Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis.

BACKGROUND: Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. METHODS: Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. RESULTS: SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. CONCLUSIONS: This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.

Outcomes of patients with COVID-19 requiring extracorporeal membrane oxygenation and continuous renal replacement therapy in the United States.

BACKGROUND: Coronavirus disease 2019 (COVID-19) infection is associated with significant morbidity and mortality. Some patients develop severe acute respiratory distress syndrome and kidney failure requiring the combination of extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). METHODS: Retrospective cohort study of 127 consecutive patients requiring combined ECMO and CRRT support in intensive care units at an ECMO center in Marietta, GA, United States. RESULTS: Sixty and 67 patients with and without COVID-19, respectively, required ECMO-CRRT support. After adjusting for confounding variables, patients with COVID-19 had increased mortality at 30 days (hazard ratio [HR], 5.19; 95% confidence interval [CI], 2.51-10.7; P<0.001) and 90 days (HR, 6.23; 95% CI, 2.60-14.9; P<0.001). CONCLUSIONS: In this retrospective study, patients with COVID-19 who required ECMO-CRRT had increased mortality when compared to patients without COVID-19.

Evaluation of active tactile sensibility in a single-tooth implant opposing a natural tooth with either an immediate or delayed functional loading protocol: A parallel design clinical study.

STATEMENT OF PROBLEM: High primary stability makes immediate loading more predictable, but immediately loaded implants are subjected to higher stresses and strains during the healing phase than implants that are left to heal for 3 months. Whether an earlier sensory-motor phenomenon with an immediate loading protocol helps to reduce the risk of overloading at the implant-bone interface is unclear. PURPOSE: The purpose of this concurrent parallel design clinical study was to evaluate and compare active tactile sensibility for a single-tooth implant opposing a natural tooth in the mandibular posterior region with either a delayed or immediate functional loading -protocol. MATERIAL AND METHODS: In this parallel group randomized trial, 2 test groups were formed: the DL group comprised 20 participants with the delayed loading protocol (loading after 3 months), and the IL group comprised 20 participants with the immediate loading protocol (loading within 2 days). Natural tooth-to-tooth contact on the side contralateral to the implant site (split mouth) in both test groups was used as a control to evaluate active tactile sensibility, which was evaluated in the test and control sites of both groups by using interocclusal articulating foils of varying thickness in maximum intercuspation. Active tactile sensibility was compared between the DL and IL groups at 3 and 6 months of follow-up. The nonparametric Mann-Whitney test was used for intergroup comparisons (P=.05). RESULTS: A significant difference was found for 8-µm- and 12-µm-thick articulating foil at 3 months and for 8-µm-thick foil at 6 months (P<.05), indicating a difference in active tactile sensibility between the DL and IL groups. No implant failure was recorded in this short clinical study. CONCLUSIONS: An immediate loading protocol can be performed in implants with sufficient primary stability. Upon loading, the IL group has shown more active tactile perception than the DL group.

Efficacy of Arthrocentesis and Stabilization Splints in Treatment of Temporomandibular Joint Disc Displacement Disorder Without Reduction: A Systematic Review and Meta-analysis.

Background: Temporomandibular joint disc displacement disorders are a group of temporomandibular disorders beside from other inflammatory disorders and growth related disorders of joint. The purpose of this analysis was to evaluate the efficacy of arthrocentesis procedure in comparison with stabilization splints used for disc displacement disorders without reduction. Materials and Methods: A systematic search was done in electronic databases (PubMed, Cochrane Central, Web of Science). In addition to this hand search of references and grey literatures was done. Qualities of randomized controlled clinical trials were assessed by Cochrane's tool for Systematic Reviews of Interventions and the Newcastle-Ottawa Scale was followed to assess the prospective and retrospective studies. Outcome variables pain (VAS) and maximum mouth opening were assessed by the software review manager 5.03. Results: A total of five studies were included in the review. Three studies showed greater improvement of symptoms in patients of arthrocentesis group in terms of maximum mouth opening, pain (VAS) value. Two other studies found no significant advantage of arthrocentesis over the other treatment protocol. The meta-analysis resulted in statistically significant difference between outcome variables favouring arthrocentesis group (VAS 1-10) (Mean Difference: 3.10; 95% CI 1.74, 4.45; P ≤ .00001, Mean difference: 2.00; 95% CI 0.29, 3.71; P = 0.02). Conclusion: Arthrocentesis showed effective result in terms of increase in mouth opening and reduction of pain level compared to stabilization splint and other non-invasive approaches in patients with disc displacement disorders without reduction. Overall, results supported the rationale of using arthrocentesis in patients with disc displacement disorders without reduction.

