Nevin Manimala

Epilepsia. 2022 Nov 19. doi: 10.1111/epi.17471. Online ahead of print.

ABSTRACT

OBJECTIVE: A realistic seizure diary simulator is currently unavailable for many research needs, including clinical trial analysis, and evaluation of seizure detection and seizure forecasting tools. In recent years, important statistical features of seizure diaries have been characterized. These include: (1) heterogeneity of individual seizure frequencies, (2) the relation between average seizure rate and standard deviation, (3) multiple risk cycles, (4) seizure clusters, and (5) limitations on inter-seizure intervals. The present study unifies these features into a single model.

METHODS: Our approach, Cyclic Heterogeneous Overdispersed Clustered Open-source L-relationship Adjustable Temporally limited E-diary Simulator (CHOCOLATES) is based on a hierarchical model centered on a Gamma Poisson generator with several modifiers. This model accounts for the aforementioned statistical properties. The model was validated by simulating 10,000 randomized clinical trials (RCTs) of medication to compare with 23 historical RCTs. Metrics of 50% responder rate (RR50) and median percent change (MPC) were evaluated. We also used CHOCOLATES as input to a seizure forecasting tool to test the flexibility of the model. We examined the area under the ROC curve (AUC) for test data with and without cycles and clusters.

RESULTS: The model recapitulated typical findings in 23 historical RCTs without the necessity of introducing an additional “placebo effect”. The model produced the following RR50 values: placebo: 17±4%; drug 38±5%; and the following MPC values: placebo: 13±6%; drug 40±4%. These values are similar to historical data: for RR50: placebo, 21±10%, drug: 43±13%; and for MPC: placebo: 17±10%, drug: 41±11%. The seizure forecasts achieved AUC of 0.68 with cycles and clusters, whereas without them the AUC was 0.51.

SIGNIFICANCE: CHOCOLATESrepresents the most realistic seizure occurrence simulator to date, based on observations from thousands of patients in different contexts. This tool is open-source and flexible, and can be used for many applications, including clinical trial simulation and testing of seizure forecasting tools.

PMID:36401798 | DOI:10.1111/epi.17471

Mol Diagn Ther. 2022 Nov 19. doi: 10.1007/s40291-022-00623-0. Online ahead of print.

ABSTRACT

BACKGROUND: Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies. We conducted a systematic review and meta-analysis of all the studies reporting DNA sequencing data of MBMs, in order to identify recurrently mutated genes and molecular pathways significantly enriched for genetic alterations.

METHODS: We searched PubMed, Embase and Scopus for articles published from the inception of each database to June 30, 2021. We included in the analysis all the studies that reported individual patient data on DNA sequencing of MBMs, assessing single nucleotide variants (SNVs) and/or gene copy number variations (CNVs) in at least five tumor samples. Meta-analysis was performed for genes evaluated for SNVs and/or CNVs in at least two studies. Pooled proportions of samples with SNVs and/or CNVs was calculated by applying random-effect models based on the DerSimonian-Laird method. Gene-set enrichment analysis (GSEA) was performed to identify molecular pathways significantly enriched for mutated genes.

RESULTS: Ten studies fulfilled the inclusion criteria and were included in the analysis, for a total of 531 samples of MBMs evaluated. Twenty-seven genes were found recurrently mutated with a meta-analytic rate of SNVs higher than 5%. GSEA conducted on the list of these 27 recurrently mutated genes revealed vascular endothelial growth factor-activated receptor activity and transmembrane receptor protein tyrosine kinase activity to be among the top 10 gene ontology (GO) molecular functions significantly enriched for mutated genes, while regulation of apoptosis and cell proliferation were among the top 10 significantly enriched GO biological processes. Notably, a high meta-analytic rate of SNVs was found in several actionable cancer-associated genes, such as all the vascular endothelial growth factor (VEGF) receptor isoforms (i.e., Flt1 and Flt2 genes, for both SNV rate: 0.22, 95% CI 0.04-0.49; KDR gene, SNV rate: 0.1, 95% CI 0.05-0.16). Finally, two tumor suppressor genes were characterized by a high meta-analytic rate of CNVs: CDKN2A/B (CNV rate: 0.59, 95% CI 0.23-0.90) and PTEN (CNV rate: 0.31, 95% CI 0.02-0.95).

CONCLUSION: MBMs harbored actionable molecular alterations that could be exploited as therapeutic targets to improve the poor prognosis of patients.

PMID:36401787 | DOI:10.1007/s40291-022-00623-0

Int Urol Nephrol. 2022 Nov 19. doi: 10.1007/s11255-022-03413-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Sleep disorder is a common and unpleasant symptom in patients with chronic kidney disease (CKD), bringing a heavy burden on the patients and families. As a non-pharmacological therapy, exercise interventions are widely recommended for CKD patients. However, whether exercise can improve overall sleep quality in such a population remains ambiguous. The systematic review and meta-analysis aimed to evaluate the effect of exercise interventions on sleep quality in CKD patients.

