Enhancing long-term survival prediction with two short-term events: Landmarking with a flexible varying coefficient model.

Patients with cardiovascular diseases who experience disease-related short-term events, such as hospitalizations, often exhibit diverse long-term survival outcomes compared to others. In this study, we aim to improve the prediction of long-term survival probability by incorporating two short-term events using a flexible varying coefficient landmark model. Our objective is to predict the long-term survival among patients who survived up to a pre-specified landmark time since the initial admission. Inverse probability weighting estimation equations are formed based on the information of the short-term outcomes before the landmark time. The kernel smoothing method with the use of cross-validation for bandwidth selection is employed to estimate the time-varying coefficients. The predictive performance of the proposed model is evaluated and compared using predictive measures: area under the receiver operating characteristic curve and Brier score. Simulation studies confirm that parameters under the landmark models can be estimated accurately and the predictive performance of the proposed method consistently outperforms existing methods that either do not incorporate or only partially incorporate information from two short-term events. We demonstrate the practical application of our model using a community-based cohort from the Atherosclerosis Risk in Communities (ARIC) study.

Metabolomic profiles in Jamaican children with and without autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a wide range of behavioral and cognitive impairments. While genetic and environmental factors are known to contribute to its etiology, the underlying metabolic perturbations associated with ASD which can potentially connect genetic and environmental factors, remain poorly understood. Therefore, we conducted a metabolomic case-control study and performed a comprehensive analysis to identify significant alterations in metabolite profiles between children with ASD and typically developing (TD) controls. Objective: To elucidate potential metabolomic signatures associated with ASD in children and identify specific metabolites that may serve as biomarkers for the disorder. Methods: We conducted metabolomic profiling on plasma samples from participants in the second phase of Epidemiological Research on Autism in Jamaica (ERAJ-2), which was a 1:1 age (±6 months)-and sex-matched cohort of 200 children with ASD and 200 TD controls (2-8 years old). Using high-throughput liquid chromatography-mass spectrometry techniques, we performed a targeted metabolite analysis, encompassing amino acids, lipids, carbohydrates, and other key metabolic compounds. After quality control and imputation of missing values, we performed univariable and multivariable analysis using normalized metabolites while adjusting for covariates, age, sex, socioeconomic status, and child's parish of birth. Results: Our findings revealed unique metabolic patterns in children with ASD for four metabolites compared to TD controls. Notably, three of these metabolites were fatty acids, including myristoleic acid, eicosatetraenoic acid, and octadecenoic acid. Additionally, the amino acid sarcosine exhibited a significant association with ASD. Conclusions: These findings highlight the role of metabolites in the etiology of ASD and suggest opportunities for the development of targeted interventions.

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Targeting Efficient Features of Urate Oxidase to Increase Its Solubility.

With the demand for mass production of protein drugs, solubility has become a serious issue. Extrinsic and intrinsic factors both affect this property. A homotetrameric cofactor-free urate oxidase (UOX) is not sufficiently soluble. To engineer UOX for optimum solubility, it is important to identify the most effective factor that influences solubility. The most effective feature to target for protein engineering was determined by measuring various solubility-related factors of UOX. A large library of homologous sequences was obtained from the databases. The data was reduced to six enzymes from different organisms. On the basis of various sequence- and structure-derived elements, the most and the least soluble enzymes were defined. To determine the best protein engineering target for modification, features of the most and least soluble enzymes were compared. Metabacillus fastidiosus UOX was the most soluble enzyme, while Agrobacterium globiformis UOX was the least soluble. According to the comparison-constant method, positive surface patches caused by arginine residue distribution are appropriate targets for modification. Two Arg to Ala mutations were introduced to the least soluble enzyme to test this hypothesis. These mutations significantly enhanced the mutant's solubility. While different algorithms produced conflicting results, it was difficult to determine which proteins were most and least soluble. Solubility prediction requires multiple algorithms based on these controversies. Protein surfaces should be investigated regionally rather than globally, and both sequence and structural data should be considered. Several other biotechnological products could be engineered using the data reduction and comparison-constant methods used in this study.

Regression analysis of multivariate recurrent event data allowing time-varying dependence with application to stroke registry data.

