Nevin Manimala

Virol J. 2024 Mar 6;21(1):55. doi: 10.1186/s12985-024-02328-8.

ABSTRACT

Over the course of the COVID-19 pandemic, several SARS-CoV-2 variants have emerged that may exhibit different etiological effects such as enhanced transmissibility and infectivity. However, genetic variations that reduce virulence and deteriorate viral fitness have not yet been thoroughly investigated. The present study sought to evaluate the effects of viral genetic makeup on COVID-19 epidemiology in Pakistan, where the infectivity and mortality rate was comparatively lower than other countries during the first pandemic wave. For this purpose, we focused on the comparative analyses of 7096 amino-acid long polyprotein pp1ab. Comparative sequence analysis of 203 SARS-CoV-2 genomes, sampled from Pakistan during the first wave of the pandemic revealed 179 amino acid substitutions in pp1ab. Within this set, 38 substitutions were identified within the Nsp3 region of the pp1ab polyprotein. Structural and biophysical analysis of proteins revealed that amino acid variations within Nsp3’s macrodomains induced conformational changes and modified protein-ligand interactions, consequently diminishing the virulence and fitness of SARS-CoV-2. Additionally, the epistatic effects resulting from evolutionary substitutions in SARS-CoV-2 proteins may have unnoticed implications for reducing disease burden. In light of these findings, further characterization of such deleterious SARS-CoV-2 mutations will not only aid in identifying potential therapeutic targets but will also provide a roadmap for maintaining vigilance against the genetic variability of diverse SARS-CoV-2 strains circulating globally. Furthermore, these insights empower us to more effectively manage and respond to potential viral-based pandemic outbreaks of a similar nature in the future.

PMID:38449001 | DOI:10.1186/s12985-024-02328-8

Parasit Vectors. 2024 Mar 6;17(1):113. doi: 10.1186/s13071-024-06156-1.

ABSTRACT

BACKGROUND: This paper describes changes in the prevalence and intensity of schistosome parasite infections in a project integrating mass drug administration (MDA), water, sanitation, and hygiene (WaSH), and behavioral change interventions.

METHODS: The Geshiyaro Project comprises three intervention arms. Arm 1 is subdivided into “Arm 1 pilot” (one district) and Arm 1 (four other districts), both receiving integrated community-wide MDA with intensive WaSH interventions. Arm 2 involves 17 districts with community-wide MDA interventions, while Arm 3 serves as a control with school-based MDA interventions in three districts. A total of 150 individuals, stratified by age group, were randomly selected from each of the 45 sentinel sites. Arm sizes were 584 (Arm 1 pilot), 1636 (Arm 1), 2203 (Arm 2), and 2238 (Arm 3). Statistical tests were employed to compare infection prevalence and intensity across the different arms.

RESULTS: The prevalence of schistosome parasite infection ranged from 0% to 2.6% and from 1.7% to 25.7% across districts, employing the Kato-Katz (KK) and point-of-care circulating cathodic antigen (POC-CCA) diagnostics, respectively. The mean infection intensity level showed no marked difference between baseline and follow-up surveys when measured by KK, except in Arm 2 (t = 6.89, P < 0.0001). Infection prevalence decreased significantly in Arm 1 (t = 8.62, P < 0.0001), Arm 2 (t = 6.94, P < 0.0001), and Arm 3 (t = 8.83, P < 0.0001), but not in Arm 1 pilot (t = 1.69, P = 0.09) by POC-CCA, when trace was considered positive. The decrease was significant only in Arm 1 (t = 3.28, P = 0.0001) and Arm 2 (t = 7.62, P < 0.0001) when the trace was considered negative in POC-CCA. Arm 2 demonstrated a significant difference in difference (DID) compared to the control group, Arm 3, regardless of whether trace in POC-CCA was considered positive (DID = 3.9%, df = 8780, P = 0.025) or negative (DID = -5.2, df = 8780, P = 0.0004).

