Clinical Outcome Variables Research Articles

Targeting G9a/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma.

As the variable clinical outcome of patients with hepatoblastoma (HB) cannot be explained by genetics alone, the identification of drugs with the potential to effectively reverse epigenetic alterations is a promising approach to overcome poor therapy response. The gene ubiquitin like with PHD and ring finger domains 1 (UHRF1) represents an encouraging epigenetic target due to its regulatory function in both DNA methylation and histone modifications and its clinical relevance in HB. Patient-derived xenograft in vitro and in vivo models were used to study drug response. The mechanistic basis of CM-272 treatment was elucidated using RNA sequencing and western blot experiments. We validated in comprehensive data sets that UHRF1 is highly expressed in HB and associated with poor outcomes. The simultaneous pharmacological targeting of UHRF1-dependent DNA methylation and histone H3 methylation by the dual inhibitor CM-272 identified a selective impact on HB patient-derived xenograft cell viability while leaving healthy fibroblasts unaffected. RNA sequencing revealed downregulation of the IGF2-activated survival pathway as the main mode of action of CM-272 treatment, subsequently leading to loss of proliferation, hindered colony formation capability, reduced spheroid growth, decreased migration potential, and ultimately, induction of apoptosis in HB cells. Importantly, drug response depended on the level of IGF2 expression, and combination assays showed a strong synergistic effect of CM-272 with cisplatin. Preclinical testing of CM-272 in a transplanted patient-derived xenograft model proved its efficacy but also uncovered side effects presumably caused by its strong antitumor effect in IGF2-driven tumors. The inhibition of UHRF1-associated epigenetic traces, such as IGF2-mediated survival, is an attractive approach to treat high-risk HB, especially when combined with the standard-of-care therapeutic cisplatin.

Multimodality management for chronic subdural hematoma in China: protocol and characteristics of an ambidirectional, nationwide, multicenter registry study

BackgroundDespite its prevalence, there is ongoing debate regarding the optimal management strategy for chronic subdural hematoma (CSDH), reflecting the variability in clinical presentation and treatment outcomes. This ambidirectional, nationwide, multicenter registry study aims to assess the efficacy and safety of multimodality treatment approaches for CSDH in the Chinese population.Methods/designA multicenter cohort of CSDH patients from 59 participating hospitals in mainland China was enrolled in this study. The treatment modalities encompassed a range of options and baseline demographics, clinical characteristics, radiographic findings, and surgical techniques were documented. Clinical outcomes, including hematoma resolution, recurrence rates, neurological status, and complications, were assessed at regular intervals during treatment, 3 months, 6 months, 1 year, and 2 years follow-up.ResultBetween March 2022 and August 2023, a comprehensive cohort comprising 2173 individuals who met the criterion was assembled across 59 participating clinical sites. Of those patients, 81.1% were male, exhibiting an average age of 70.12 ± 14.53 years. A historical record of trauma was documented in 48.0% of cases, while headache constituted the predominant clinical presentation in 58.1% of patients. The foremost surgical modality employed was the burr hole (61.3%), with conservative management accounting for 25.6% of cases. Notably, a favorable clinical prognosis was observed in 88.9% of CSDH patients at 3 months, and the recurrence rate was found to be 2.4%.ConclusionThis registry study provides critical insights into the multimodality treatment of CSDH in China, offering a foundation for advancing clinical practices, optimizing patient management, and ultimately, improving the quality of life for individuals suffering from this challenging neurosurgical condition.Trial registrationChiCTR2200057179

Increased regulatory activity of intestinal innate lymphoid cells type 3 (ILC3) prevents experimental autoimmune encephalomyelitis severity

