Category: Nevin Manimala

Pediatr Blood Cancer. 2024 May 16:e31053. doi: 10.1002/pbc.31053. Online ahead of print.

ABSTRACT

BACKGROUND: Monomorphic post-transplant lymphoproliferative disorder (mPTLD) is a major cause of morbidity/mortality following solid organ transplant (SOT), with infection, mPTLD progression and organ rejection presenting equal risks. Balancing these risks is challenging, and the intensity of therapy required by individual patients is not defined. Although an increasing body of evidence supports the use of a stepwise escalation of therapy through reduction in immunosuppression (RIS) to rituximab monotherapy and low-dose chemo-immunotherapy, many centres still use B-cell non-Hodgkin lymphoma (B-NHL) protocols, especially when managing Burkitt/Burkitt-like (BL) PTLD. This study sought to define outcomes for children managed in the UK or Spanish centres using low-intensity first-line treatments.

PROCEDURE: Retrospective data were anonymously collected on patients younger than 18 years of age, with post-SOT mPTLD diagnosed between 2000 and 2020. Only patients given low-intensity treatment at initial diagnosis were included.

RESULTS: Fifty-six patients were identified. Age range was 0.9-18 years (median 10.7). Most (62.5%) had early-onset PTLD. Haematopathological analysis showed 75% were diffuse large B-cell like, 14.3% were BL and nine of 33 (27%) harboured a MYC-rearrangement. Stage III-IV disease was present in 78.6%. All but one had RIS, 26 received rituximab monotherapy and 24 low-dose chemo-immunotherapy, mostly R-COP. Intensified B-NHL chemotherapy was required in 10/56 (17.9%). There were a total of 13 deaths in this cohort, three related to PTLD progression. The 1-year overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were 92.8%, 78.6% and 80.2%, respectively.

CONCLUSIONS: R-COP provides an effective low-dose chemotherapy option. Escalation to more intensive therapies in the minority of inadequately controlled patients is an effective strategy.

PMID:38757407 | DOI:10.1002/pbc.31053

Protein Sci. 2024 Jun;33(6):e5028. doi: 10.1002/pro.5028.

ABSTRACT

Prolyl-tRNA synthetase (ProRS), belonging to the family of aminoacyl-tRNA synthetases responsible for pairing specific amino acids with their respective tRNAs, is categorized into two distinct types: the eukaryote/archaeon-like type (E-type) and the prokaryote-like type (P-type). Notably, these types are specific to their corresponding cognate tRNAs. In an intriguing paradox, Thermus thermophilus ProRS (TtProRS) aligns with the E-type ProRS but selectively charges the P-type tRNA^Pro, featuring the bacterium-specific acceptor-stem elements G72 and A73. This investigation reveals TtProRS’s notable resilience to the inhibitor halofuginone, a synthetic derivative of febrifugine emulating Pro-A76, resembling the characteristics of the P-type ProRS. Furthermore, akin to the P-type ProRS, TtProRS identifies its cognate tRNA through recognition of the acceptor-stem elements G72/A73, along with the anticodon elements G35/G36. However, in contrast to the P-type ProRS, which relies on a strictly conserved R residue within the bacterium-like motif 2 loop for recognizing G72/A73, TtProRS achieves this through a non-conserved sequence, RTR, within the otherwise non-interacting eukaryote-like motif 2 loop. This investigation sheds light on the adaptive capacity of a typically conserved housekeeping enzyme to accommodate a novel substrate.

PMID:38757396 | DOI:10.1002/pro.5028

J Res Adolesc. 2024 May 16. doi: 10.1111/jora.12943. Online ahead of print.

ABSTRACT

This study examines the degree to which two middle childhood executive control aspects, working memory and combined inhibitory control/flexible shifting, predict adolescent substance use and externalizing and internalizing problems. Participants were 301 children (ages 3-6 years; 48.2% male) recruited from a Midwestern city in the United States and followed into adolescence (ages 14-18 years). Working memory had a statistically significant unadjusted association with externalizing problems (r = -.30, p = .003) in a confirmatory factor analysis. Neither factor significantly predicted any of the adolescent outcomes in a structural equation model that adjusted for each EC aspect, sociodemographic covariates, and middle childhood externalizing and internalizing problems. Stronger prediction of EC aspects might not emerge until they become more fully differentiated later in development.

