, GSN leverages multiple statistical and hypothesis-driven feature extraction methods to selectively assemble genes with specificity for scRNA-seq data while CSN unifies elements based on diverse region demarcation principles, exploiting the representations from GSN and precise identification from different regional homogeneity perspectives. Furthermore, we develop a multi-objective Pareto pruning operation (Pareto PrO) to expand the dynamic capabilities of CGCN, optimizing the sub-network structure for accurate cell type annotation. Multiple comparison experiments on real scRNA-seq datasets from various species have demonstrated that PredGCN surpasses existing state-of-the-art methods, including its scalability to cross-species datasets. Moreover, PredGCN can uncover unknown cell types and provide functional genomic analysis by quantifying the influence of genes on cell clusters, bringing new insights into cell type identification and characterizing scRNA-seq data from different perspectives.

AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/IrisQi7/PredGCN and test data is available at https://figshare.com/articles/dataset/PredGCN/25251163.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:38924517 | DOI:10.1093/bioinformatics/btae421

Am J Respir Crit Care Med. 2024 Jun 26. doi: 10.1164/rccm.202311-2013OC. Online ahead of print.

ABSTRACT

RATIONALE: Outdoor fine particulate air pollution (PM2.5) contributes to millions of deaths around the world each year, but much less is known about the long-term health impacts of other particulate air pollutants including ultrafine particles (a.k.a. nanoparticles) which are in the nanometer size range (<100 nm), widespread in urban environments, and not currently regulated.

OBJECTIVES: Estimate the associations between long-term exposure to outdoor ultrafine particles and mortality.

METHODS: Outdoor air pollution levels were linked to the residential addresses of a large, population-based cohort from 2001 – 2016. Associations between long-term exposure to outdoor ultrafine particles and nonaccidental and cause-specific mortality were estimated using Cox proportional hazards models.

MEASUREMENTS: An increase in long-term exposure to outdoor ultrafine particles was associated with an increased risk of nonaccidental mortality (Hazard Ratio = 1. 073, 95% Confidence Interval = 1. 061, 1. 085) and cause-specific mortality, the strongest of which was respiratory mortality (Hazard Ratio = 1.174, 95% Confidence Interval = 1.130, 1.220).

MAIN RESULTS: Long-term exposure to outdoor ultrafine particles was associated with increased risk of mortality. We estimated the mortality burden for outdoor ultrafine particles in Montreal and Toronto, Canada to be approximately 1100 additional nonaccidental deaths every year. Furthermore, we observed possible confounding by particle size which suggests that previous studies may have underestimated or missed important health risks associated with ultrafine particles.

CONCLUSIONS: As outdoor ultrafine particles are not currently regulated, there is great potential for future regulatory interventions to improve population health by targeting these common outdoor air pollutants.

PMID:38924496 | DOI:10.1164/rccm.202311-2013OC

J ECT. 2024 Jun 20. doi: 10.1097/YCT.0000000000001028. Online ahead of print.

ABSTRACT

OBJECTIVES: To evaluate the association between 3 ECT quality measures (seizure duration, Postictal Suppression Index [PSI], and heart rate response) and therapeutic compliance as indicated by transitioning from acute to continuation to maintenance phases of ECT.

METHODS: This was a retrospective chart review of patients who received ECT between July 2016 and July 2019. ECT quality measures were lagged by 1 ECT session to examine the effect of the prior session’s quality measure on progressing to a higher ECT phase at the subsequent ECT session. Associations with therapeutic compliance were analyzed using mixed-effects ordinal regression and mixed-effects partial proportional odds models.

RESULTS: Seizure duration was associated with 8% higher adjusted odds of progressing to out of the acute phase (95% confidence interval [CI]: 2% to 15%, P = 0.007) and 18% higher adjusted odds of progressing to the maintenance phase (95% CI: 10% to 28%, P < 0.001); PSI was associated with 9% higher adjusted odds of progressing out of the acute phase (95% CI: 3% to 16%, P = 0.005), whereas heart rate response was not statistically associated with therapeutic compliance. Greater therapeutic compliance was also associated with bilateral electrode placement and older age.

CONCLUSIONS: Longer seizure duration was associated with greater therapeutic compliance across all ECT phases, PSI was associated with progressing out of the acute phase, and heart rate response was not associated with therapeutic compliance. Our findings assist ECT psychiatrists in optimizing ECT quality measures to promote better compliance with ECT.

PMID:38924479 | DOI:10.1097/YCT.0000000000001028

Bioconjug Chem. 2024 Jun 26. doi: 10.1021/acs.bioconjchem.4c00028. Online ahead of print.

ABSTRACT

Cationic polymers offer an alternative to viral vectors in nucleic acid delivery. However, the development of polymer vehicles capable of high transfection efficiency and minimal toxicity has remained elusive, and continued exploration of the vast design space is required. Traditional single polymer syntheses with large monomer bases are very time-intensive, limiting the speed at which new formulations are identified. In this work, we present an experimental method for the quick probing of the design space, utilizing a combinatorial set of 90 polymer blends, derived from 6 statistical copolymers, to deliver pDNA. This workflow facilitated rapid screening of polyplex compositions, successfully tailoring polyplex hydrophobicity, particle size, and payload binding affinity. This workflow identified blended polyplexes with high levels of transfection efficiency and cell viability relative to single copolymer controls and commercial JetPEI, indicating synergistic benefits from copolymer blending. Polyplex composition was coupled with biological outputs to guide the synthesis of single terpolymer vehicles, with high-performing polymers P10 and M20, providing superior transfection of HEK293T cells in serum-free and serum-containing media, respectively. Machine learning coupled with SHapley Additive exPlanations (SHAP) was used to identify polymer/polyplex attributes that most impact transfection efficiency, viability, and overall effective efficiency. Subsequent transfections on ARPE-19 and HDFn cells found that P10 and M20 were surpassed in performance by M10, contrasting with results in HEK293T cells. This cell type dependency reinforced the need to evaluate transfection conditions with multiple cell models to potentially identify moieties more beneficial to delivery in certain tissues. Overall, the workflow employed can be used to expedite the exploration of the polymer design space, bypassing extensive synthesis, and to develop improved polymer delivery vehicles more readily for nucleic acid therapies.