CONCLUSIONS: The prevalence of schistosomiasis was low when employing the KK diagnostic but moderate in some locations by the POC-CCA diagnostic. The infection level had decreased across all arms of the Geshiyaro study at mid-term of the 7-year project, but further efforts are needed to reduce the rate of parasite transmission based on the POC-CCA diagnostic scores.

PMID:38448997 | DOI:10.1186/s13071-024-06156-1

J Transl Med. 2024 Mar 6;22(1):244. doi: 10.1186/s12967-024-05042-9.

ABSTRACT

AIMS: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for hematological malignancies. However, viral infections, particularly EBV infection, frequently occur following allo-HSCT and can result in multi-tissue and organ damage. Due to the lack of effective antiviral drugs, these infections can even progress to post-transplant lymphoproliferative disorders (PTLD), thereby impacting the prognosis. In light of this, our objective is to develop a prediction model for EBV infection following allo-HSCT.

METHODS: A total of 466 patients who underwent haploidentical hematopoietic stem cell transplantation (haplo-HSCT) between September 2019 and December 2020 were included in this study. The patients were divided into a development cohort and a validation cohort based on the timing of their transplantation. Our aim was to develop and validate a grading scale using these cohorts to predict the risk of EBV infection within the first year after haplo-HSCT. Additionally, single-cell RNA sequencing (sc-RNAseq) data from the bone marrow of healthy donors were utilized to assess the impact of age on immune cells and viral infection.

RESULTS: In the multivariate logistic regression model, four predictors were retained: donor age, female-to-male transplant, graft MNC (mononuclear cell) dose, and CD8 dose. Based on these predictors, an EBV reactivation predicting score system was constructed. The scoring system demonstrated good calibration in both the derivation and validation cohorts, as confirmed by the Hosmer-Lemeshow test (p > 0.05). The scoring system also exhibited favorable discriminative ability, as indicated by the C statistics of 0.72 in the derivation cohort and 0.60 in the validation cohort. Furthermore, the clinical efficacy of the scoring system was evaluated using Kaplan-Meier curves based on risk ratings. The results showed significant differences in EBV reactivation rates between different risk groups, with p-values less than 0.001 in both the derivation and validation cohorts, indicating robust clinical utility. The analysis of sc-RNAseq data from the bone marrow of healthy donors revealed that older age had a profound impact on the quantity and quality of immune subsets. Functional enrichment analysis highlighted that older age was associated with a higher risk of infection. Specifically, CD8 + T cells from older individuals showed enrichment in the pathway of “viral carcinogenesis”, while older CD14 + monocytes exhibited enrichment in the pathway of “regulation of viral entry into host cell.” These findings suggest that older age may contribute to an increased susceptibility to viral infections, as evidenced by the altered immune profiles observed in the sc-RNAseq data.

CONCLUSION: Overall, these results demonstrate the development and validation of an effective scoring system for predicting EBV reactivation after haplo-HSCT, and provide insights into the impact of age on immune subsets and viral infection susceptibility based on sc-RNAseq analysis of healthy donors’ bone marrow.

PMID:38448996 | DOI:10.1186/s12967-024-05042-9

BMC Med. 2024 Mar 7;22(1):83. doi: 10.1186/s12916-024-03300-7.

ABSTRACT

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms.

METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI).

RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes.

CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

PMID:38448992 | DOI:10.1186/s12916-024-03300-7

BMC Psychol. 2024 Mar 6;12(1):126. doi: 10.1186/s40359-024-01604-0.

ABSTRACT

INTRODUCTION: As the incidence of mental disorders continues to rise, and pharmacy staff can significantly affect the willingness of patients with mental disorders to seek help; we aimed to evaluate the stigmatizing attitude of the pharmacy staff toward these patients in Iran.

METHODS: We conducted this cross-sectional study between April 2020 and December 2021 in Tehran, Iran, and included pharmacists, pharmacy technicians and pharmacy students, with the experience of working in a pharmacy for at least three months. The social distance scale (SDS) and dangerousness scale (DS) were used to measure the stigmatizing attitude of the participants. Higher scores indicated more stigmatizing attitudes.