METHODS: PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from inception to April 22, 2022. A randomized controlled trial (RCT) added an exercise intervention to conventional treatment/usual care to assess the effect on sleep quality in CKD patients. Two authors independently selected literature, extracted data, assessed the risk of bias using the Cochrane risk of bias tool 2, and assessed the certainty of the evidence using the Grading of Recommendations, Assessment, Development, and Evaluation. The outcome was analyzed using a random-effect model using the Hartung-Knapp-Sidik-Jonkman method as a standardized mean difference (SMD). Additional statistical analysis includes the Egger regression test, subgroup analysis, sensitivity analysis, and meta-regression.

RESULTS: Nineteen articles (20 RCTs) enrolling 989 patients with CKD were included. The pooled SMD suggested favorably associated exercise interventions (SMD – 0.16; 95% CI – 0.62 to 0.31; very low evidence) with substantial heterogeneity (I² = 87%). Subgroup analyses demonstrated that SMD for sleep quality favored moderate intensity and aerobic exercise, no matter the time, but not statistically significant. Meta-regression showed that the effect size of exercise interventions on sleep quality was not associated with the total sample size, the proportion of males, duration of intervention, mean age, and exercise volume but was associated with baseline sleep scores. In addition, there may be an exercise threshold for the effect of exercise on sleep in CKD patients (i.e., 80 min/week).

CONCLUSION: This systematic review and meta-analysis suggest that exercise interventions may be associated with improved sleep quality in patients with CKD. However, high heterogeneity and a small effect size limit this result. More studies and standardized reporting of exercise intervention characteristics should be conducted in the future to strengthen the most convincing evidence in this field.

PMID:36401765 | DOI:10.1007/s11255-022-03413-z

Int J Clin Pharm. 2022 Nov 19. doi: 10.1007/s11096-022-01517-1. Online ahead of print.

ABSTRACT

BACKGROUND: Cardiovascular disease (CVD) is a predominant cause of mortality. Pharmacists play an important role in secondary prevention of CVD, however, their role in cardiac rehabilitation is under-reported and services are under-utilised.

AIM: To explore the role of pharmacists in cardiac rehabilitation, the impact of their interventions on patient outcomes, and prospects of future role development.

METHOD: Databases searched were PubMed, Embase, Medline, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and PsycINFO from January 2006 to October 2021. Randomised and non-randomised controlled trials were selected if they assessed the role of pharmacists in cardiac rehabilitation. Cochrane risk of bias tool, Joanna Briggs Institute (JBI) Critical Appraisal Tool for Quasi-Experimental Studies and the National Heart, Lung and Blood Institute (NIH) quality assessment tool, were used to assess quality and a narrative synthesis was conducted.

RESULTS: The search yielded 786 studies, only five met the inclusion criteria. The pharmacist-led interventions included patient education, medication review and reconciliation, and medication adherence encouragement. Four out of the five studies showed that pharmacist-led interventions in cardiac rehabilitation significantly improved patient clinical and non-clinical outcomes. One study showed a statistically significant reduction in low density lipoprotein-cholesterol (LDL-C) levels to optimal target of < 70 mg/dL (80% vs 60%, p = 0.0084). Two studies reported better medication adherence, and two studies showed greater improvement in all domains of health-related quality of life observed in the intervention group.

CONCLUSION: Pharmacist-led interventions in cardiac rehabilitation could lower CVD risk factors and hence recurrence. Although these findings support pharmacists’ involvement in cardiac rehabilitation, larger intervention studies are needed to evaluate the feasibility of pharmacist-led interventions and their impact on hospital admissions and mortality risk.

PMID:36401764 | DOI:10.1007/s11096-022-01517-1

J Endocrinol Invest. 2022 Nov 19. doi: 10.1007/s40618-022-01943-y. Online ahead of print.

ABSTRACT

INTRODUCTION: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women during reproductive age. It is characterized clinically by oligo-ovulation or anovulation, hyper-androgenism, and the presence of polycystic ovaries. Often comorbid with insulin resistance, dyslipidemia, and obesity, it also carries significant risk for the development of cardio-vascular and metabolic sequelae, including diabetes and metabolic syndrome. In light of these evidences, the most therapeutic option prescribed to PCOS women with obesity, regardless of the phenotype from the severity of clinical expression, is lifestyle correction by diet and physical activity.

PURPOSE: The aim of this study was to evaluate the association between PCOS with KD in overweight and/or obese women with PCOS, and evaluate the possible beneficial effects on metabolic and endocrine parameters, compared to a standard, balanced hypocaloric diet such as Mediterranean diet (MD).