Peri-implant stress distribution assessment of various attachment systems for implant supported overdenture prosthesis by finite element analysis - A systematic review.

Background: Various attachments like ball, bar-clip, magnetic attachments are used in implant supported overdentures. Finite Element Analysis (FEA) a newly innovated technology has been used in dental implantology to evaluate stress distribution patterns. There is little evidence available regarding the stress distribution in peri-implant region for implant supported overdentures. The purpose of the review was to generate scientific evidence on peri-implant stress distribution in FEA model with different types of attachments employed in implant supported overdentures. Materials and methods: Systematic review was conducted as per the Preferred Reporting Items for Systematic Reviews Guidelines and Meta-Analyses statement (PRISMA). A comprehensive search was undertaken by two reviewers from January 2020 to June 2020 with no year limits to published articles. Only in-vitro FEA studies were included. Following electronic databases were searched for published studies- PubMed, Web of Science. Characteristics of the studies tabulated and analysis of articles was done to compare different attachment systems. Results: Locator attachments showed better stress distribution than ball attachment system in all the studies but one. Two studies showed results in favour of ball attachment compared to bar-clip attachment system when stress was evaluated distal to the implants. No significant difference in terms of stress concentration could be generated between ball versus magnetic/equator versus locator attachment system due to less number of studies and conflicting results. Conclusion: Various studies showed different results due to heterogenicity in selected attachment systems and study designs. Locator attachments showed favourable stress distribution around peri-implant bone than other attachments.

A comparative evaluation of neurophysiological activity, active tactile sensibility and stereognostic ability of complete denture prosthesis, and implant-supported prosthesis wearer-A pilot study.

AIM: The study aimed to evaluate the effect of implant-supported prosthesis in completely edentulous participants in terms of osseoperception ability, neural activity, and stereognostic ability in comparison to removable prosthetic options. MATERIALS AND METHODS: A total sample of 18 patients, irrespective of gender and age were allocated into three groups according to the three-treatment protocol (upper and lower complete denture, upper complete denture opposing lower implant-retained overdenture, implant-supported fixed prosthesis in both arches). Four weeks after completion of the treatment procedure active tactile sensibility (ATS) was checked by using varying thicknesses (12, 40, 80, 100, 200 µ) of articulating foils and papers. Functional magnetic resonance imaging (fMRI) was performed to record neurophysiological activity in cerebral cortex in all the participants. Various forms of test pieces (heat cure acrylic resin) were used to evaluate stereognostic ability. Data regarding the neurophysiological activity were analyzed by using Krushkal-Wallis test and p ≤ 0.05 was considered to be statistically significant. Data from stereognostic ability test procedure and ATS were compared by using chi-squared test and p ≤ 0.05 was considered to be statistically significant. RESULTS: Statistically significant difference was found in between the articulating foils in terms of true negative responses as the foil thickness increased in participants wearing complete denture in both the arches (p = 0.004) and implant-supported fixed prosthesis in both the arches (p = 0.010). Participants in implant-supported fixed prosthesis group showed significantly more activation in primary motor cortex (right side), somatosensory cortex (left side), angular gyrus (both sides), temporal lobe (left) compared to other groups. No significant difference found in thalamus and premotor cortex region in between the participants of different groups. No statistically significant difference found in between the groups in terms of true responses identifying correct shapes. Mean number of correct responses in stereognostic ability test were 4.16 (83.33%), 3.5 (70%), 3.83 (76.66%) for participants of complete denture group, upper complete denture opposing lower implant retained overdenture group, and implant-supported fixed prosthesis group, respectively. CONCLUSION: Primary motor cortex, somatosensory cortex, and other regions of brain were diffusely activated in participants wearing implant-supported fixed prosthesis in both the arches. Less number of false responses were recorded in participants of implant-supported fixed prosthesis group and upper complete denture opposing lower implant-retained overdenture group in ATS test compared to participants wearing complete denture in both the arches.