Experimental autoimmune encephalomyelitis (EAE) induced in inbred rodents, i.e., genetically identical animals kept under identical environmental conditions, shows variable clinical outcomes. We investigated such variations of EAE in Dark Agouti rats immunized with spinal cord homogenate and identified four groups: lethal, severe, moderate, and mild, at day 28 post immunization. Higher numbers of CD4+ T cells, helper T cells type 1 (Th1) and 17 (Th17) in particular, were detected in the spinal cord of the severe group in comparison with the moderate group. In addition, increased proportion of Th1 and Th17 cells, and heightened levels of interferon (IFN)-γ and interleukin (IL)-6 were detected in the small intestine lamina propria of the severe group. A selective agonist of free fatty acid receptor type 2 (Ffar2) applied orally in the inductive phase of EAE shifted the distribution of the disease outcomes towards milder forms. This effect was paralleled with potentiation of intestinal innate lymphoid cells type 3 (ILC3) regulatory properties, and diminished Th1 and Th17 cell response in the lymph nodes draining the site of immunization. Our results suggest that different clinical outcomes in DA rats are under determinative influence of intestinal ILC3 activity during the inductive phase of EAE.

Life-threatening infections in human newborns: Reconciling age-specific vulnerability and interindividual variability

In humans, the interindividual variability of clinical outcome following exposure to a microorganism is immense, ranging from silent infection to life-threatening disease. Age-specific immune responses partially account for the high incidence of infection during the first 28 days of life and the related high mortality at population level. However, the occurrence of life-threatening disease in individual newborns remains unexplained. By contrast, inborn errors of immunity and their immune phenocopies are increasingly being discovered in children and adults with life-threatening viral, bacterial, mycobacterial and fungal infections. There is a need for convergence between the fields of neonatal immunology, with its in-depth population-wide characterization of newborn-specific immune responses, and clinical immunology, with its investigations of infections in patients at the cellular and molecular levels, to facilitate identification of the mechanisms of susceptibility to infection in individual newborns and the design of novel preventive and therapeutic strategies.

Non-IG::MYC in diffuse large B-cell lymphoma confers variable genomic configurations and MYC transactivation potential

MYC translocation occurs in 8–14% of diffuse large B-cell lymphoma (DLBCL), and may concur with BCL2 and/or BCL6 translocation, known as double-hit (DH) or triple-hit (TH). DLBCL-MYC/BCL2-DH/TH are largely germinal centre B-cell like subtype, but show variable clinical outcome, with IG::MYC fusion significantly associated with inferior survival. While DLBCL-MYC/BCL6-DH are variable in their cell-of-origin subtypes and clinical outcome. Intriguingly, only 40-50% of DLBCL with MYC translocation show high MYC protein expression (>70%). We studied 186 DLBCLs with MYC translocation including 32 MYC/BCL2/BCL6-TH, 75 MYC/BCL2-DH and 26 MYC/BCL6-DH. FISH revealed a MYC/BCL6 fusion in 59% of DLBCL-MYC/BCL2/BCL6-TH and 27% of DLBCL-MYC/BCL6-DH. Targeted NGS showed a similar mutation profile and LymphGen genetic subtype between DLBCL-MYC/BCL2/BCL6-TH and DLBCL-MYC/BCL2-DH, but variable LymphGen subtypes among DLBCL-MYC/BCL6-DH. MYC protein expression is uniformly high in DLBCL with IG::MYC, but variable in those with non-IG::MYC including MYC/BCL6-fusion. Translocation breakpoint analyses of 8 cases by TLC-based NGS showed no obvious genomic configuration that enables MYC transactivation in 3 of the 4 cases with non-IG::MYC, while a typical promoter substitution or IGH super enhancer juxtaposition in the remaining cases. The findings potentially explain variable MYC expression in DLBCL with MYC translocation, and also bear practical implications in its routine assessment.

Investigating the effects of SARS-CoV-2 genetic mutations: Transmissibility, clinical severity, diagnostic implications and case study vaccine designs

SARS-CoV-2 comprises a diverse group of viruses responsible for illnesses ranging from the common cold to more serious respiratory diseases. Among coronaviruses, the four primary subgroups of note are Alphacoronavirus, Beta, Gamma, and Delta coronavirus. This paper examines genetic mutations on the transmissibility of variants in comparison to the original strains, emphasizing the potential consequences for pathogenicity and transmissibility. It underscores the significance of identifying genomic variants and their correlation with viral infectivity and COVID-19 severity to facilitate pandemic control and evolution investigation. Furthermore, the review paper explores the intricate relationship between specific mutations and the severity of COVID-19 symptoms, drawing on global data from clinical studies and surveillance to aid healthcare professionals in resource allocation and tailored treatment strategies. The review encompasses analyses of symptom severity, variations in clinical outcomes among different SARS-CoV-2 variants, and innovative approaches such as reverse vaccinology and adapted vaccines targeting Omicron subvariants. These findings collectively contribute to our understanding of the evolving pandemic and offer potential solutions for its mitigation and control.