PMID:38757393 | DOI:10.1111/jora.12943

Trop Med Int Health. 2024 May 16. doi: 10.1111/tmi.14001. Online ahead of print.

ABSTRACT

OBJECTIVES: Although the link between poverty and tuberculosis (TB) is widely recognised, limited studies have investigated the association between neighbourhood factors and TB incidence. Since the factors influencing different episodes of TB might be different, this study focused on the first episode of TB disease (first-episode TB).

METHODS: All first episodes in previously linked and geocoded TB notification data from 2007 to 2015 in Cape Town, South Africa, were aggregated at the neighbourhood level and merged with the 2011 census data. We conducted an ecological study to assess the association between neighbourhood incidence of first-episode TB and neighbourhood factors (total TB burden [all episodes] in the previous year, socioeconomic index, mean household size, mean age, and percentage males) using a negative binomial regression. We also examined the presence of hotspots in neighbourhood TB incidence with the Global Moran’s I statistic and assessed spatial dependency in the association between neighbourhood factors and TB incidence using a spatial lag model.

RESULTS: The study included 684 neighbourhoods with a median first-episode TB incidence rate of 114 (IQR: 0-345) per 100,000 people. We found lower neighbourhood socioeconomic index (SEI), higher neighbourhood total TB burden, lower neighbourhood mean household size, and lower neighbourhood mean age were associated with increased neighbourhood first-episode TB incidence. Our findings revealed a hotspot of first-episode TB incidence in Cape Town and evidence of spatial dependency in the association between neighbourhood factors and TB incidence.

CONCLUSION: Neighbourhood TB burden and SEI were associated with first-episode TB incidence, and there was spatial dependency in this association. Our findings can inform targeted interventions to reduce TB in high-risk neighbourhoods, thereby reducing health disparities and promoting health equity.

PMID:38757387 | DOI:10.1111/tmi.14001

Protein Sci. 2024 Jun;33(6):e4988. doi: 10.1002/pro.4988.

ABSTRACT

Identifying unknown functional properties of proteins is essential for understanding their roles in both health and disease states. The domain composition of a protein can reveal critical information in this context, as domains are structural and functional units that dictate how the protein should act at the molecular level. The expensive and time-consuming nature of wet-lab experimental approaches prompted researchers to develop computational strategies for predicting the functions of proteins. In this study, we proposed a new method called Domain2GO that infers associations between protein domains and function-defining gene ontology (GO) terms, thus redefining the problem as domain function prediction. Domain2GO uses documented protein-level GO annotations together with proteins’ domain annotations. Co-annotation patterns of domains and GO terms in the same proteins are examined using statistical resampling to obtain reliable associations. As a use-case study, we evaluated the biological relevance of examples selected from the Domain2GO-generated domain-GO term mappings via literature review. Then, we applied Domain2GO to predict unknown protein functions by propagating domain-associated GO terms to proteins annotated with these domains. For function prediction performance evaluation and comparison against other methods, we employed Critical Assessment of Function Annotation 3 (CAFA3) challenge datasets. The results demonstrated the high potential of Domain2GO, particularly for predicting molecular function and biological process terms, along with advantages such as producing interpretable results and having an exceptionally low computational cost. The approach presented here can be extended to other ontologies and biological entities to investigate unknown relationships in complex and large-scale biological data. The source code, datasets, results, and user instructions for Domain2GO are available at https://github.com/HUBioDataLab/Domain2GO. Additionally, we offer a user-friendly online tool at https://huggingface.co/spaces/HUBioDataLab/Domain2GO, which simplifies the prediction of functions of previously unannotated proteins solely using amino acid sequences.

