Category: Nevin Manimala

Clin Transl Oncol. 2023 Sep 11. doi: 10.1007/s12094-023-03317-z. Online ahead of print.

ABSTRACT

PURPOSE: This study investigated the prognostic potential of baseline C-reactive protein (CRP) levels and early CRP kinetics in a real-world cohort of patients with metastatic renal cell carcinoma (mRCC) under first-line (1L) therapy with immune checkpoint inhibitors (CPI).

METHODS/PATIENTS: Analyses were performed retrospectively in a cohort of 61 mRCC patients under CPI-based 1L therapy. Patients were stratified based on baseline CRP (< 10 vs ≥ 10 mg/l) and CRP change within the initial three months of CPI therapy (normal: baseline < 10 mg/l, normalized: baseline ≥ 10 mg/l and nadir < 10 mg/l, non-normalized: baseline and nadir ≥ 10 mg/l). Finally, the association of baseline CRP and CRP change with progression-free (PFS) and overall survival (OS) was evaluated.

RESULTS: Baseline CRP was not significantly associated with both PFS (p = 0.666) and OS (p = 0.143). Following stratification according to early CRP kinetics, 23, 25 and 13 patients exhibited normal, normalized and non-normalized CRP levels, respectively. Patients with normal and normalized CRP had a markedly prolonged PFS (p = 0.091) and OS (p = 0.008) compared to patients with non-normalized CRP. Consequently, significantly better PFS (p = 0.031) and OS (p = 0.002) were observed for the combined normal-normalized group. In multivariate analysis including ECOG and IMDC risk, normalized CRP kinetics alone or in combination with the normal group was identified as significant independent risk factor for OS, whereas a statistical trend was observed for PFS.

CONCLUSIONS: The present study emphasizes the prognostic potential of early CRP kinetics in CPI-treated mRCC. As a standard laboratory parameter, CRP can be easily implemented into clinical routine to facilitate therapy monitoring.

PMID:37695463 | DOI:10.1007/s12094-023-03317-z

J Endocrinol Invest. 2023 Sep 11. doi: 10.1007/s40618-023-02190-5. Online ahead of print.

ABSTRACT

AIMS: SIRT1 deficiency has been associated with diabetes, and a variant of the SIRT1 gene has been found to be involved in human autoimmune diabetes; however, it is unclear whether this genetic variation exists in Han Chinese with type 1 diabetes (T1D) and whether it contributes to development of T1D. Therefore, we aimed to explore the association of the SIRT1 gene single-nucleotide polymorphisms (SNPs) rs10997866 and rs3818292 in a Han Chinese population with T1D.

METHODS: This study recruited 2653 unrelated Han Chinese individuals, of whom 1289 had T1D and 1364 were healthy controls. Allelic and genotypic distributions of SIRT1 polymorphisms (rs10997866 and rs3818292) were determined by MassARRAY. Basic characteristics, genotype and allele frequencies of selected SNPs were compared between the T1D patients and healthy controls. Further genotype-phenotype association analysis of the SNPs was performed on the T1D patients divided into three groups according to genotype. Statistical analyses included the chi-square test, Mann‒Whitney U test, Kruskal‒Wallis H test and logistic regression.

RESULTS: The allelic (G vs. A) and genotypic (GA vs. AA) distributions of SIRT1 rs10997866 were significantly different in T1D patients and healthy controls (P = 0.039, P = 0.027), and rs10997866 was associated with T1D susceptibility under dominant, overdominant and additive models (P = 0.026, P = 0.030 and P = 0.027, respectively). Moreover, genotype-phenotype association analysis showed the GG genotype of rs10997866 and the GG genotype of rs3818292 to be associated with higher titers of IA-2A (P = 0.013 and P = 0.038, respectively).

CONCLUSION: SIRT1 rs10997866 is significantly associated with T1D susceptibility, with the minor allele G conferring a higher risk of T1D. Moreover, SIRT1 gene rs10997866 and rs3818292 correlate with the titer of IA-2A in Han Chinese individuals with T1D.