In multivariate recurrent event data, each patient may repeatedly experience more than one type of event. Analysis of such data gets further complicated by the time-varying dependence structure among different types of recurrent events. The available literature regarding the joint modeling of multivariate recurrent events assumes a constant dependency over time, which is strict and often violated in practice. To close the knowledge gap, we propose a class of flexible shared random effects models for multivariate recurrent event data that allow for time-varying dependence to adequately capture complex correlation structures among different types of recurrent events. We developed an expectation-maximization algorithm for stable and efficient model fitting. Extensive simulation studies demonstrated that the estimators of the proposed approach have satisfactory finite sample performance. We applied the proposed model and the estimating method to data from a cohort of stroke patients identified in the University of Texas Houston Stroke Registry and evaluated the effects of risk factors and the dependence structure of different types of post-stroke readmission events.

Factors associated with blood mercury concentrations and their interactions with three glutathione S-transferase genes (GSTT1, GSTM1, and GSTP1): an exposure assessment study of typically developing Jamaican children.

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms. METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general linear models (GLMs). RESULTS: We identified the child's age, consumption of saltwater fish, canned fish (sardine, mackerel), string beans, grain, and starches (pasta, macaroni, noodles) as the environmental factors significantly associated with BHgCs (all P < 0.05). A significant interaction between consumption of canned fish (sardine, mackerel) and GSTP1 in relation to BHgC using either a co-dominant or recessive genetic model (overall interaction P = 0.01 and P < 0.01, respectively) indicated that consumption of canned fish (sardine, mackerel) was significantly associated with higher mean BHgC only among children with the GSTP1 Ile105Val, Ile/Ile [Ratio of mean Hg (95% CI) = 1.59 (1.09, 2.32), P = 0.02] and Ile/Val [Ratio of mean Hg (95% CI) = 1.46 (1.12, 1.91), P = 0.01] genotypes. CONCLUSIONS: Since this is the first study from Jamaica to report these findings, replication in other populations is recommended.

Major Stressful Life Events and the Risk of Pancreatic, Head and Neck Cancers: A Case-Control Study.

BACKGROUND: Major stressful life events have been shown to be associated with an increased risk of lung cancer, breast cancer and the development of various chronic illnesses. The stress response generated by our body results in a variety of physiological and metabolic changes which can affect the immune system and have been shown to be associated with tumor progression. In this study, we aim to determine if major stressful life events are associated with the incidence of head and neck or pancreatic cancer (HNPC). METHODS: This is a matched case-control study. Cases (CAs) were HNPC patients diagnosed within the previous 12 months. Controls (COs) were patients without a prior history of malignancy. Basic demographic data information on major stressful life events was collected using the modified Holmes-Rahe stress scale. A total sample of 280 was needed (79 cases, 201 controls) to achieve at least 80% power to detect odds ratios (ORs) of 2.00 or higher at the 5% level of significance. RESULTS: From 1 January 2018 to 31 August 2021, 280 patients were enrolled (CA = 79, CO = 201) in this study. In a multivariable logistic regression analysis after controlling for potential confounding variables (including sex, age, race, education, marital status, smoking history), there was no difference between the lifetime prevalence of major stressful event in cases and controls. However, patients with HNPC were significantly more likely to report a major stressful life event within the preceding 5 years when compared to COs (p = 0.01, OR = 2.32, 95% CI, 1.18-4.54). CONCLUSIONS: Patients with head, neck and pancreatic cancers are significantly associated with having a major stressful life event within 5 years of their diagnosis. This study highlights the potential need to recognize stressful life events as risk factors for developing malignancies.

Multimorbidity phenotypes in ankylosing spondylitis and their association with disease activity and functional impairment: Data from the prospective study of outcomes in ankylosing spondylitis cohort.