PMID:38757367 | DOI:10.1002/pro.4988

Curr HIV Res. 2024 May 16. doi: 10.2174/011570162X313718240514042111. Online ahead of print.

ABSTRACT

BACKGROUND: HIV and syphilis are sexually transmitted infections with overlapping risk factors, potentially leading to increased HIV transmission and treatment challenges. Understanding the clinical management of syphilis co-infection among people living with HIV is crucial for public health interventions.

OBJECTIVE: This retrospective cohort study aimed to assess the prevalence of syphilis co-infection, clinical characteristics, treatment response, and public health implications among people living with HIV in southern Turkey.

METHODS: Records of 1352 people living with HIV 18 years and older, followed at a tertiary infectious diseases clinic between 2013 and 2023, were analyzed. Data on demographics, clinical stage of syphilis and HIV/AIDS, laboratory parameters, treatment response, and co-infections were collected. Statistical analyses were performed using SPSS 20.0 software.

RESULTS: Among the people living with HIV, 103 (7.6%) were diagnosed with syphilis. Most cases were male (97.1%), with a median age of 33 (IQR 28-49) years. Heterosexual transmission was predominant (60.2%), with a history of condomless sexual intercourse in 90.3% of cases. The majority (88.3%) were asymptomatic with latent syphilis. Syphilis was diagnosed concurrently with HIV in 77.7% of cases. Serological response to syphilis treatment was observed in 46.8% of patients, while 53.2% showed a serofast reaction. Neurosyphilis was rare, diagnosed in only one patient. Co-infections with hepatitis B and C were detected in 3.9% and 1.9% of patients, respectively.

CONCLUSION: Syphilis co-infection among people living with HIV is a significant public health concern in southern Turkey. Routine screening for syphilis, along with comprehensive education on sexually transmitted infection prevention, is essential for early detection and optimal management. Further research is needed to improve treatment outcomes and address emerging challenges in HIV-syphilis co-infection management.

PMID:38757313 | DOI:10.2174/011570162X313718240514042111

Clin Exp Rheumatol. 2024 May 1. doi: 10.55563/clinexprheumatol/ne4k8y. Online ahead of print.

ABSTRACT

OBJECTIVES: To examine the value of a novel high-resolution thermographic marker in the detection of joint inflammation compared to joint ultrasound (US) and to suggest thermographic cut-off values of joint inflammatory activity.

METHODS: Infrared thermographies were performed in patients with inflammatory arthritides and healthy controls. Patients were moreover examined clinically and by joint-US [Power-Doppler-(PDUS), Greyscale-US (GSUS)]. Regions of interest (ROIs) were defined for every joint and absolute temperature values within the ROIs were documented. The hottest areas (“hotspots”) were identified by a clustering algorithm and the Hotspot/ROI-Ratio (HRR)-values were calculated. Subsequently, the HRR of patient-joints with different grades of hypervascularity (PDUS I°-III°) were compared among each other and with PDUS 0° control-joints. Diagnostic HRR-performance was tested by receiver-operating-characteristics.

RESULTS: 360 joints of 75 arthritis-patients and 1,808 joints of 70 controls were thermographically examined. HRR-values were statistically different between PDUS I-III vs. PDUS 0 and vs. healthy subjects for all four joint groups as well as in the majority of cases between patient-joints with different grades of hypervascularity (PDUS I°-III°; p<0.05). Taking joint-US as a reference, the best performance of HRR was found at the level of the wrist-joints by an area under the curve (AUC) of 0.91 (95%CI 0.84-0.98) with a sensitivity of 0.83 and specificity of 0.88.

CONCLUSIONS: HRR showed an excellent performance in the differentiation of joints with US inflammatory activity from non-inflamed joints. Moreover, HRR was able to differentiate between joints with different grades of hypervascularity, making HRR a promising tool to assist disease activity monitoring.

PMID:38757297 | DOI:10.55563/clinexprheumatol/ne4k8y

Clin Exp Rheumatol. 2024 May 1. doi: 10.55563/clinexprheumatol/n0kjax. Online ahead of print.