PMID:37695462 | DOI:10.1007/s40618-023-02190-5

J Endocrinol Invest. 2023 Sep 11. doi: 10.1007/s40618-023-02186-1. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the impact of pasireotide (PAS) therapy on hormonal and glycometabolic outcome in patients with acromegaly previously treated with combination medical therapies or unconventional dosages of first-generation somatostatin receptor ligands (fg-SRLs).

METHODS: Retrospective study carried out in two referral centers for pituitary diseases. Twenty-one acromegalic patients were switched to PAS (12 had biochemical control, 9 were uncontrolled). Data were collected after 3- and 6-months PAS treatment, and at the last available visit (median 35 months).

RESULTS: After switching to PAS therapy, a significant reduction in IGF-1 values was observed [median 39%; 0.79 xULN (IQR 0.5-1.01) vs 1.29 xULN (IQR 1.06-1.83); p = 0.009]. IGF-1 reduction was statistically significant in the 9 patients previously uncontrolled (61%, p = 0.016), and in the 12 controlled subjects (33%, p = 0.037). At last follow-up, the number of patients reaching an acceptable biochemical control (IGF-1 < 1.3 xULN) raised from 57 to 90% (p = 0.032). Mean HbA1c levels increased from 5.7% (5.5-5.9) to 6.0% (5.9-7) (p = 0.002), and the percentage of diabetic patients raised from 14% (3/21) to 67% (14/21) (p = 0.004). At the last evaluation HbA1c was ≥ 7.0% in 5 patients (24%). Antidiabetic drugs were initiated in 9 new patients, and in 7 out of 9 metformin alone was effective. Younger age and male sex were predictors for the maintenance of glucose homeostasis.

CONCLUSION: PAS monotherapy can be effective in acromegalic patients previously treated with combination medical therapies or unconventional dosages of fg-SRLs. Glucose imbalance can be managed in the vast majority of cases by use of lifestyle interventions and metformin.

PMID:37695461 | DOI:10.1007/s40618-023-02186-1

Int Endod J. 2023 Sep 11. doi: 10.1111/iej.13973. Online ahead of print.

ABSTRACT

AIM: To evaluate two- and three-dimensionally the effect of resorbable collagen-based bone-filling material on periapical healing of endodontic lesions with four-wall defects following endodontic microsurgery (EMS).

METHODOLOGY: This parallel, randomized controlled superiority clinical trial involved 86 lesions with the strictly endodontic origin and four-wall defect morphology. EMS procedures were performed by calibrated postgraduate residents. Before flap closure, osteotomies were randomized to the control or treatment group. In the control group, the flap was repositioned with no material added. In the treatment group, a collagen-based bone-filling augmentation material was placed into the osteotomy. Clinical and radiographic examinations were completed after 12 months. Periapical healing was evaluated by blinded evaluators using periapical (PA) radiographs according to Molven’s criteria and cone beam computed tomography (CBCT) scans according to PENN’s 3D criteria. Cortical plate healing was scored according to the RAC/B index. The data were analysed using Fisher’s exact test, Logistic regression models and Chi-squared test. The significance level was predetermined at p < .05.

RESULTS: Sixty-six cases were evaluated at the 12-month follow-up, with 30 and 36 cases in the control and treatment groups, respectively. Only the asymptomatic cases (control = 26, treatment = 32) were included in the radiographic evaluation. Twenty-three cases (88.5%) in the control and 28 (87.5%) cases in the treatment group demonstrated complete healing on PA radiographs (p = 1.000). On CBCT, 10 (38.4%) and 21 (65.6%) cases had completely healed in the control and treatment groups, respectively (p = .095). The re-establishment of the buccal cortical plate was detected in 12 (46.2%) and 22 (68.8%) cases in the control and treatment groups, respectively (p = .243).

CONCLUSION: Within the limitations of the present study, the use of collagen-based bone-filling material had no statistically significant effect on the periapical healing of endodontic lesions with four-wall defect following EMS at the 12-month follow-up when evaluated by PA radiographs or CBCT scans. However, the observed higher percentage of a re-established cortical plate in the treatment group could suggest a clinical benefit that is of interest after surgical endodontic treatment.

PMID:37695450 | DOI:10.1111/iej.13973

Acta Neurochir (Wien). 2023 Sep 11. doi: 10.1007/s00701-023-05780-7. Online ahead of print.