Interleukin-8 genetic polymorphism and its relation to Helicobacter pylori infection and Helicobacter pylori-associated gastric diseases

Helicobacter pylori (H. pylori) infection has a variety of clinical outcomes, and host genetic factors play an important role in this process. Cytokines are important factors in mediating and controlling the inflammatory process during H. pylori infection. Interleukin-8 (IL-8) plays a critical role in the epithelial cell response to H. pylori infection and the development of H. pylori-related gastric disorders. The IL-8 gene has an A/T base pair polymorphism in the promoter region (-251), which has been linked to an increase in interleukin production by gastric epithelial cells. In this context, the goal of our study was to determine the polymorphism in the IL-8 gene and its relation to H. pylori infection and H. pylori-associated gastric diseases. Gastric biopsy specimens were collected from 44 patients with H. pylori infection and 29 patients without H. pylori infection. The rapid urease test and detection of the glmM gene were used to diagnose H. pylori infection. Polymerase chain reaction-restriction fragment length polymorphism was used to identify the polymorphism in the Il-8 gene (at position-251). The presence of the A/A and T/A genotypes of the IL-8 gene was found to be significantly associated with susceptibility to H. pylori infection (p = 0.012 and p = 0.004, respectively). Also, the IL-8 A allele was significantly associated with H. pylori infection in our study (p = 0.002). We did not find a significant association between IL-8 gene polymorphism and a higher risk of gastritis and peptic ulcer disease. In conclusion, IL-8 gene polymorphism at -251 position was significantly associated with H. pylori infection.

Gut Microbiota-mediated Alleviation of Dextran Sulfate Sodium-induced Colitis in Mice

Background and AimsGut dysbiosis characterized by an imbalanced microbiota is closely involved in the pathogenesis of a widespread gastrointestinal inflammatory disorder, inflammatory bowel disease (IBD). However, it is unclear how the complex intestinal microbiota affects development or resistant of mucosal inflammation. Our aim was to investigate the impact of the gut microbiota on susceptibility in a mouse model of ulcerative colitis. MethodsWe compared the susceptibility to dextran sulfate sodium (DSS)-induced colitis of inbred BALB/c mice obtained from the three main distributors of laboratory animals in Japan. Clinical symptoms of the colitis and the faecal microbiota were assessed. Cohousing approach was used to identify whether the gut microbiota is a primary factor determining disease susceptibility. ResultsHere, we showed differences in the susceptibility of BALB/c mice from the vendors to DSS colitis. Analysis of the gut microbiota using 16S rRNA sequencing revealed clear separation of the gut microbial composition among mice from the vendors. Notably, the abundance of the phylum Actinobacteriota was strongly associated with disease activity. We also observed the expansion of butyrate-producing Roseburia species in mice with decreased susceptibility of the disease. Further cohousing experiments showed that variation in clinical outcomes was more correlated with the gut microbiota than genetic variants among substrains from different suppliers. ConclusionsA BALB/c substrain that was resistant to DSS-induced colitis was observed, and the severity of DSS-induced colitis was mainly influenced by the gut microbiota. Targeting butyrate-producing bacteria could have therapeutic potential for ulcerative colitis.

Erratum to: DUSP22-rearranged ALK-negative anaplastic large cell lymphoma is a pathogenetically distinct disease but can have variable clinical outcome.

Erratum to: DUSP22-rearranged ALK-negative anaplastic large cell lymphoma is a pathogenetically distinct disease but can have variable clinical outcome.

Varied presentations of primary cutaneous lymphoma: A case series from a tertiary care center in South India.