ABSTRACT

OBJECTIVES: To describe use and treatment persistence for Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) by line of therapy, and the mechanism of action for the drug switched to after JAKi discontinuation.

METHODS: This was a retrospective, observational analysis using the OPAL dataset, a large collection of deidentified electronic medical records from 112 rheumatologists around Australia. Adult patients with RA were included if they initiated tofacitinib (TOF), baricitinib (BARI) or upadacitinib (UPA) between 1 October 2015 and 30 September 2021. Data were summarised using descriptive statistics. Kaplan-Meier survival was used to analyse treatment persistence.

RESULTS: 5,900 patients initiated JAKi within the study window (TOF n=3,662, BARI n=1,875, UPA n=1,814). Median persistence was similar across JAKi within each line of therapy where there was sufficient follow-up, and almost 3 years for first-line: 34.9 months (95% CI 30.8, 40.7; n=1,408) for TOF, 33.6 months (95% CI 25.7, not reached; n=545) for BARI. While JAKi to JAKi switching occurred across all lines of therapy, switches to a tumour necrosis factor inhibitor (TNFi) were more frequent after first- or second-line JAKi. JAKi monotherapy use at baseline increased with line of therapy, and was highest at follow-up after switching to another JAKi. ‘Lack of efficacy’ was the most common reason for discontinuing JAKi.

CONCLUSIONS: In this large analysis of Australian real-world practice separated by line of therapy, treatment persistence for JAKi was high overall subject to differential follow-up, but declined in later lines. JAKi to JAKi switching was observed across all lines of therapy.

PMID:38757292 | DOI:10.55563/clinexprheumatol/n0kjax

Euro Surveill. 2024 May;29(20). doi: 10.2807/1560-7917.ES.2024.29.20.2400242.

ABSTRACT

At the end of 2022 and most notably during the first half of 2023, the number of invasive group A streptococcus (iGAS) notifications increased in Norway, largely affecting children younger than 10 years, as observed in several other countries. Following this atypical season, a new surge in the number of iGAS notifications began in December 2023 and peaked between January and February 2024, now particularly affecting both children younger than 10 years and older adults (70 years and above).

PMID:38757285 | DOI:10.2807/1560-7917.ES.2024.29.20.2400242

Clin Exp Rheumatol. 2024 May 17. doi: 10.55563/clinexprheumatol/icoqy3. Online ahead of print.

ABSTRACT

OBJECTIVES: This study explores the clinical characteristics associated with the occurrence of acute anterior uveitis (AAU) in patients with axial spondyloarthritis (axSpA) within a large, multicentre database.

METHODS: This observational, cross-sectional study of patients with axSpA used data from the Chinese Spondyloarthritis Registry between August 1, 2018, and March 31, 2020. The demographic and clinical features of patients with and without AAU were compared. Univariate and multivariate analyses were performed to determine the association between variables and uveitis.

RESULTS: A total of 4304 patients were included in this study. The prevalence of AAU in patients with axSpA was 10.59%. Multivariate logistic regression analysis revealed a positive correlation between AAU and age at diagnosis (odds ratio [OR], 1.026; p<0.001), disease duration (OR, 2.117; p<0.001), current or past Achilles tendinitis (OR, 1.692; p<0.001), current or past dactylitis (OR, 1.687; p=0.002), current or past psoriasis (OR, 3.932; p<0.001), presence of human leukocyte antigen-B27 (HLA-B27) (OR, 2.787; p<0.001), and a good response to non-steroidal anti-inflammatory drugs (NSAIDs) (OR, 1.343; p=0.027).

CONCLUSIONS: AAU was the most common extra-articular manifestation in the Chinese Spondyloarthritis Registry. In Chinese patients with axSpA, older age at diagnosis, longer disease duration, presence of HLA-B27, current or past Achilles tendinitis, current or past dactylitis, current or past psoriasis, and a good response to NSAIDs were positively associated with AAU.

PMID:38757280 | DOI:10.55563/clinexprheumatol/icoqy3