Pathophysiological pathway differences in children who present with COVID-19 ARDS compared to COVID -19 induced MIS-C.

COVID-19 has infected more than 275 million worldwide (at the beginning of 2022). Children appear less susceptible to COVID-19 and present with milder symptoms. Cases of children with COVID-19 developing clinical features of Kawasaki-disease have been described. Here we utilise Mass Spectrometry proteomics to determine the plasma proteins expressed in healthy children pre-pandemic, children with multisystem inflammatory syndrome (MIS-C) and children with COVID-19 induced ARDS. Pathway analyses were performed to determine the affected pathways. 76 proteins are differentially expressed across the groups, with 85 and 52 proteins specific to MIS-C and COVID-19 ARDS, respectively. Complement and coagulation activation are implicated in these clinical phenotypes, however there was significant contribution of FcGR and BCR activation in MIS-C and scavenging of haem and retinoid metabolism in COVID-19 ARDS. We show global proteomic differences in MIS-C and COVID-ARDS, although both show complement and coagulation dysregulation. The results contribute to our understanding of MIS-C and COVID-19 ARDS in children.

Effect of dopaminergic agonist group of drugs in treatment of sleep bruxism: A systematic review.

STATEMENT OF PROBLEM: Various factors are responsible for sleep bruxism; however, whether the dopaminergic agonist group of drugs is effective in the treatment of sleep bruxism is unclear. PURPOSE: The purpose of this systematic review was to evaluate the effect of the dopaminergic agonist group of drugs in controlling sleep bruxism in comparison with no treatment or placebo-controlled treatment. MATERIAL AND METHODS: Two electronic databases, PubMed and Cochrane Central, were searched by using the keywords bruxism, sleep bruxism, dopamine, and dopamine agonist. After screening titles and abstracts, only those articles which met predefined inclusion criteria were selected for full-text assessment. Clinical trials using the dopaminergic agonist group of drugs as a treatment approach to sleep bruxism were included. RESULTS: The literature search yielded a total of 64 articles from the 2 electronic databases (PubMed, 53; Cochrane Central, 11). After removal of the duplicates (n=8), the initial screening of titles and abstracts was performed by 2 independent reviewers, removing 46 articles. A total of 10 articles were selected for full-text reading, and 4 studies were included for qualitative analysis. CONCLUSIONS: Levodopa (L-DOPA) and Bromocriptine showed decrease in root mean square value in electromyography per bruxism burst (P<.001) and 20% to 30% reduction of bruxism episodes during sleep in 2 different studies. However, treatment with bromocriptine led to conflicting result in another study in terms of frequency of bruxism episodes and amplitude of muscle contractions in electromyography (EMG). Bruxism bursts and episodes were also not significantly improved with another dopaminergic agonist group of drugs, Pramipexole (P>.001). Based on the limited evidence and conflicting results, significant conclusions cannot be generated, and further studies are required.

Enhancement of Sensorimotor Cortical Adaptation after Dental Implantation in Comparison to the Conventional Denture - Demonstration by Functional MRI at 1-5T.

BACKGROUND AND PURPOSE: Dental implantation is thought to be associated with enhancement of neuro-cortical sensorimotor activity which has been lost due to an edentulous state. Such changes are either feeble or absent after the placement of a conventional denture. In the present study, we test this hypothesis using blood oxygen level-dependent (BOLD) activity on functional MRI (fMRI) as a bio-surrogate. MATERIALS AND METHODS: fMRI was performed in 12 consecutive edentulous subjects (mean age = 59.2 years) after the placement of a conventional complete denture (CD) and subsequently after intraoral dental implantation (IOD). The semi-quantitative data of the BOLD activity was compiled to depict the activation seen in both scenarios in six anatomical regions. Statistical analysis was done to evaluate the significance of enhancement in BOLD activity in these regions in patients having an IOD as compared to those having a CD. RESULTS: The enhancement of BOLD activity on fMRI after placement of an IOD was much more significant as compared to that noted with CD. Using Wilcoxon's signed-rank test the nonparametric data showed a significant positive elevation in global and regional assigned mean ranks of BOLD activity. CONCLUSION: Intraoral implantation leads to a significant elevation in the BOLD activity of the sensorimotor cortex as compared to the placement of a conventional CD.