Recent studies indicate an upsurge of primary cutaneous lymphoma (PCL) in the Indian population. Of late, we too have come across varied presentations of PCL in relatively younger individuals. Hence, we decided to study the clinical and immunohistological profile of patients with PCL in our department. All cases diagnosed as PCL from October 2016 to October 2019 were included. Clinical details, complete blood count, peripheral smear, imaging, histopathology, and immunohistochemistry of skin specimens were analyzed. Lymph node biopsy and bone marrow studies were done in most cases. Human T lymphotropic virus-1 (HTLV1) serology was done in 10 cases. Of the 24 patients with PCL, 12 were below 50 years of age. Twenty-three patients (95.8%) had T-cell lymphoma and only one had B-cell PCL. Mycosis fungoides (MF) (n = 17; 71%) was the most common type of PCL. There were two (8.3%) cases each of adult T-cell lymphoma/leukemia (ATLL) and Sezary syndrome. MF had varied clinical morphology at presentation and variable clinical outcomes. Both cases of ATLL had features of immunosuppression in the form of infective dermatoses. We observed an increased proportion of T-cell type of PCL, with the age of onset being relatively early. HTLV-1 positivity was noted in three out of the 10 cases tested. More studies are needed to determine the factors responsible for the younger age of onset of PCL and the role of HTLV-1 infection in the development of PCL.

Quantitative assessment of daratumumab in serum via intact light chain measurement using liquid chromatography-high resolution mass spectrometry: a method suitable for therapeutic drug monitoring.

Daratumumab, a pivotal treatment for multiple myeloma, exhibits considerable inter-patient variability in pharmacological clinical outcomes, likely attributed to serum concentration that may underscore the need for its therapeutic drug monitoring. This study aims to develop and validate a straightforward analytical method for quantifying daratumumab in serum, focusing on intact light chain determination, using liquid chromatography high-resolution mass spectrometry. The sample preparation involved immunoglobulin enrichment using Melon gel followed by a reduction step to dissociate the light from the heavy chains of immunoglobulins. The latter were then separated using a MabPac RP 2.1 × 50 mm chromatographic column and the intact light chains were detected and quantified using a Q Exactive Orbitrap mass spectrometer operating in ESI-positive ion mode at 17 500 resolution. The method demonstrated excellent linearity (R2 > 0.992) across a serum concentration range of 100 to 2000 μg mL-1 and good precision and accuracy: intra- and interday relative errors ranged from -5.1% to 6.5%, with a relative standard deviation of less than 5.8%. Clinical suitability was confirmed by analyzing 80 clinical samples from multiple myeloma patients treated with 1800 mg of daratumumab. 99% of the samples fell within the analytical range with a mean daratumumab concentration evaluated before the next administration (Ctrough) of 398 μg mL-1. These findings highlighted that intact light chain monoclonal antibody quantification could be a valid and robust alternative to either immunoassays or to LC-MS/MS targeting peptides for measuring daratumumab in clinical samples, positioning it as a suitable method for therapeutic drug monitoring applications.

Advancements in nuclear imaging using radiolabeled nanobody tracers to support cancer immunotherapy.

The evolving landscape of cancer immunotherapy has revolutionized cancer treatment. However, the dynamic tumor microenvironment has led to variable clinical outcomes, indicating a need for predictive biomarkers. Noninvasive nuclear imaging, using radiolabeled modalities, has aided in patient selection and monitoring of their treatment response. This approach holds promise for improving diagnostic accuracy, providing a more personalized treatment regimen, and enhancing the clinical response. Nanobodies or single-domain antibodies, derived from camelid heavy-chain antibodies, allow early timepoint detection of targets with high target-to-background ratios. To date, a plethora of nanobodies have been developed for nuclear imaging of tumor-specific antigens, immune checkpoints, and immune cells, both at a preclinical and clinical level. This review comprehensively outlines the recent advancements in nanobody-based nuclear imaging, both on preclinical and clinical levels. Additionally, the impact and expected future advancements on the use of nanobody-based radiopharmaceuticals in supporting cancer diagnosis and treatment follow-up are discussed.

