Tag: nevin manimala

BMC Med. 2023 Jul 27;21(1):274. doi: 10.1186/s12916-023-02965-w.

ABSTRACT

BACKGROUND: Persistent infection by oncogenic human papillomavirus (HPV) is necessary although not sufficient for development of cervical cancer. Behavioural, environmental, or comorbid exposures may promote or protect against malignant transformation. Randomised evidence is limited and the validity of observational studies describing these associations remains unclear.

METHODS: In this umbrella review, we searched electronic databases to identify meta-analyses of observational studies that evaluated risk or protective factors and the incidence of HPV infection, cervical intra-epithelial neoplasia (CIN), cervical cancer incidence and mortality. Following re-analysis, evidence was classified and graded based on a pre-defined set of statistical criteria. Quality was assessed with AMSTAR-2. For all associations graded as weak evidence or above, with available genetic instruments, we also performed Mendelian randomisation to examine the potential causal effect of modifiable exposures with risk of cervical cancer. The protocol for this study was registered on PROSPERO (CRD42020189995).

RESULTS: We included 171 meta-analyses of different exposure contrasts from 50 studies. Systemic immunosuppression including HIV infection (RR = 2.20 (95% CI = 1.89-2.54)) and immunosuppressive medications for inflammatory bowel disease (RR = 1.33 (95% CI = 1.27-1.39)), as well as an altered vaginal microbiome (RR = 1.59 (95% CI = 1.40-1.81)), were supported by strong and highly suggestive evidence for an association with HPV persistence, CIN or cervical cancer. Smoking, number of sexual partners and young age at first pregnancy were supported by highly suggestive evidence and confirmed by Mendelian randomisation.

CONCLUSIONS: Our main analysis supported the association of systemic (HIV infection, immunosuppressive medications) and local immunosuppression (altered vaginal microbiota) with increased risk for worse HPV and cervical disease outcomes. Mendelian randomisation confirmed the link for genetically predicted lifetime smoking index, and young age at first pregnancy with cervical cancer, highlighting also that observational evidence can hide different inherent biases. This evidence strengthens the need for more frequent HPV screening in people with immunosuppression, further investigation of the vaginal microbiome and access to sexual health services.

PMID:37501128 | DOI:10.1186/s12916-023-02965-w

BMC Geriatr. 2023 Jul 27;23(1):459. doi: 10.1186/s12877-023-04038-2.

ABSTRACT

BACKGROUND: Hip fractures are devastating injuries causing disability, dependence, and institutionalisation, yet hospital care is highly variable. This study aimed to determine hospital organisational factors associated with recovery of mobility and change in patient residence after hip fracture.

METHODS: A cohort of patients aged 60 + years in England and Wales, who sustained a hip fracture from 2016 to 2019 was examined. Patient-level Hospital Episodes Statistics, National Hip Fracture Database, and mortality records were linked to 101 factors derived from 18 hospital-level organisational metrics. After adjustment for patient case-mix, multilevel models were used to identify organisational factors associated with patient residence at discharge, and mobility and residence at 120 days after hip fracture.

RESULTS: Across 172 hospitals, 165,350 patients survived to discharge, of whom 163,230 (99%) had post-hospital discharge destination recorded. 18,323 (11%) died within 120 days. Among 147,027 survivors, 58,344 (40%) across 143 hospitals had their residence recorded, and 56,959 (39%) across 140 hospitals had their mobility recorded, at 120 days. Nineteen organisational factors independently predicted residence on hospital discharge e.g., return to original residence was 31% (95% confidence interval, CI:17-43%) more likely if the anaesthetic lead for hip fracture had time allocated in their job plan, and 8-13% more likely if hip fracture service clinical governance meetings were attended by an orthopaedic surgeon, physiotherapist or anaesthetist. Seven organisational factors independently predicted residence at 120 days. Patients returning to their pre-fracture residence was 26% (95%CI:4-42%) more likely if hospitals had a dedicated hip fracture ward, and 20% (95%CI:8-30%) more likely if treatment plans were proactively discussed with patients and families on admission. Seventeen organisational factors predicted mobility at 120 days. More patients re-attained their pre-fracture mobility in hospitals where (i) care involved an orthogeriatrician (15% [95%CI:1-28%] improvement), (ii) general anaesthesia was usually accompanied by a nerve block (7% [95%CI:1-12%], and (iii) bedside haemoglobin testing was routine in theatre recovery (13% [95%CI:6-20%]).

CONCLUSIONS: Multiple, potentially modifiable, organisational factors are associated with patient outcomes up to 120 days after a hip fracture, these factors if causal should be targeted by service improvement initiatives to reduce variability, improve hospital hip fracture care, and maximise patient independence.