OBJECTIVES: To examine the association of multimorbidity phenotypes at baseline with disease activity and functional status over time in ankylosing spondylitis (AS). METHODS: Patient-reported AS morbidities (comorbidities, N = 28 and extra-musculoskeletal manifestations, EMMs, N = 3) within 3 years of enrollment with a prevalence ≥1 %, were included from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) cohort. We defined multimorbidity as ≥2 morbidities (MM2+) and substantial multimorbidity as ≥5 morbidities (MM5+). Multimorbidity clusters or phenotypes were identified using K-median clustering. Disease activity (ASDAS-CRP) and functional status (BASFI) measures were collected every 6 months. Generalized estimating equation method was used to examine the associations of multimorbidity counts and multimorbidity clusters with measures of disease activity and functional status over time. RESULTS: Among 1,270 AS patients (9,885 visits) with a median follow-up of 2.9 years (IQ range: 1.0-6.8 years), the prevalence of MM2+ and MM5+ was 49 % and 9 % respectively. We identified five multimorbidity clusters: depression (n = 321, 25 %), hypertension (n = 284, 22 %), uveitis (n = 274, 22 %), no morbidities (n = 238, 19 %), and miscellaneous (n = 153, 12 %). Patients in the depression cluster were more likely to be female and had significantly more morbidities and worse disease activity and functional status compared to those with no morbidities. CONCLUSION: Approximately 49 % of AS patients in the PSOAS cohort had multimorbidity and five distinct multimorbidity phenotypes were identified. In addition to the number of morbidities, the type of morbidity appears to be important to longitudinal outcomes in AS. The depression cluster was associated with worse disease activity and function.

In Silico Design and Evaluation of a Novel Therapeutic Agent Against the Spike Protein as a Novel Treatment Strategy for COVID-19 Treatment.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that is associated with severe damage to other human organs. It causes by a novel coronavirus, and it is spreading all over the world. To date, there is some approved vaccine or therapeutic agent which could be effective against this disease. But their effectiveness against mutated strains is not studied completely. The spike glycoprotein on the surface of the coronaviruses gives the virus the ability to bind to host cell receptors and enter cells. Inhibition of attachment of these spikes can lead to virus neutralization by inhibiting viral entrance. AIMS: In this study, we tried to use the virus entrance strategy against itself by utilizing virus receptor (ACE-2) in order to design an engineered protein consisting of a human Fc antibody fragment and a part of ACE-2, which reacts with virus RBD, and we also evaluated this interaction by computational methods and in silico methods. Subsequently, we have designed a new protein structure to bind with this site and inhibit the virus from attaching to its cell receptor, mechanically or chemically. METHODS: Various in silico software, bioinformatics, and patent databases were used to retrieve the requested gene and protein sequences. The physicochemical properties and possibility of allergenicity were also examined. Three-dimensional structure prediction and molecular docking were also performed to develop the most suitable therapeutic protein. RESULTS: The designed protein consisted of a total of 256 amino acids with a molecular weight of 28984.62 and 5.92 as a theoretical isoelectric point. Instability and aliphatic index and grand average of hydropathicity are 49.99, 69.57 and -0.594, respectively. CONCLUSIONS: In silico studies can provide a good opportunity to study viral proteins and new drugs or compounds since they do not need direct exposure to infectious agents or equipped laboratories. The suggested therapeutic agent should be further characterized in vitro and in vivo.

Dissemination of the Acinetobacter baumannii isolates belonging to global clone 2 containing AbGRI resistance islands in a referral hospital.