Effect of complete dentures on oral stereognostic ability in edentulous patients: A systematic review.

Aim: Oral stereognosis is an important sensation for a human being to percept any type of materials that are introduced in the oral cavity. It is defined as the ability of an individual to recognize objects using only tactile sensation without using vision, audition, balance, somatic function, taste, or smell. The primary purpose of this review was to evaluate the effect of complete dentures on oral stereognostic ability in edentulous subjects. Settings and Design: Systematic review based on PRISMA guidelines. Materials and Methods: A systematic search of the electronic databases like PubMed and Web of Science was done using keywords - "stereognosis," "oral stereognosis," "complete denture," and "complete edentulism." In addition to this, a manual search of references mentioned in the articles and gray literature was done. Data extraction and assessment were done by two independent reviewers. Statistical Analysis Used: Qualitative analysis. Results: The literature search yielded a total of 61 articles. Thirteen duplicate articles were removed and 36 articles were rejected after initial screening of titles and abstracts. A total of 12 articles were selected for full text reading and 5 of them were included for qualitative analysis. Conclusion: All the included studies showed complete denture treatment therapy improved stereognostic ability in terms of correct identification of test pieces and time taken to identify the objects. There is also a direct relationship between the adaptability of dentures and stereognostic ability.

Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is one of the major causes of intracerebral hemorrhage and vascular dementia in older adults. Early diagnosis will provide clinicians with an opportunity to intervene early with suitable strategies, highlighting the importance of pre-symptomatic CAA biomarkers. OBJECTIVE: Investigation of pre-symptomatic CAA related blood metabolite alterations in Dutch-type hereditary CAA mutation carriers (D-CAA MCs). METHODS: Plasma metabolites were measured using mass-spectrometry (AbsoluteIDQ® p400 HR kit) and were compared between pre-symptomatic D-CAA MCs (n = 9) and non-carriers (D-CAA NCs, n = 8) from the same pedigree. Metabolites that survived correction for multiple comparisons were further compared between D-CAA MCs and additional control groups (cognitively unimpaired adults). RESULTS: 275 metabolites were measured in the plasma, 22 of which were observed to be significantly lower in theD-CAAMCs compared to D-CAA NCs, following adjustment for potential confounding factors age, sex, and APOE ε4 (p < 00.05). After adjusting for multiple comparisons, only spermidine remained significantly lower in theD-CAAMCscompared to theD-CAA NCs (p  < 0.00018). Plasma spermidine was also significantly lower in D-CAA MCs compared to the cognitively unimpaired young adult and older adult groups (p < 0.01). Spermidinewas also observed to correlate with CSF Aß40 (rs = 0.621, p = 0.024), CSF Aß42 (rs = 0.714, p = 0.006), and brain Aß load (rs = -0.527, p = 0.030). CONCLUSION: The current study provides pilot data on D-CAA linked metabolite signals, that also associated with Aß neuropathology and are involved in several biological pathways that have previously been linked to neurodegeneration and dementia.

Plasma metabolites associated with biomarker evidence of neurodegeneration in cognitively normal older adults.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently has no cure. Identifying biochemical changes associated with neurodegeneration prior to symptom onset, will provide insight into the biological mechanisms associated with neurodegenerative processes, that may also aid in identifying potential drug targets. The current study therefore investigated associations between plasma neurofilament light chain (NF-L), a marker of neurodegeneration, with plasma metabolites that are products of various cellular processes. Plasma NF-L, measured by ultrasensitive Single molecule array (Simoa) technology (Quanterix) and plasma metabolites, measured by mass-spectrometry (AbsoluteIDQ® p400HR kit, BIOCRATES), were assessed in the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort comprising 100 cognitively normal older adults. Metabolites belonging to biogenic amine (creatinine, symmetric dimethylarginine, asymmetric dimethylarginine; ADMA, kynurenine, trans-4-hydroxyproline), amino acid (citrulline, proline, arginine, asparagine, phenylalanine, threonine) and acylcarnitine classes were observed to have positive correlations with plasma NF-L, suggesting a link between neurodegeneration and biological pathways associated with neurotransmitter regulation, nitric oxide homoeostasis, inflammation and mitochondrial function. Additionally, after stratifying participants based on low/high brain amyloid-ß load (Aß ±) assessed by positron emission tomography, while creatinine, SDMA and citrulline correlated with NF-L in both Aß- and Aß+ groups, ADMA, proline, arginine, asparagine, phenylalanine and acylcarnitine species correlated with NF-L only in the Aß+ group after adjusting for confounding variables, suggesting that the association of these metabolites with neurodegeneration may be relevant to AD-related neuropathology. Metabolites identified to be associated with plasma NF-L may have the potential to serve as prognostic markers for neurodegenerative diseases, however, further studies are required to validate the current findings in an independent cohort, both cross-sectionally and longitudinally.