RESULTS: We included a total of 186 participants with a mean age of 32.97 ± 9.41 years, of which 101 (54.3%) were male, and 75 (40.3%) were pharmacists, 101 (54.3%) were pharmacy technicians, and 8 (4.3%) were pharmacy students. The mean SDS score was 14.2 ± 4.13, and the mean DS score was 33.85 ± 8.92. The greatest tendency for social distance was reported for a patient with a mental disorder, ‘being the caretaker of their children for an hour or two’ and ‘marrying their children.’ The most perceived dangerousness was reported for a patient with a mental disorder ‘owning a gun.’ Positive personal history of psychopharmacological treatment was statistically correlated with lower DS (P = 0.001) and SDS (P = 0.007) scores. Positive family history of psychiatric inpatient admission was significantly correlated with higher DS (P = 0.05) and SDS (P = 0.03) scores. Higher rates of ‘received psychiatric prescriptions per month’ was associated with lower DS scores (P = 0.04).

CONCLUSION: Our participants did not have an overall positive attitude toward patients with mental disorders. Although, compared to previous studies, they held a more positive attitude. Positive personal history of psychopharmacological treatment predicted a more positive attitude and positive family history of psychiatric inpatient admission predicted a more negative attitude.

PMID:38448985 | DOI:10.1186/s40359-024-01604-0

J Orthop Surg Res. 2024 Mar 6;19(1):169. doi: 10.1186/s13018-024-04646-7.

ABSTRACT

OBJECTIVE: The objective of this study is to investigate the impact of four natural product extracts, namely, aloe-emodin, quercetin, curcumin, and tannic acid, on the in vitro bacteriostatic properties and biocompatibility of gentamicin-loaded bone cement and to establish an experimental groundwork supporting the clinical utility of antibiotic-loaded bone cements (ALBC).

METHODS: Based on the components, the bone cement samples were categorized as follows: the gentamicin combined with aloe-emodin group, the gentamicin combined with quercetin group, the gentamicin combined with curcumin group, the gentamicin combined with tannic acid group, the gentamicin group, the aloe-emodin group, the quercetin group, the curcumin group, and the tannic acid group. Using the disk diffusion test, we investigated the antibacterial properties of the bone cement material against Staphylococcus aureus (n = 4). We tested cell toxicity and proliferation using the cell counting kit-8 (CCK-8) and examined the biocompatibility of bone cement materials.

RESULTS: The combination of gentamicin with the four natural product extracts resulted in significantly larger diameters of inhibition zones compared to gentamicin alone, and the difference was statistically significant (P < 0.05). Except for the groups containing tannic acid, cells in all other groups showed good proliferation across varying time intervals without displaying significant cytotoxicity (P < 0.05).

CONCLUSION: In this study, aloe-emodin, quercetin, curcumin, and tannic acid were capable of enhancing the in vitro antibacterial performance of gentamicin-loaded bone cement against S. aureus. While the groups containing tannic acid displayed moderate cytotoxicity in in vitro cell culture, all other groups showed no discernible cytotoxic effects.

PMID:38448971 | DOI:10.1186/s13018-024-04646-7

Respir Res. 2024 Mar 6;25(1):115. doi: 10.1186/s12931-024-02722-4.

ABSTRACT

BACKGROUND: Respiratory diseases are a major health burden, and educational inequalities may influence disease prevalence. We aim to evaluate the causal link between educational attainment and respiratory disease, and to determine the mediating influence of several known modifiable risk factors.

METHODS: We conducted a two-step, two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies (GWAS) and single nucleotide polymorphisms (SNPs) as instrumental variables for educational attainment and respiratory diseases. Additionally, we performed a multivariable MR analysis to estimate the direct causal effect of each exposure variable included in the analysis on the outcome, conditional on the other exposure variables included in the model. The mediating roles of body mass index (BMI), physical activity, and smoking were also assessed.