Acinetobacter baumannii strains belonging to global clone 2 (GC2) contain resistance islands (AbGRIs), which are composed of genes conferring resistance to older and newer antibiotics. Here, to locate these genes in AbGRIs, the GC2 strains from Tehran, Iran were examined. Among the 170 A. baumannii, 90 isolates were identified as GC2. Of the genes that confer resistance to older antibiotics, tetA(B), tetR(B) (tetracyclines), strA, and strB (aminoglycosides) were located in AbGRI1 of 65 GC2 isolates (72.2%). Of the other aminoglycosides, the aphA1b was located in AbGRI2-12b (63.6%), AbGRI2-12a (21.2%), or AbGRI2-1 (15.1%). The aacC1 and aadA1 genes were co-located within AbGRI2-1 (5.5%). The armA was located in AbGRI3-4 (77.7%) and AbGRI3ABI221 (22.2%). Of sulfonamides, the sul1 was located within AbGRI2-1 (5.5%). Of beta-lactams, the blaTEM was located in AbGRI2-12b (42%), AbGRI2-12a (14%), AbGRI2-1 (10%), or AbGRI2ABI257 (34%). The oxa23 gene conferring resistance to newer antibiotics (carbapenems) was located in AbaR4 (81.1%); of them, the AbaR4 was located within AbGRI1 in 45.2% of the isolates. This study showed that the GC2 isolates, which contained at least one AbGRI, disseminate in the hospital. Hence, it is likely that the AbGRIs play a significant role in conferring resistance to older and newer antibiotics in GC2 isolates from Iran. IMPORTANCE The majority of Acinetobacter baumannii isolates that are resistant to multiple antibiotics belong to one of the two major global clones, namely global clone 1 (GC1) and global clone 2 (GC2). The resistance islands, which contain variable assortments of transposons, integrons, and specific resistance genes, have been characterized in the genome of these GCs. In GC2 A. baumannii, the chromosomally located A. baumannii genomic resistance islands (AbGRIs) carry the genes conferring resistance to older and newer antibiotics. In this context, we tested whether GC2 isolates collected from a referral hospital carry the AbGRIs containing these genes. This study provided evidence for the circulation of the GC2 A. baumannii strains harboring AbGRI resistance islands between different wards of a referral hospital.

Prevalence and epidemiological investigation of mgrB-dependent colistin resistance in extensively drug resistant Klebsiella pneumoniae in Iran.

Carbapenemases-producing K. pneumoniae are challenging antimicrobial therapy of hospitalised patients, which is further complicated by colistin resistance. The aim of this study was to investigate the molecular epidemiological insights into carbapenemases-producing and colistin-resistant clinical K. pneumoniaeA total of 162 colistin resistant clinical strains of K. pneumoniae were collected during 2017-2019. Antimicrobial susceptibility and the colistin minimum inhibitory concentration were determined. Using PCR assay, the prevalence of resistance-associated genes including blaKPC, blaIMP, blaVIM, blaOXA-48, blaNDM-1 and mcr-1 to -9 was examined. Additionally, a PCR assay was used to examine the mgrB gene in colistin-resistant bacteria. 94.4% of the tested strains were resistant to imipenem and 96.3% were resistant to meropenem. Colistin resistance (MIC > 4 µg/L) was observed in 161 isolates (99.4%) by Colistin Broth Disk Elution method. The KPC enzyme was the most common carbapenemase and was identified in 95 strains (58.6%), followed by the IMP, VIM and OXA-48 detected in 47 (29%), 23 (14.2%) and 12 (7.4%) isolates, respectively. However, no NDM-1 gene was detected. Additionally, none of the studied isolates harbored mcr variants, while mgrB gene was observed in 152 (92.6%) isolates. Colistin resistance of K. pneumoniae isolates may be associated with mgrB gene mutation. To stop the spread of resistant K. pneumoniae, surveillance must be improved, infection prevention protocols must be followed, and antibiotic stewardship must be practised.

Mobile genetic elements carrying aminoglycoside resistance genes in Acinetobacter baumannii isolates belonging to global clone 2.

Aminoglycosides are used to treat infections caused by carbapenem-resistant Acinetobacter baumannii (CRAB) strains. However, resistance to aminoglycosides has increased remarkably in the last few years. Here, we aimed to determine the mobile genetic elements (MGEs) associated with resistance to aminoglycosides in the global clone 2 (GC2) A. baumannii. Among the 315 A. baumannii isolates, 97 isolates were identified as GC2, and 52 of GC2 isolates (53.6%) were resistant to all the aminoglycosides tested. The AbGRI3s carrying armA were detected in 88 GC2 isolates (90.7%), and of them, 17 isolates (19.3%) carried a new variant of AbGRI3 (AbGRI3ABI221). aphA6 was located in TnaphA6 of 30 isolates out of 55 aphA6-harboring isolates, and 20 isolates were found to harbor TnaphA6 on a RepAci6 plasmid. Tn6020 carrying aphA1b was detected in 51 isolates (52.5%), which was located within AbGRI2 resistance islands. The pRAY* carrying the aadB gene was detected in 43 isolates (44.3%), and no isolate was found to contain a class 1 integron harboring this gene. The GC2 A. baumannii isolates contained at least one MGE carrying the aminoglycoside resistance gene, located mostly either in the chromosome within AbGRIs or on the plasmids. Thus, it is likely that these MGEs play a role in the dissemination of aminoglycoside resistance genes in GC2 isolates from Iran.