Exploring the influence of physical activity on the efficacy of chondroprotective agents for osteoarthritis: The role of diffusion conditions

Osteoarthritis is a common and debilitating joint disease that primarily affects the knee and hip joints, resulting in a significant loss of articular cartilage. While non-steroidal anti-inflammatory drugs are often used to treat pain in osteoarthritis, they are not a suitable long-term solution because of their associated adverse events. Slow-acting symptom-modifying or structure/disease-modifying osteoarthritis drugs have demonstrated safety with minimal side effects, but their efficacy remains controversial. We hypothesize that differences in physical activity patterns among patients with knee or hip osteoarthritis could partly explain the large heterogeneity in response to oral glucosamine/chondroitin. Our hypothesis suggests that stagnant synovial fluid may restrict the diffusion of these drugs into the joint cartilage cells, leading to variable clinical outcomes. In this study, we provide evidence to support this hypothesis and propose a simple post-intake physical therapy procedure to enhance the effectiveness of chondroprotective agents. If validated, this approach could be a valuable addition to non-operative osteoarthritis management, potentially leading to remarkable improvements in patient outcomes.

Serum Copeptin Level as a Predictor of One-Year Mortality after Acute Decompensated Heart Failure Hospitalization

Background: Acutely decompensated heart failure patients have variable clinical outcomes. Some predictors of mortality in acute heart failure as resting heart rate, blood pressure, Pro-BNP level, and others have been identified. This study addresses the question whether copeptin may add value in the one-year prognosis in this category of high-risk patients. Results: To assess the relationship of serum copeptin level with one year mortality, we evaluated serum copeptin at admission and after 72 hours in 106 consecutive patients hospitalized for acute decompensated heart failure between May 2021 and November 2021 in a tertiary care hospital. Twenty-four patients (23.3%) died during the one-year follow-up period. The mortality was significantly higher in patients with advancing age, male sex, smokers, NYHA class IV heart failure, lower ejection fractions, higher heart rate, higher burden of arrhythmic events, lower creatinine clearance, and higher levels of copeptin at baseline and at day 3. Copeptin level at day 1 with cutoff value of ˃25.4 pmol/l predicted mortality with sensitivity 87.5% and specificity 70.73% [hazard ratio (95% confidence interval): (0.725 - 0.898), P<0.001], while copeptin level at day 3 with cutoff value ˃ 26.1 pmol/l predicted mortality with sensitivity 100% and specificity 73.17% [hazard ratio (95% confidence interval): (0.876 - 0.981), P<0.001]. Finally, increase in copeptin level from bassline was independently associated with increased mortality. (p˂0.001). Conclusions: Elevated copeptin level at baseline and 72 hours post-admission is suggested to be a strong predictor of one year mortality in patients with acute decompensated heart failure.

Recurrence risk stratification of hepatocellular carcinomas based on immune gene expression and features extracted from pathological images.

Immune-based therapy is a promising type of treatment for hepatocellular carcinoma (HCC) but has only been partially successful due to the high heterogeneity in HCC tumor. The differences in the degree of tumor cell progression and in the activity of tumor immune microenvironment could lead to varied clinical outcome. Accurate subgrouping for recurrence risk is an approach to address the issue of such heterogeneity. It remains under investigation as whether integrating quantitative whole slide image (WSI) features with the expression profile of immune marker genes can improve the risk stratification, and whether clinical outcome prediction can assist in understanding molecular biology that drives the outcome. We included a total of 231 patients from the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) project. For each patient, we extracted 18 statistical metrics corresponding to a global region of interest and 135 features regarding nucleus shape from WSI. A risk score was developed using these image features with high-dimensional survival modeling. We also introduced into the model the expression profile of 66 representative marker genes relevant to currently available immunotherapies. We stratified all patients into higher and lower-risk subgroup based on the final risk score selected from multiple models generated, and further investigated underlying molecular mechanisms associated with the risk stratification. One WSI feature and three immune marker genes were selected into the final recurrence-free survival (RFS) prediction model following the best integrated modeling framework. The resultant score showed a significantly improved prediction performance on the test dataset (mean time-dependent AUCs = 0.707) as compared to those of other types (e.g: mean time-dependent AUCs of AJCC tumor stage = 0.525) of input data integration. To assess that the risk score could provide a higher-resolution risk stratification, a lower-risk subgroup (or a higher-risk subgroup) was arbitrarily assigned according to score falling below (or above) the median score. The lower risk subgroup had significantly longer median RFS time than that of the higher-risk patients (median RFS = 903 vs. 265 days, log-rank test p-value< 0.0001). Additionally, the higher-risk subgroup, in contrast to the lower-risk patients were characterized with a significant downregulation of immune checkpoint genes, suppressive signal in tumor immune response pathways, and depletion of CD8 T cells. These observations for the higher-risk subgroup suggest that new targets for adoptive or checkpoint-based combined systemic therapies may be useful. We developed a novel prognostic model to predict RFS for HCC patients, using one feature that can be automatically extracted from routine histopathological images, as well as the expression profiles of three immune marker genes. The methodology used in this paper demonstrates the feasibility of developing prognostic models that provide both useful risk stratification along with valuable biological insights into the underlying characteristics of the subgroups identified.