FINDINGS: MR analyses provide evidence of genetically predicted educational attainment on the risk of FEV1 (β = 0.10, 95% CI 0.06, 0.14), FVC (β = 0.12, 95% CI 0.07, 0.16), FEV1/FVC (β = – 0.005, 95% CI – 0.05, 0.04), lung cancer (OR = 0.54, 95% CI 0.45, 0.65) and asthma (OR = 0.86, 95% CI 0.78, 0.94). Multivariable MR dicated the effect of educational attainment on FEV1 (β = 0.10, 95% CI 0.04, 0.16), FVC (β = 0.07, 95% CI 0.01, 0.12), FEV1/FVC (β = 0.07, 95% CI 0.01, 0.01), lung cancer (OR = 0.55, 95% CI 0.42, 0.71) and asthma (OR = 0.88, 95% CI 0.78, 0.99) persisted after adjusting BMI and cigarettes per day. Of the 23 potential risk factors, BMI, smoking may partially mediate the relationship between education and lung disease.

CONCLUSION: High levels of educational attainment have a potential causal protective effect on respiratory diseases. Reducing smoking and adiposity may be a target for the prevention of respiratory diseases attributable to low educational attainment.

PMID:38448970 | DOI:10.1186/s12931-024-02722-4

Trials. 2024 Mar 6;25(1):169. doi: 10.1186/s13063-024-08011-1.

ABSTRACT

BACKGROUND: Good vision highly depends on the transparency of the cornea, which is the “windscreen” of the eye. In fact, corneal blindness due to transparency loss is the second most common cause of blindness worldwide, and corneal transplantation is the main cure. Importantly, the cornea is normally avascular but can secondarily be invaded by pathological (blood and lymphatic) vessels due to severe inflammation, and the survival prognosis of a corneal graft mainly depends on the preoperative vascular condition of the recipient’s cornea. Whereas transplants placed into avascular recipient beds enjoy long-term survival rates of > 90%, survival rates significantly decrease in pathologically pre-vascularized, so-called high-risk recipients, which account for around 10% of all performed transplants in Germany and > 75% in lower and middle-income countries worldwide.

METHODS: This parallel-grouped, open-randomized, multicenter, prospective controlled exploratory investigator-initiated trial (IIT) intends to improve graft survival by preconditioning pathologically vascularized recipient corneas by (lymph)angioregressive treatment before high-risk corneal transplantation. For this purpose, corneal crosslinking (CXL) will be used, which has been shown to potently regress corneal blood and lymphatic vessels. Prior to transplantation, patients will be randomized into 2 groups: (1) CXL (intervention) or (2) no pretreatment (control). CXL will be repeated once if insufficient reduction of corneal neovascularization should be observed. All patients (both groups) will then undergo corneal transplantation. In the intervention group, remaining blood vessels will be additionally regressed using fine needle diathermy (on the day of transplantation). Afterwards, the incidence of graft rejection episodes will be evaluated for 24 months (primary endpoint). Overall graft survival, as well as regression of corneal vessels and/or recurrence, among other factors, will be analyzed (secondary endpoints).

DISCUSSION: Based on preclinical and early pilot clinical evidence, we want to test the novel concept of temporary (lymph)angioregressive pretreatment of high-risk eyes by CXL to promote subsequent corneal graft survival. So far, there is no evidence-based approach to reliably improve graft survival in the high-risk corneal transplantation setting available in clinical routine. If successful, this approach will be the first to promote graft survival in high-risk transplants. It will significantly improve vision and quality of life in patients suffering from corneal blindness.

TRIAL REGISTRATION: ClinicalTrials.gov NCT05870566. Registered on 22 May 2023.

PMID:38448965 | DOI:10.1186/s13063-024-08011-1

Diabetol Metab Syndr. 2024 Mar 6;16(1):62. doi: 10.1186/s13098-024-01289-w.