Vasculitis presenting as carpal tunnel syndrome: a case report.

BACKGROUND: Carpal tunnel syndrome is the most common focal mononeuropathy which presents with pain in the wrist and hand, paresthesia, loss of sensation in the distribution of the median nerve, and in more severe cases, weakness and atrophy of the thenar muscles. Meanwhile, carpal tunnel syndrome can present as an initial manifestation of underlying systemic vasculitis disorder and result in severe physical disabilities. CASE PRESENTATION: A 27-year-old Iranian man was referred to our electrodiagnosis center with a clinical diagnosis of carpal tunnel syndrome in April 2020. Surgical intervention had been taken into account for him because of unsuccessful conservative therapies. On admission, thenar eminence was reduced. Electrodiagnostic findings were not compatible with median nerve entrapment at the wrist. All sensory modalities in the distribution of the right median nerve were decreased. Additionally, a mild increase in erythrocyte sedimentation rate was noted in laboratory tests. Because of the high vasculitis suspicion, we recommended the nerve biopsy and/or starting a high-dose corticosteroid. However, the surgery release was performed. After 6 months, the patient was referred for progressive weakness and numbness in the upper and lower limbs. After documentation of vasculitis neuropathy by biopsy, a diagnosis of non-systemic vasculitic neuropathy was confirmed. A rehabilitation program started immediately. Rehabilitation led to gradual improvement and recovery of function and muscle strength, and no complications remained, except mild leg paralysis. CONCLUSIONS: Physicians should be suspicious of the median nerve vasculitis mononeuropathy in a patient with carpal tunnel syndrome-like symptoms. Median nerve vasculitis mononeuropathy as an initial presenting feature of vasculitis neuropathy can further result in severe physical impairments and disabilities.

A Statistical Perspective on Microsolvation.

The lack of a procedure to determine equilibrium thermodynamic properties of a small system interacting with a bath is frequently seen as a weakness of conventional statistical mechanics. A typical example for such a small system is a solute surrounded by an explicit solvation shell. One way to approach this problem is to enclose the small system of interest in a large bath of explicit solvent molecules, considerably larger than the system itself. The explicit inclusion of the solvent degrees of freedom is obviously limited by the available computational resources. A potential remedy to this problem is a microsolvation approach where only a few explicit solvent molecules are considered and surrounded by an implicit solvent bath. Still, the sampling of the solvent degrees of freedom is challenging with conventional grand canonical Monte Carlo methods, since no single chemical potential for the solvent molecules can be defined in the realm of small-system thermodynamics. In this work, a statistical thermodynamic model based on the grand canonical ensemble is proposed that avoids the conventional system size limitations and accurately characterizes the properties of the system of interest subject to the thermodynamic constraints of the bath. We extend an existing microsolvation approach to a generalized multibath "microstatistical" model and show that the previously derived approaches result as a limit of our model. The framework described here is universal and we validate our method numerically for a Lennard-Jones model fluid.

Demonstration of ultrasound-mediated therapeutic delivery of fibrin-targeted pioglitazone-loaded echogenic liposomes into the arterial bed for attenuation of peri-stent restenosis.