METHODS: Participants were assigned to receive, in a 1:1 ratio, one of the two following dietary sequences: KD or MD. In all subjects anthropometric parameters, body composition and metabolic and endocrine parameters were obtained at baseline and after dietetic treatment.

RESULTS: Our results showed a significant change in the anthropometric and biochemical parameters in both groups after both diet therapies, with statistically significant differences (p < 0.001). Though, the reductions of all parameters were significantly greater in KD group than in MD group.

CONCLUSION: Our results suggest that a reduction of dietary intake of carbohydrates by KD may be considered as a valuable non-pharmacological treatment for PCOS.

PMID:36401759 | DOI:10.1007/s40618-022-01943-y

Qual Life Res. 2022 Nov 19. doi: 10.1007/s11136-022-03286-w. Online ahead of print.

ABSTRACT

PURPOSE: Treatment benefit as assessed using clinical outcome assessments (COAs), is a key endpoint in many clinical trials at both the individual and group level. Anchor-based methods can aid interpretation of COA change scores beyond statistical significance, and help derive a meaningful change threshold (MCT). However, evidence-based guidance on the selection of appropriately related anchors is lacking.

METHODS: A simulation was conducted which varied sample size, change score variability and anchor correlation strength to assess the impact of these variables on recovering the simulated MCT for interpreting individual and group-level results. To assess MCTs derived at the individual-level (i.e. responder definitions; RDs), Receiver Operating Characteristic (ROC) curves and Predictive Modelling (PM) analyses were conducted. To assess MCTs for interpreting change at the group-level, the mean change method was conducted.

RESULTS: Sample sizes, change score variability and magnitude of anchor correlation affected accuracy of the estimated MCT. For individual-level RDs, ROC curves were less accurate than PM methods at recovering the true MCT. For both methods, smaller samples led to higher variability in the returned MCT, but higher variability still using ROC. Anchors with weaker correlations with COA change scores had increased variability in the estimated MCT. An anchor correlation of around 0.50-0.60 identified a true MCT cut-point under certain conditions using ROC. However, anchor correlations as low as 0.30 were appropriate when using PM under certain conditions. For interpreting group-level results, the MCT derived using the mean change method was consistently underestimated regardless of the anchor correlation.

CONCLUSION: Sample size and change score variability influence the necessary anchor correlation strength when recovering individual-level RDs. Often, this needs to be higher than the commonly accepted threshold of 0.30. Stronger correlations than 0.30 are required when using the mean change method. Results can assist researchers selecting and assessing the quality of anchors.

PMID:36401757 | DOI:10.1007/s11136-022-03286-w

Clin Exp Med. 2022 Nov 19. doi: 10.1007/s10238-022-00946-6. Online ahead of print.

ABSTRACT

Immunotherapy is the main standard treatment for non-small cell lung cancer (NSCLC) patients. Immune suppressive cells in tumor microenvironment can counteract its efficacy. Myeloid-derived suppressor cells (MDSCs) include two major subsets: polymorphonuclear (PMN-MDSCs) and monocytic (M-MDSCs). Many studies explored the prognostic impact of these cell populations in NSCLC patients. The aim of this systematic review is to select studies for a meta-analysis, which compares prognosis between patients with high vs low circulating MDSC levels. We collected hazard ratios (HRs) and relative 95% confidence intervals (CIs) in terms of progression-free survival (PFS) or recurrence-free survival (RFS), and overall survival (OS). Among 139 studies retrieved from literature search, 14 eligible studies (905 NSCLC patients) met inclusion criteria. Low circulating MDSC levels favor a better PFS/RFS (HR = 1.84; 95% CI = 1.28-2.65) and OS (HR = 1.78; 95% CI = 1.29-2.46). The subgroup analysis based on MDSC subtypes (total-, PMN-, and M-MDSCs) obtained a statistical significance only for M-MDSCs, both in terms of PFS/RFS (HR = 2.67; 95% CI = 2.04-3.50) and OS (HR = 2.10; 95% CI = 1.61-2.75). NSCLC patients bearing high M-MDSC levels in peripheral blood experience a worse prognosis than those with low levels, both in terms of PFS/RFS and OS. This finding suggests that detecting and targeting this MDSC subset could help to improve NSCLC treatment efficacy.

PMID:36401744 | DOI:10.1007/s10238-022-00946-6

Int J Clin Oncol. 2022 Nov 19. doi: 10.1007/s10147-022-02267-w. Online ahead of print.

ABSTRACT

BACKGROUND: The risk of survivors developing a secondary bone sarcoma after being treated for pediatric cancers is well established. The aim of this study was to examine the clinical characteristics and outcomes of patients with secondary osteosarcoma (SOS).