ABSTRACT

OBJECTIVES: we performed this meta- analysis to investigate the impact of insulin receptor substrate 1 (IRS1) gene rs1801278 on susceptibility to gestational diabetes mellitus (GDM).

METHODS: The pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated, and p value is used to determine statistical significance. Sensitivity analysis was performed under three models (dominant, recessive and allele model), and the pooled ORs and 95%CI were calculated. Funnel plots and Begger’s regression test were employed to test the publication bias.

RESULTS: The meta-analysis included 4777 participants (2116 cases and 2661 controls). The IRS1 rs1801278 (C/T) were not significant associated with GDM risk under the dominant and allele models, OR (95%CI) = 1.22 (0.88-1.70) and 1.24 (0.91-1.68), respectively (both p values were more than 0.05). But we also found the IRS1 rs1801278 (C/T) were significant associated with GDM risk under the recessive model, OR (95%CI) = 0.37 (0.16-0.86), p = 0.030. Our results showed that none of the studies affected the quality of the pooled OR. We also found no significant publication bias existed in this meta study for three genetic models, P_{TT + CT vs. CC} = 0.445; P_{CC+CT vs. TT}= 0.095; P_{C vs. T} = 0.697.

CONCLUSION: this meta-analysis indicated that IRS1 rs1801278 (C/T) was associated with the GDM risk under the recessive model but was not associated with the GDM risk under dominant and allele models.

PMID:38448958 | DOI:10.1186/s13098-024-01289-w

Antimicrob Resist Infect Control. 2024 Mar 6;13(1):29. doi: 10.1186/s13756-024-01385-6.

ABSTRACT

BACKGROUND: Antimicrobial stewardship programmes are needed in long-term care facilities (LTCFs) to tackle antimicrobial resistance. We aimed to identify factors associated with antibiotic use in LTCFs. Such information would be useful to guide antimicrobial stewardship programmes.

METHOD: We conducted a systematic review of studies retrieved from PubMed, Cochrane Library, Embase, APA PsycArticles, APA PsycINFO, APA PsycTherapy, ScienceDirect and Web of Science. We included quantitative studies that investigated factors associated with antibiotic use (i.e., antibiotic prescribing by health professionals, administration by LTCF staff, or use by residents). Participants were LTCF residents, their family, and/or carers. We performed a qualitative narrative synthesis of the findings.

RESULTS: Of the 7,591 screened records, we included 57 articles. Most studies used a longitudinal design (n = 34/57), investigated resident-level (n = 29/57) and/or facility-level factors (n = 32/57), and fewer prescriber-level ones (n = 8/57). Studies included two types of outcome: overall volume of antibiotic prescriptions (n = 45/57), inappropriate antibiotic prescription (n = 10/57); two included both types. Resident-level factors associated with a higher volume of antibiotic prescriptions included comorbidities (5 out of 8 studies which investigated this factor found a statistically significant association), history of infection (n = 5/6), potential signs of infection (e.g., fever, n = 4/6), positive urine culture/dipstick results (n = 3/4), indwelling urinary catheter (n = 12/14), and resident/family request for antibiotics (n = 1/1). At the facility-level, the volume of antibiotic prescriptions was positively associated with staff turnover (n = 1/1) and prevalence of after-hours medical practitioner visits (n = 1/1), and negatively associated with LTCF hiring an on-site coordinating physician (n = 1/1). At the prescriber-level, higher antibiotic prescribing was associated with high prescription rate for antibiotics in the previous year (n = 1/1).

CONCLUSIONS: Improving infection prevention and control, and diagnostic practices as part of antimicrobial stewardship programmes remain critical steps to reduce antibiotic prescribing in LTCFs. Once results confirmed by further studies, implementing institutional changes to limit staff turnover, ensure the presence of a professional accountable for the antimicrobial stewardship activities, and improve collaboration between LTCFs and external prescribers may contribute to reduce antibiotic prescribing.

PMID:38448955 | DOI:10.1186/s13756-024-01385-6