Peri-stent restenosis following stent implantation is a major clinical problem. We have previously demonstrated that ultrasound-facilitated liposomal delivery of pioglitazone (PGN) to the arterial wall attenuated in-stent restenosis. To evaluate ultrasound mediated arterial delivery, in Yucatan miniswine, balloon inflations were performed in the carotid and subclavian arteries to simulate stent implantation and induce fibrin formation. The fibrin-binding peptide, GPRPPGGGC, was conjugated to echogenic liposomes (ELIP) containing dinitrophenyl-L-alanine-labelled pioglitazone (DNP-PGN) for targeting purposes. After pre-treating the arteries with nitroglycerine, fibrin-binding peptide-conjugated PGN-loaded ELIP (PAFb-DNP-PGN-ELIP also termed atheroglitatide) were delivered to the injured arteries via an endovascular catheter with an ultrasound core, either with or without ultrasound application (EKOSTM Endovascular System, Boston Scientific). In arteries treated with atheroglitatide, there was substantial delivery of PGN into the superficial layers (5 µm from the lumen) of the arteries with and without ultrasound, [(1951.17 relative fluorescence units (RFU) vs. 1901.17 RFU; P-value = 0.939)]. With ultrasound activation there was increased penetration of PGN into the deeper arterial layers (up to 35 µm from the lumen) [(13195.25 RFU vs. 7681.00 RFU; P-value = 0.005)]. These pre-clinical data demonstrate ultrasound mediated therapeutic vascular delivery to deeper layers of the injured arterial wall. This model has the potential to reduce peri- stent restenosis.

Why Do Some Patients Have Severe Sacroiliac Disease But No Syndesmophytes in Ankylosing Spondylitis? Data From a Nested Case-Control Study.

OBJECTIVE: Sacroiliac (SI) joint and spinal inflammation are characteristic of ankylosing spondylitis (AS), but some patients with AS have been identified who have discordant radiographic disease. We studied an AS subgroup with long-standing disease and fused SI joints. We identified factors associated with discrepant degrees of radiographic damage between the SI joints and spine. METHODS: From the Prospective Study of Outcomes in AS (PSOAS) cohort, patients with a disease duration ≥ 20 years and fused SI joints were included in a nested case-control design. Patients with and without syndesmophytes were used as cases and controls for analysis. We used classification and regression tree (CART) analysis to determine risk factors for syndesmophytes presence and reexamined the validity of the risk factors using univariable logistic regression models. RESULTS: There were 354 patients in the subgroup, 23 of whom lacked syndesmophytes. CART analysis showed females were less likely to have syndesmophytes. The next important predictor was age of symptom onset in males, with age of onset ≤ 16 years being less likely to have syndesmophytes. Univariable analysis confirmed females were less likely to have syndesmophytes (odds ratio [OR] 0.17, 95% CI 0.07-0.41). Syndesmophyte presence was associated with HLA-B27 positivity (P = 0.03) and age of symptom onset > 16 years old (OR 2.72, 95% CI 1.15-6.45). All 23 patients who lacked syndesmophytes were HLA-B27 positive. CONCLUSION: Using CART analysis and univariable modeling, women were less likely to have syndesmophytes despite advanced disease duration and SI joint disease. Patients with younger age of symptom onset were less likely to have syndesmophytes. All patients without syndesmophytes were HLA-B27 positive, indicating HLA-B27 positivity may be more associated with SI disease than spinal disease.

Impact of SNPs, off-targets, and passive permeability on efficacy of BCL6 degrading drugs assigned by virtual screening and 3D-QSAR approach.

B-cell lymphoma 6 (BCL6) regulates various genes and is reported to be overexpressed in lymphomas and other malignancies. Thus, BCL6 inhibition or its tagging for degradation would be an amenable therapeutic approach. A library of 2500 approved drugs was employed to find BCL6 inhibitory molecules via virtual screening. Moreover, the 3D core structure of 170 BCL6 inhibitors was used to build a 3D QSAR model and predict the biological activity. The SNP database was analyzed to study the impact on the destabilization of BCL6/drug interactions. Structural similarity search and molecular docking analyses were used to assess the interaction between possible off-targets and BCL6 inhibitors. The tendency of drugs for passive membrane permeability was also analyzed. Lifitegrast (DB11611) had favorable binding properties and biological activity compared to the BI-3802. Missense SNPs were located at the essential interaction sites of the BCL6. Structural similarity search resulted in five BTB-domain containing off-target proteins. BI-3802 and Lifitegrast had similar chemical behavior and binding properties against off-target candidates. More interestingly, the binding affinity of BI-3802 (against off-targets) was higher than Lifitegrast. Energetically, Lifitegrast was less favorable for passive membrane permeability. The interaction between BCL6 and BI-3802 is more prone to SNP-derived variations. On the other hand, higher nonspecific binding of BI-3802 to off-target proteins could bring about higher undesirable properties. It should also be noted that energetically less desirable passive membrane translocation of Lifitegrast would demand drug delivery vehicles. However, further empirical evaluation of Lifitegrast would unveil its true potential.