ABSTRACT

BACKGROUND: Elective use of intraparenchymal intracranial pressure (ICP) monitoring is a valuable resource in the investigation of hydrocephalus and other cerebrospinal fluid disorders. Our preliminary study aims to investigate ICP changes in the immediate period following dural breach, which has not yet been reported on.

METHOD: This is a prospective cohort study of patients undergoing elective ICP monitoring, recruited between March and May 2022. ICP readings were obtained at opening and then at 5-min intervals for a 30-min duration.

RESULTS: Ten patients were recruited, mean age 45 years, with indications of a Chiari malformation (n = 5), idiopathic intracranial hypertension (n = 3) or other ICP-related pathology (n = 2). Patients received intermittent bolus sedation (80%) vs general anaesthesia (20%). Mean opening pressure was 22.9 mmHg [± 6.0], with statistically significant decreases present every 5 min, to a total reduction of 15.2 mmHg at 20 min (p = < 0.0001), whereafter the ICP plateaued with no further statistical change.

DISCUSSION: Our results highlight an intracranial opening pressure ‘spike’ phenomenon. This spike was 15.2 mmHg higher than the plateau, which is reached at 20 min after insertion. Several possible causes exist which require further research in larger cohorts, including sedation and pain response. Regardless of causation, this study provides key information on the use of ICP monitoring devices, guiding interpretation and when to obtain measurements.

PMID:37695437 | DOI:10.1007/s00701-023-05780-7

Drugs. 2023 Sep 11. doi: 10.1007/s40265-023-01936-y. Online ahead of print.

ABSTRACT

BACKGROUND: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs).

OBJECTIVE: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA).

METHODS: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www.

CLINICALTRIALS: gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework.

RESULTS: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07-0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57-76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04-5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06-0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59-1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS.

CONCLUSIONS: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.

PMID:37695433 | DOI:10.1007/s40265-023-01936-y

Psychol Trauma. 2023 Sep 11. doi: 10.1037/tra0001581. Online ahead of print.

ABSTRACT

OBJECTIVE: Global emotion dysregulation mediates the relationship between child maltreatment and severe depressive symptoms; however, there is a lack of research on maladaptive personality traits and their contribution to individual differences in global emotion dysregulation within this conceptual model. The present study tested a preliminary serial mediation model where maladaptive personality traits and global emotion dysregulation mediate the relationship between child maltreatment and severe depressive symptoms.

METHOD: A total of 200 patients with mood disorders (M_age = 36.5 years; 54% females) were assessed for maladaptive personality traits (Personality Inventory for Diagnostic and Statistical Manual of Mental Disorders [5th ed.] Brief Form), global emotion dysregulation (Difficulties in Emotion Regulation Scale-Short), childhood trauma (Childhood Trauma Questionnaire), and depressive symptoms (Patient Health Questionnaire-9).

RESULTS: Ordinary least squares regression and partial least squares-structural equation modeling revealed a consistent and significant indirect effect of child maltreatment on severe depressive symptoms through negative affectivity, detachment, psychoticism, and global emotion dysregulation. Among child maltreatment types, only emotional abuse had a significant indirect effect on severe depressive symptoms through maladaptive personality traits and global emotion dysregulation, b = 0.50, SE = 0.09, 95% confidence intervals [0.326, 0.694] after controlling for age, gender, and remaining types of child maltreatment.

CONCLUSIONS: Findings support the view that maladaptive personality traits shed important insights on individual differences in global emotion dysregulation, and this information could aid clinical formulation and treatment of childhood adversity-related psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

PMID:37695361 | DOI:10.1037/tra0001581

J Exp Psychol Gen. 2023 Sep 11. doi: 10.1037/xge0001440. Online ahead of print.