PMID:37501122 | DOI:10.1186/s12877-023-04038-2

J Transl Med. 2023 Jul 27;21(1):506. doi: 10.1186/s12967-023-04374-2.

ABSTRACT

BACKGROUND: The activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate the tumor microenvironment (TME), as this harsh milieu often impairs adaptive immune responses. Oncolytic viral therapy presents an opportunity to overcome the immunosuppression in tumors by destroying tumor cells and thereby releasing antigens and immunostimulatory factors. These effects can be further amplified by the introduction of transgenes expressed by the virus.

METHODS: Lokon oncolytic adenoviruses (LOAd) belong to a platform of chimeric serotype Ad5/35 viruses that have their replication restricted to tumor cells, but the expression of transgenes is permitted in all infected cells. LOAd732 is a novel oncolytic adenovirus that expresses three essential immunostimulatory transgenes: trimerized membrane-bound CD40L, 4-1BBL and IL-2. Transgene expression was determined with flow cytometry and ELISA and the oncolytic function was evaluated with viability assays and xenograft models. The activation profiles of DCs were investigated in co-cultures with tumor cells or in an autologous antigen-specific T cell model by flow cytometry and multiplex proteomic analysis. Statistical differences were analyzed with Kruskal-Wallis test followed by Dunn’s multiple comparison test.

RESULTS: All three transgenes were expressed in infected melanoma cells and DCs and transgene expression did not impair the oncolytic activity in tumor cells. DCs were matured post LOAd732 infection and expressed a multitude of co-stimulatory molecules and pro-inflammatory cytokines crucial for T-cell responses. Furthermore, these DCs were capable of expanding and stimulating antigen-specific T cells in addition to natural killer (NK) cells. Strikingly, the addition of immunosuppressive cytokines TGF-β1 and IL-10 did not affect the ability of LOAd732-matured DCs to expand antigen-specific T cells and these cells retained an enhanced activation profile.

CONCLUSIONS: LOAd732 is a novel immunostimulatory gene therapy based on an oncolytic adenovirus that expresses three transgenes, which are essential for mediating an anti-tumor immune response by activating DCs and stimulating T and NK cells even under imunosuppressive conditions commonly present in the TME. These qualities make LOAd732 an appealing new immunotherapy approach.

PMID:37501121 | DOI:10.1186/s12967-023-04374-2

Acta Neuropathol Commun. 2023 Jul 27;11(1):124. doi: 10.1186/s40478-023-01602-0.

ABSTRACT

To date, several studies on genomic events underlying medulloblastoma (MB) biology have expanded our understanding of this tumour entity and led to its division into four groups-WNT, SHH, group 3 (G3) and group 4 (G4). However, there is little information about the relevance of pathogenic mitochondrial DNA (mtDNA) mutations and their consequences across these. In this report, we describe the case of a female patient with MB and a mitochondriopathy, followed by a study of mtDNA variants in MB groups. After being diagnosed with G4 MB, the index patient was treated in line with the HIT 2000 protocol with no indications of relapse after five years. Long-term side effects of treatment were complemented by additional neurological symptoms and elevated lactate levels ten years later, resulting in suspected mitochondrial disease. This was confirmed by identifying a mutation in the MT-TS1 gene which appeared homoplasmic in patient tissue and heteroplasmic in the patient’s mother. Motivated by this case, we explored mtDNA mutations across 444 patients from ICGC and HIT cohorts. While there was no statistically significant enrichment of mutations in one MB group, both cohorts encompassed a small group of patients harbouring potentially deleterious mtDNA variants. The case presented here highlights the possible similarities between sequelae caused by MB treatment and neurological symptoms of mitochondrial dysfunction, which may apply to patients across all MB groups. In the context of the current advances in characterising and interpreting mtDNA aberrations, recognising affected patients could enhance our future knowledge regarding the mutations’ impact on carcinogenesis and cancer treatment.

PMID:37501103 | DOI:10.1186/s40478-023-01602-0

BMC Res Notes. 2023 Jul 27;16(1):158. doi: 10.1186/s13104-023-06395-y.

ABSTRACT

OBJECTIVE: To examine the clinical efficacy of prophylactic metoclopramide in reducing the incidence of nausea and vomiting in emergency department (ED) patients with acute pain who were treated with intravenous tramadol.