Impact of CYP2D6 polymorphisms on the efficacy of tamoxifen in Iraqi women with breast cancer

Objectives: The aim of the present study was to investigate the impact of the CYP2D6 genetic polymorphism on clinical outcome in Iraqi breast cancer patients who were candidates for Tamoxifen therapy. Methods: Comprehensive CYP2D6 genotyping was performed in 140 Iraqi women with breast cancer who were women on adjuvant treatment with tamoxifen. Breast cancer patients recruited into the study were divided into two groups: seventy breast cancer women who had no history of recurrence at the time of sampling and had a long time on tamoxifen without recurrence and seventy breast cancer women who had recurrence at the time of sampling after one year of treatment with tamoxifen therapy. Recurrence free survival (RFS) was determined in the recruited patients. Results: Multiple genetic variants of the gene encoding the CYP2D6 enzyme were detected with significant differences in their frequencies and percentages in both recurrent and non-recurrent groups of breast cancer patients. The findings of this study suggest that interindividual variation in clinical outcome may be related to genetic variation in CYP2D6 enzyme, which is characterized by variable RFS periods. Conclusions: This study revealed that the CYP2D6 enzyme of breast cancer patients who participated in this study is highly polymorphic. The CYP2D6 gene of study participants exhibited different allelic combinations with variable frequencies. The multiple genetic variants (alleles) of the gene encoding the CYP2D6 enzyme exhibited significant differences in their frequencies and percentages in both recurrent and non-recurrent groups of breast cancer patients. .The study revealed variable Recurrence free survival (RFS) with highly polymorphic gene. Our study quotes the presence of increased CYP2D6 enzyme polymorphism is associated with variable clinical response.

Comparison of hamate versus second or third toe osteochondral graft using magnetic resonance imaging for reconstruction of proximal interphalangeal fracture-dislocations.

Hemi-hamate arthroplasty is a method used to reconstruct complex fracture-dislocations of the proximal interphalangeal joint of the fingers. Other graft sites, including the toe second and third phalanges, have been proposed as alternatives to hemi-hamate arthroplasty due to variable clinical outcomes and anatomy. Through a prospective magnetic resonance imaging (MRI)-based study in asymptomatic individuals, we aimed to characterize the anatomy of the proximal interphalangeal joint and compare this with the hamate, second and third toes to determine the closest anatomical match using pre-determined measurements. Our results show that the second and third toes have greater anatomical similarity to the proximal interphalangeal joint of the fingers compared to the hamate. High-resolution MRI is a reliable method of characterizing the anatomy of these structures and could be a useful clinical tool in determining reconstructive options in the management of this challenging injury.Level of evidence: II.

Differential cellular immune responses against Orientia tsutsugamushi Karp and Gilliam strains following acute infection in mice.