ABSTRACT

Humans are particularly sensitive to relationships between parts of objects. It remains unclear why this is. One hypothesis is that relational features are highly diagnostic of object categories and emerge as a result of learning to classify objects. We tested this by analyzing the internal representations of supervised convolutional neural networks (CNNs) trained to classify large sets of objects. We found that CNNs do not show the same sensitivity to relational changes as previously observed for human participants. Furthermore, when we precisely controlled the deformations to objects, human behavior was best predicted by the number of relational changes while CNNs were equally sensitive to all changes. Even changing the statistics of the learning environment by making relations uniquely diagnostic did not make networks more sensitive to relations in general. Our results show that learning to classify objects is not sufficient for the emergence of human shape representations. Instead, these results suggest that humans are selectively sensitive to relational changes because they build representations of distal objects from their retinal images and interpret relational changes as changes to these distal objects. This inferential process makes human shape representations qualitatively different from those of artificial neural networks optimized to perform image classification. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

PMID:37695326 | DOI:10.1037/xge0001440

Syst Biol. 2023 Sep 11:syad057. doi: 10.1093/sysbio/syad057. Online ahead of print.

ABSTRACT

The popularity of relaxed clock Bayesian inference of clade origin timings has generated several recent publications with focal results considerably older than the fossils of the clades in question. Here we critically examine two such clades: the animals (with focus on the bilaterians); and the mammals (with focus on the placentals). Each example displays a set of characteristic pathologies which, although much commented on, are rarely corrected for. We conclude that in neither case does the molecular clock analysis provide any evidence for an origin of the clade deeper than what is suggested by the fossil record. In addition, both these clades have other features (including, in the case of the placental mammals, proximity to a large mass extinction) that allow us to generate precise expectations of the timings of their origins. Thus, in these instances the fossil record can provide a powerful test of molecular clock methodology, and why it goes astray; and we have every reason to think these problems are general.

PMID:37695319 | DOI:10.1093/sysbio/syad057

J Manag Care Spec Pharm. 2023 Sep 11:1-12. doi: 10.18553/jmcp.2023.23045. Online ahead of print.

ABSTRACT

BACKGROUND: Research conducted in 2017 by Runyan et al concerning the current and future management of oncology drugs in the United States formed the basis for this research. The authors concluded that despite the high cost of oncology drugs, US payers relied on traditional management tools to manage the category, although these tools were ineffective at controlling costs. Innovative tools were not common in 2017. OBJECTIVE: To compare findings from the 2017 research with findings from a 2022 payer survey to understand how payer management of oncology drugs changed over 5 years. The study evaluates changing trends in oncology drug management. METHODS: The survey that informed the publication by Runyan et al in 2017 was reviewed, updated, and completed by 21 pharmacy and medical directors across 18 organizations representing 121.9 million covered lives. Both surveys included questions about management tools being employed in oncology and challenges to managing oncology. They used case studies in non-small cell lung cancer and chronic lymphocytic leukemia. These disease areas were chosen again in 2022 because they were included in the 2017 survey and because of the increase in competition in both categories from 2017 to 2022. The payer sample was designed to match the 2017 sample. The research was fielded from March to May 2022. The results were analyzed in Microsoft Excel; basic statistical analysis was conducted. Payers’ responses for each question were weighted by the number of reported covered lives at their organization so that the organization’s site was represented. RESULTS: On average, payers rated the management priority of oncology as a 5.3 and the budget impact as a 6.3 on a scale of 1 to 7, where 1 was low and 7 was high. Traditional tools remain dominant in this therapeutic area. However, there has been an increase in use of innovative tools. Pathways of care are trending upward since the initial survey in 2017. The Institute for Clinical and Economic Review (ICER) also influences payers’ decision-making in oncology more than it did 5 years ago. Despite these shifts, most payers allow for unrestricted access of targeted therapies in non-small cell lung cancer and chronic lymphocytic leukemia, in line with each drug’s US Food and Drug Administration-approved label. CONCLUSIONS: The increased use of pathways of care, shifting financial risk to providers, and the influence of ICER should continue to be monitored. Future research should focus on the role of pathways of care, comprehensive, evidence-based treatment protocols, in influencing prescribing decisions of hematologists and oncologists. DISCLOSURES: The authors work for Envision Pharma Group (formerly Two Labs), a company that provides consulting services to the pharmaceutical and biotech industries. As such, clients in these industries pay Envision Pharma Group for their services. This study was funded independently by Envision Pharma Group.

PMID:37695273 | DOI:10.18553/jmcp.2023.23045