RESULTS: We conducted a single-center randomized, double-blinded, placebo-controlled trial. A total of 99 ED patients presented with acute pain were recruited. Sixty-four patients were randomized, 31 patients in the treatment arm and 33 in the control arm. Overall, there were no significant differences in baseline characteristics between treatment arm and control arm. Only one patient within each arm reported having nausea symptom. No patients reported vomiting episode. There was no statistically significant difference in the proportion of patients with nausea or vomiting symptoms between the two groups (3.2% in the treatment arm vs. 3.0% in the control arm, p = 1.000). The administration of prophylactic metoclopramide may not provide additional benefit in reducing the occurrence of nausea and/or vomiting episode in ED patients with acute pain treated with intravenous tramadol. Trial registration Randomized clinical trial TCTR20220525001; registration date: 21 October 2021. Retrospectively registered.

PMID:37501098 | DOI:10.1186/s13104-023-06395-y

Chaos. 2023 Jul 1;33(7):073151. doi: 10.1063/5.0159675.

ABSTRACT

Dynamical systems that are used to model power grids, the brain, and other physical systems can exhibit coexisting stable states known as attractors. A powerful tool to understand such systems, as well as to better predict when they may “tip” from one stable state to the other, is global stability analysis. It involves identifying the initial conditions that converge to each attractor, known as the basins of attraction, measuring the relative volume of these basins in state space, and quantifying how these fractions change as a system parameter evolves. By improving existing approaches, we present a comprehensive framework that allows for global stability analysis of dynamical systems. Notably, our framework enables the analysis to be made efficiently and conveniently over a parameter range. As such, it becomes an essential tool for stability analysis of dynamical systems that goes beyond local stability analysis offered by alternative frameworks. We demonstrate the effectiveness of our approach on a variety of models, including climate, power grids, ecosystems, and more. Our framework is available as simple-to-use open-source code as part of the DynamicalSystems.jl library.

PMID:37499248 | DOI:10.1063/5.0159675

JCO Oncol Pract. 2023 Jul 27:OP2300146. doi: 10.1200/OP.23.00146. Online ahead of print.

ABSTRACT

PURPOSE: Burkitt lymphoma is an aggressive B-cell lymphoma requiring intensive therapy, which places patients at risk for severe toxicity. However, few studies have described these patients’ clinical outcomes and health care utilization, particularly among older adults.

METHODS: We conducted a retrospective analysis of adults 40 years and older with Burkitt lymphoma at Massachusetts General Hospital and Dana-Farber Cancer Institute from February 1999 to December 2020 (N = 97). We abstracted patient characteristics, clinical outcomes, and health care utilization (unplanned hospitalizations, intensive care unit [ICU] admissions) during therapy from the electronic health record. Using univariate logistic regression, we examined factors associated with rates of unplanned hospitalization and ICU admission during therapy.

RESULTS: Among evaluable patients (median age, 69 years; 23.7% female; 19.3% with bone marrow involvement), 45.8% (38 of 83) experienced unplanned hospitalization and 23.2% (19 of 82) experienced ICU admission during therapy. Among those 70 years and older, rates of unplanned hospitalization and ICU admission were 36.8% (14 of 38) and 29.0% (11 of 38), respectively. Bone marrow involvement (odds ratio [OR], 3.00; P = .069) was associated with a nonsignificantly greater likelihood of unplanned hospitalization. Older age (OR, 1.06; P = .039), Charlson comorbidity index >0 (OR, 3.14; P = .038), and hypoalbuminemia (OR, 3.22; P = .035) were associated with greater likelihood of ICU admission. Overall, 8.7% (8 of 92) of patients died during treatment, all of whom were 70 years and older.

CONCLUSION: Adults with Burkitt lymphoma experience substantial rates of unplanned hospitalizations and ICU admissions, with older adults at especially high risk for ICU admission and death during treatment. Our findings underscore the need to develop supportive care interventions for patients with Burkitt lymphoma to help improve clinical outcomes and health care utilization.

PMID:37499211 | DOI:10.1200/OP.23.00146

J Holist Nurs. 2023 Jul 27:8980101231186033. doi: 10.1177/08980101231186033. Online ahead of print.

ABSTRACT

Purpose: To evaluate the impact of an abbreviated (4-week) and asynchronous, mindfulness-based intervention (MBI) on nurses’ perceived stress and mindful attention and awareness. Design: An evidence-based quality improvement pilot program. Methods: The participants (n = 15 nurses) attended a 4-week, asynchronous MBI. The participants attended a 90-minute webinar on mindfulness as a prerequisite, followed by 4 weeks of guided meditation and informal mindfulness practice materials. The MBI was offered remotely with self-modulated practice. Participants also provided the number of days per week they participated in formal meditation practice. Project participants completed pre- and post-intervention questionnaires. Project instruments included the Mindful Attention Awareness Scale (MAAS) and the 10-item Perceived Stress Scale (PSS). Findings: 12 complete pre-and post-intervention surveys were analyzed. Significant improvements were noted in participant mean MAAS scores post-intervention (p = .004). Cumulative PSS scores also decreased post-intervention (p = .009). Conclusion: The 4-week MBI demonstrated a statistically significant impact on nurses’ perceived stress and mindful attention and awareness. Additionally, this Doctor of Nursing Practice (DNP) student led program was offered in an asynchronous and remote format, which was received well by program participants and may be a practical option for future MBIs.