Additive or Interactive Associations of Food Allergies with Glutathione S-Transferase Genes in Relation to ASD and ASD Severity in Jamaican Children.

To investigate additive and interactive associations of food allergies with three glutathione S-transferase (GST) genes in relation to ASD and ASD severity in Jamaican children. Using data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of food allergies with polymorphisms in GST genes (GSTM1, GSTP1 and GSTT1) in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domains specific comparison scores (CSs) by fitting general linear models. Although food allergies and GST genes were not associated with ASD, ASD cases allergic to non-dairy food had higher mean ADOS-2 Restricted and Repetitive Behaviors (RRB) CS (8.8 vs. 8.0, P = 0.04). In addition, allergy to dairy was associated with higher mean RRB CS only among ASD cases with GSTT1 DD genotype (9.9 vs. 7.8, P < 0.01, interaction P = 0.01), and GSTP1 Val/Val genotype under a recessive genetic model (9.8 vs. 7.8, P = 0.02, interaction P = 0.06). Our findings are consistent with the role for GST genes in ASD and food allergies, though require replication in other populations.

Interactions between Environmental Factors and Glutathione S-Transferase (GST) Genes with Respect to Detectable Blood Aluminum Concentrations in Jamaican Children.

Aluminum (Al) is a metallic toxicant at high concentrations following natural or unnatural exposures. Dietary intake is considered as the main source of aluminum exposure in children. We used data from 366 typically developing (TD) children (ages 2−8 years) who participated as controls in an age- and sex-matched case−control study in Jamaica. We investigated additive and interactive associations among environmental factors and children's genotypes for glutathione S-transferase (GST) genes (GSTT1, GSTM1, GSTP1), in relation to having a detectable blood aluminum concentration (BAlC) of >5.0 µg/L, using multivariable logistic regression models. Findings from interactive models revealed that the odds of having a detectable BAlC was significantly higher among children who ate string beans (p ≤ 0.01), whereas about 40% lower odds of having a detectable BAlC was observed in children with higher parental education level, (p = 0.02). A significant interaction between consumption of saltwater fish and GSTP1 in relation to having a detectable BAlC using either co-dominant or dominant genetic models (overall interaction p = 0.02 for both models) indicated that consumption of saltwater fish was associated with higher odds of having a detectable BAlC only among children with the GSTP1 Ile105Val Ile/Ile genotype using either co-dominant or dominant models [OR (95% CI) = 2.73 (1.07, 6.96), p = 0.04; and OR (95% CI) = 2.74 (1.08, 6.99), p = 0.03]. Since this is the first study from Jamaica that reports such findings, replication in other populations is warranted.

Severity of Child Autistic Symptoms and Parenting Stress in Mothers of Children with Autism Spectrum Disorder in Japan and USA: Cross-Cultural Differences.

The purpose of this study was to compare the relationship between parenting stress and autistic symptom severity in the U.S. and Japan. Fifty-two U.S. and 51 Japanese mothers of children aged 2-12 with autism completed measures of parenting stress and child characteristics, including the parenting stress index (PSI), the social communication questionnaire (SCQ), and social responsiveness scale-2 (SRS-2). There was a nonlinear relationship between the child's autistic symptom severity and parenting stress in both countries. We also found some cultural differences: in the parent domain, the relationships between children's SCQ scores and PSI scores differed significantly between the U.S. and Japan. Our findings suggest that autistic severity symptom scores may reflect cross-cultural differences in parenting beliefs, views toward autism, and response styles for evaluating children's behavior. The findings also suggest that parents need support regardless of the child's autism severity, including those with mild to moderate symptoms. Expanding on this line of research and understanding cultural influences on parenting stress may help service providers and agencies offer more culturally sensitive services, parent-education courses, and intervention programs.