METHODS: The study concerns survivors of childhood and adolescence primary neoplasms (PN) treated with chemotherapy, with or without radiotherapy and surgery, subsequently diagnosed with SOS.

RESULTS: We identified 26 patients (13 females, 13 males) who developed SOS a median 7.3 years after being diagnosed with a PN (5/7 of these patients tested for Li-Fraumeni and found positive for the syndrome). The sample’s median age was 8.0 and 15.0 years when their PN and SOS were diagnosed, respectively. To treat their PN, 24 out of 26 patients had been given radiotherapy, and 19 had received chemotherapy including doxorubicin. A considerable number of SOS occurred at unfavorable sites (nine hip bone, six skull). All but one patient received chemotherapy with tailored schedules, omitting doxorubicin in 19 cases. Eighteen of the 26 patients underwent surgery. The 5- and 10-year overall survival and probabilities after the diagnosis of SOS (95% confidence interval) were 50% (32.7-76.5%) and 38.9% (22.4-67.4%); 5- and 10-year progression-free survival was 47% (29.9-73.7%) and 35.2% (19.3-64.4%), respectively.

CONCLUSIONS: The survival rates after SOS are lower than in patients with primary osteosarcoma, but not negligible. It is therefore mandatory to discuss the best choice of treatment for such patients at a referral center, in terms of their chances of cure and quality of life.

PMID:36401730 | DOI:10.1007/s10147-022-02267-w

Appl Biochem Biotechnol. 2022 Nov 19. doi: 10.1007/s12010-022-04227-6. Online ahead of print.

ABSTRACT

Cervical cancer (CC), although being a potentially avoidable disease, is the second most often diagnose gynecological cancer, with at minimum 530,000 new instant reported each year, and optimism for CC remains poor. Nearly half of individuals with locally advanced cervical cancer have a poor pathological response to standard therapy. As a result, research into the molecular pathogenesis of cervical cancer and associated therapeutic targets is a must. MicroRNAs (miRNAs) are possible biomarkers in cervical cancer; elevations or reductions in many distinct miRNAs discovered in individuals with this illness indicate that miRNA could contain a function to play in the illness’s pathogenesis. Nevertheless, little is known about their significance in detecting individuals who do not respond to traditional therapy. As a consequence, the intention of this study is to look at the relationship among the synthesis of miRNAs (miR 217 and miR-140-3p), which can be utilized as molecular biomarkers to predict pathological responses in cervical cancer patients after radiation and chemotherapy. Various analytical techniques were used to analyze the data, including quantitative real-time PCR (qRT-PCR), growth and apoptosis analysis, western blot analysis, luciferase reporter gene analysis, immunohistochemistry, and statistical analysis. The results show that such miRNAs participate a crucial responsibility in CC cell proliferation inhibition. They might be a new therapeutic target for microRNA-mediated cell proliferation inhibition in cervical cancer.

PMID:36401723 | DOI:10.1007/s12010-022-04227-6

Intern Emerg Med. 2022 Nov 19. doi: 10.1007/s11739-022-03142-2. Online ahead of print.

ABSTRACT

Cardiac surgery in Jehovah’s Witnesses (JW) patients who refuse blood transfusion is challenging requiring dedicated strategies. We aimed to analyze non-selected JW patients undergoing cardiac surgery and to compare with matched controls both perioperative outcomes and long-term survival. We retrospectively analyzed JW patients undergoing cardiac surgery from January 2016 to March 2021 and compared them with matched controls. The primary outcome was a composite of in-hospital perioperative adverse events and in-hospital mortality. The secondary outcome was all-cause mortality at long-term follow-up. A total of 113 JW patients and 113 controls were included. Baseline clinical characteristics, including laboratory parameters were comparable. Overall, there were no statistical differences between JW vs controls in terms of in-hospital mortality (2.7% vs 1.8%, p = 1.00) but mortality was remarkably high (40%) in JW patients with post-op hemoglobin < 8 g/dl. Logistic regression analysis found that the JW group was not associated with a higher occurrence of the composite outcome (adjusted odds ratio 0.91, 95% confidence interval [CI] 0.54-1.57). After a median follow-up of 1397 [IQR 922.7-1723.5] days, JW patients were not associated with a significantly higher all-cause mortality (adjusted hazard ratio 0.77, 95% CI 0.24-2.42). Cardiac surgery can be safely performed in non-anemic JW patients despite the refusal of blood transfusions. Favorable clinical outcomes can be achieved by the use of specific perioperative strategies for bloodless surgery with no differences as compared to control patients except in JW patients with a very low level of post-operative hemoglobin not supported by immediate transfusions.

PMID:36401716 | DOI:10.1007/s11739-022-03142-2