PMID:37499197 | DOI:10.1177/08980101231186033

Eur J Prev Cardiol. 2023 Jul 27:zwad243. doi: 10.1093/eurjpc/zwad243. Online ahead of print.

ABSTRACT

BACKGROUND: It is unclear whether the future risk of cardiovascular events in breast cancer (BC) survivors is greater than in the general population.

OBJECTIVES: This meta-analysis quantifies the risk of cardiovascular disease development in breast cancer patients, compared to the risk in a general matched cancer-free population and reports the incidence of cardiovascular events in patients with BC.

METHODS: We searched PubMed, Scopus, and Web of Science databases (up to March 23, 2022) for observational studies and post-hoc analyses of RCTs. Cardiovascular death, heart failure (HF), atrial fibrillation (AF), coronary artery disease (CAD), myocardial infarction (MI), stroke were the individual endpoints for our meta-analysis. We pooled incidence rates (IRs) and risk in hazard ratios (HRs), using random-effects meta-analyses. Heterogeneity was reported through the I^2 statistic, and publication bias was examined using funnel plots and Egger’s test in the meta-analysis of risk.

RESULTS: 142 studies were identified in total, 26 (836,301 patients) relevant to the relative risk, and 116 (2,111,882 patients) relevant to IRs. Compared to matched cancer-free controls, BC patients had higher risk for cardiovascular death within five years of cancer diagnosis (HR = 1.09; 95% CI: 1.07, 1.11), HF within ten years (HR = 1.21; 95% CI: 1.1, 1.33), and AF within three years (HR = 1.13; 95% CI: 1.05, 1.21). The pooled IR for cardiovascular death was 1.73 (95% CI 1.18, 2.53), 4.44 (95% CI 3.33, 5.92) for HF, 4.29 (95% CI 3.09, 5.94) for CAD, 1.98 (95% CI 1.24, 3.16) for MI, 4.33 (95% CI 2.97, 6.30) for stroke of any type, and 2.64 (95% CI 2.97, 6.30) for ischemic stroke.

CONCLUSION: breast cancer exposure was associated with the increased risk for cardiovascular death, HF and AF. The pooled incidence for cardiovascular endpoints varied depending on population characteristics and endpoint studied.

PMID:37499186 | DOI:10.1093/eurjpc/zwad243

JCO Glob Oncol. 2023 Jul;9:e2200244. doi: 10.1200/GO.22.00244.

ABSTRACT

PURPOSE: Acute leukemias are associated with substantial morbidity and mortality, particularly in the adult population. Despite an increasing burden of acute leukemia in developing countries, there are limited data on clinical outcomes and prognostic factors in this setting. In this study, we aimed to describe the clinical characteristics, survival, and prognostic factors of adults with acute leukemia at the Uganda Cancer Institute (UCI).

METHODS: A retrospective cohort study was conducted between January 2009 and December 2018, reviewing data of patients 18 years or older with a cytopathologic diagnosis of acute leukemia at UCI. Data were extracted on clinical and laboratory characteristics, response to treatment, and survival. Cox-proportional hazards regression and survival analysis were performed to determine survival rates and associated factors. P < .05 was considered statistically significant.

RESULTS: In total, 233 participants were enrolled. Most (59.2%. n = 138) participants were male, with a median age of 32 years (IQR, 23-48 years), and 136 (58.4%) had AML. Overall, the 1-year survival was 16.5%, with a median survival time of 47 (IQR, 21-219) days. Predictors of mortality were being a female (adjusted hazard ratio [aHR], 2.8; 95% CI, 1.2 to 6.7; P = .022) and overweight (aHR, 4.2; 95% CI, 1.3 to 13.4; P = .015). Among the patients who had AML, the predictors were poor Eastern Cooperative Oncology Group (ECOG; aHR, 3.1; 95% CI, 1.6 to 6.2; P = .001) and HIV (aHR, 6.0; 95% CI, 1.7 to 20.5; P = .004). Among the patients who had ALL, the predictors were poor ECOG (aHR, 2.3; 95% CI, 1.3 to 4.1; P = .006).

CONCLUSION: Patients with acute leukemia in Uganda have poor overall survival. Prospective studies are recommended to better understand causes of early mortality.

PMID:37499182 | DOI:10.1200/GO.22.00244