PMID:38924453 | DOI:10.1021/acs.bioconjchem.4c00028

Int J Lab Hematol. 2024 Jun 25. doi: 10.1111/ijlh.14332. Online ahead of print.

ABSTRACT

INTRODUCTION: Reticulocyte count and novel derived parameters provide insight into the effectiveness of erythropoiesis and may be useful tools in the classification and diagnosis of anemias. However, there is no standardisation, so we consider it necessary that each laboratory evaluates the parameters according to its own methodology and instrumentation and establishes its own reference ranges. Our aim was to establish the reference intervals (RIs) of reticulocyte profile provided by the Beckman Coulter DxH 900 haematological autoanalyzer in our reference population.

METHODS: One hundred and seventy-five healthy adults (18 to 62 years) were included. Subjects were collected from the blood donation centre of the Hospital Clínico San Carlos (Madrid, Spain) upon informed consent. Whole blood was collected and assayed for 14 haematological parameters on the Beckman Coulter DxH 900 analyzer in the haematology laboratory of the Clinical Analysis Department. RIs were established as per Clinical and Laboratory Standards Institute EP28-A3c guidelines using three different statistical approaches.

RESULTS: RIs estimated using the non-parametric method and the Harrell-Davis bootstrap method were very similar. RIs estimated by the robust method were narrower. Gender partitioning was required for two haematological parameters (low haemoglobin density (LHD) and microcytic anaemia factor (MAF)). The rest of the parameters did not need to be partitioned according to Lahti’s method.

CONCLUSION: RIs have been established for 14 hematologic parameters of the reticulocyte profile for the Beckman Coulter DxH 900 haematology analyzer using a healthy cohort of adult subjects.

PMID:38924378 | DOI:10.1111/ijlh.14332

Online J Public Health Inform. 2024 Jun 26;16:e52686. doi: 10.2196/52686.

ABSTRACT

BACKGROUND: The availability and use of broadband internet play an increasingly important role in health care and public health.

OBJECTIVE: This study examined the associations between broadband internet availability and use with drug overdose deaths in the United States.

METHODS: We linked 2019 county-level drug overdose death data in restricted-access multiple causes of death files from the National Vital Statistics System at the US Centers for Disease Control and Prevention with the 2019 county-level broadband internet rollout data from the Federal Communications Commission and the 2019 county-level broadband usage data available from Microsoft’s Airband Initiative. Cross-sectional analysis was performed with the fixed-effects regression method to assess the association of broadband internet availability and usage with opioid overdose deaths. Our model also controlled for county-level socioeconomic characteristics and county-level health policy variables.

RESULTS: Overall, a 1% increase in broadband internet use was linked with a 1.2% increase in overall drug overdose deaths. No significant association was observed for broadband internet availability. Although similar positive associations were found for both male and female populations, the association varied across different age subgroups. The positive association on overall drug overdose deaths was the greatest among Hispanic and Non-Hispanic White populations.

CONCLUSIONS: Broadband internet use was positively associated with increased drug overdose deaths among the overall US population and some subpopulations, even after controlling for broadband availability, sociodemographic characteristics, unemployment, and median household income.

PMID:38922664 | DOI:10.2196/52686

J Vector Borne Dis. 2024 Apr 1;61(2):259-266. doi: 10.4103/jvbd.jvbd_105_23. Epub 2024 Jun 6.

ABSTRACT

BACKGROUND OBJECTIVES: Vector-borne haemoprotozoan diseases comprise diverse group of single celled organism transmitted by haematophagus invertebrates. The current study was aimed at the identification of major haemoprotozoan (Babesia, Theileria and Trypanosoma) in dromedary camel of North Gujarat region in India using microscopy and Polymerase Chain Reaction (PCR).

METHODS: A total of 234 blood samples were screened by the microscopic and molecular detection assays. Molecular prevalence studies of Theileria, Trypanosoma spp and Babesia was undertaken using 18s ribosomal DNA, RoTat 1.2 and SS rRNA gene respectively. The data relating to microscopic and molecular prevalence along with associated risk factors were analysed by statistical methods.

RESULTS: The overall prevalence of hamoprotozoan disease based on microscopic and molecular investigation was 23.50%. The sensitivity and specificity (95% Confidence Interval) of PCR assay was 100% in comparison to microscopy (45.45 % sensitive and 100 % specific). The kappa coefficient between PCR and microscopy indicated good level of agreement with a value of 0.704 and SE of 0.159.

INTERPRETATION CONCLUSION: Despite holding much significance to the animal sector, little work has been undertaken in regional parts of India regarding camel parasites. The present study offers first preliminary research data investigating haemoprotozoan disease using parasitological and molecular methods in camels in the region.

PMID:38922661 | DOI:10.4103/jvbd.jvbd_105_23