Scrub typhus is a leading cause of febrile illness in endemic countries due to infection with Orientia tsutsugamushi (Ot), a seriously understudied intracellular bacterium. Pulmonary involvement associated with vascular parasitism in patients is common and can develop into life threatening interstitial pneumonia. The diverse antigenicity of Ot genotypes and inter-strain differences in genome content are connected to varied virulence and clinical outcomes; however, detailed studies of strain-related pulmonary immune responses in human patients or small animal models of infection are lacking. In this study, we have used two clinically prevalent bacterial strains (Karp and Gilliam) to reveal cellular immune responses in inflamed lungs and potential biomarkers of disease severity. The results demonstrate that outbred CD-1 mice are highly susceptible to both Karp and Gilliam strains; however, C57BL/6 (B6) mice were susceptible to Karp, but resistant to Gilliam (with self-limiting infection), corresponding to their tissue bacterial burdens and lung pathological changes. Multicolor flow cytometric analyses of perfused B6 mouse lungs revealed robust and sustained influx and activation of innate immune cells (macrophages, neutrophils, and NK cells), followed by CD4+ and CD8+ T cells, during Karp infection, but such responses were greatly attenuated during Gilliam infection. The robust cellular responses in Karp-infected B6 mice positively correlated with significantly early and high levels of serum cytokine/chemokine protein levels (CXCL1, CCL2/3/5, and G-CSF), as well as pulmonary gene expression (Cxcl1/2, Ccl2/3/4, and Ifng). In vitro infection of B6 mouse-derived primary macrophages also revealed bacterial strain-dependent immune gene expression profiles. This study provided the lines of evidence that highlighted differential tissue cellular responses against Karp vs. Gilliam infection, offering a framework for future investigation of Ot strain-related mechanisms of disease pathogenesis vs. infection control.

An investigation into the critical ingredients of intensive support teams for adults with intellectual disabilities who display challenging behaviour

Aims and method NHS England recommends the commissioning of intensive support teams (ISTs) to provide effective support to people with intellectual disability (ID) when in crisis. However, there is a paucity of evidence regarding how these services should be organised. This exploratory secondary analysis of data from the IST-ID study aimed to investigate IST characteristics that relate to clinical outcomes. The primary outcome was mean change in the total score on the Aberrant Behavior Checklist and its subscales. Results A measure of mental illness severity was the only variable associated with our primary outcome of reduction in challenging behaviour. Accommodation type, affective status and gender were associated with the subdomains of irritability, hyperactivity and lethargy in unadjusted and adjusted analyses. Clinical implications Our findings indicate that variation in clinical outcomes is influenced by individual rather than organisational factors. Further research on the theoretical fidelity of the IST-ID model is needed.

Comparative analysis of external locking plate and combined frame external fixator for open distal tibial fractures: a comprehensive assessment of clinical outcomes and financial implications

BackgroundOpen distal tibial fractures pose significant challenges regarding treatment options and patient outcomes. This retrospective single-centre study aimed to compare the stability, clinical outcomes, complications, and financial implications of two surgical interventions, namely the external locking plate and the combined frame external fixator, to manage open distal tibial fractures.MethodsForty-four patients with distal open tibial (metaphyseal extraarticular) fractures treated between 2020 and 2022 were selected and formed into two main groups, Group A and Group B. Group A (19 patients) are patients that underwent treatment using the external locking plate technique, while Group B (25 patients) received the combined frame external fixator approach. Age, gender, inpatient stay, re-operation rates, complications, functional recovery (measured by the Johner-Wrush score), pain ratings (measured by the Visual Analogue Scale [VAS]), and cost analyses were evaluated for each group. Statistical analyses using SPSS were conducted to compare the outcomes between the two groups.ResultsThe research found significant variations in clinical outcomes, complications, and cost consequences between Group A and Group B. Group A had fewer hospitalisation periods (23.687.74) than Group B (33.5619.47). Re-operation rates were also considerably lower in Group A (26.3%) than in Group B (48%), owing to a greater prevalence of pin-tract infections and subsequent pin loosening in the combination frame external fixator group. The estimated cost of both techniques was recorded and analysed with the locking average of 26,619.69 ± 9,602.352 and the combined frame average of 39,095.64 ± 20,070.077.ConclusionThis study suggests that although the two approaches effectively manage open distal tibia fractures, the locking compression plate approach (Group A) has an advantage in treating open distal tibia fractures. Shorter hospitalisation times, reduced re-operation rates, and fewer complications will benefit patients, healthcare systems, and budget allocation. Group A's functional recovery results demonstrate the locking plate technique's ability to improve recovery and patient quality of life. According to the cost analysis, the locking plate technique's economic viability and cost-effectiveness may optimise healthcare resources for open distal tibia fractures. These findings might improve patient outcomes and inform evidence-based orthopaedic surgery.