Comparative evaluation of biting force and chewing efficiency of all-on-four treatment concept with other treatment modalities in completely edentulous individuals.

AIM: To compare and evaluate biting force and chewing efficiency of all-on-four treatment concept, implant-supported overdenture, and conventional complete denture. SETTINGS AND DESIGN: Invivo - comparative study. MATERIALS AND METHODS: A total of 12 edentulous patients were included in the study and conventional complete dentures were fabricated. Patients were divided into two groups. In Group 1, complete dentures were replaced with implant-supported overdenture, and in Group 2, complete dentures were replaced with hybrid denture supported by all-on-four treatment concept. The biting force was assessed using a bite force sensor and electromyographic recordings were made by electromyogram for masticatory muscles when chewing three different consistencies of foods. STATISTICAL ANALYSIS USED: The data was statistically analyzed using software SPSS version 22.0. Paired t-test was used for intra-group comparison and unpaired t-test was used for intergroup comparison. RESULTS: The difference in biting force and chewing efficiency for all-on-four treatment concept was statistically significant for overdenture and complete denture. The highest biting force and chewing efficiency were observed for all-on-four treatment concept, followed by implant-supported overdenture and complete denture. CONCLUSION: The study concluded that the completely edentulous individuals with atrophic posterior alveolar ridges can be rehabilitated successfully with improved biting force and chewing efficiency by All-on-four treatment concept.

Evaluation of efficacy of platelet-rich fibrin membrane and bone graft in coverage of immediate dental implant in esthetic zone: An in vivo study.

OBJECTIVE: This study compared and evaluated the clinical and radiographic results of guided bone regeneration using platelet-rich fibrin (PRF) and collagen membrane as barrier membrane in immediately placed implants with severe buccal bone defect (with respect to marginal bone level, implant stability quotient [ISQ]), and histological analysis of new bone formation. MATERIALS AND METHODS: Sixteen implants were placed in patients requiring immediate implant placement and having a buccal wall defect and randomly divided into two groups one receiving PRF membranes and other collagen membrane. The sites were grafted with bone-substitute material in both the groups. After 4 months, at the time of second-stage surgery, implant stability is measured by Osstell Mentor, crestal bone level on mesial and distal sides of implant by digital intraoral periapical, buccal defect clinically by probe and histological analysis of biopsied bone. RESULTS: The results were insignificant and comparable in both the groups when comparison was made between the groups. The mean buccal defect, mean values of average ISQ, crestal bone level in both the groups at baseline and after 4 months were compared. No significant difference between both the groups was found after 4 months. Bone quality seemed to be equal in both groups after histological analysis. Within the limits of the study, both the groups had shown similar results in all criteria. CONCLUSION: Within the limitation of the study, it can be concluded that both the treatment modalities are successful in terms of buccal defect reduction, stability, and increase in crestal bone level.

Semiprecision attachment: a connecting link between the removable and fixed prosthesis.

Oral rehabilitation of partially edentulous arches requires careful treatment planning before any prosthodontic intervention. The connection of the metal framework of fixed (fixed dental prosthesis (FPD)) and removable partial denture using adhesive attachments is a good alternative prosthetic option when solely fixed prosthesis (FPD or implant) cannot be used due to anatomical limitation. Attachments are the tiny interlocking devices that act as a hybrid link to join removable prosthesis to the abutment and direct the masticatory forces along the long axis of the abutment. This joint acts as a non-rigid stress breaker, which helps in distributing the occlusal load. Precision and semiprecision attachment have always been bordered by an aura of mystery due to technique sensitive procedure and lack of knowledge. The following case describes a combined contemporary and conventional approach and treatment sequence with the use of attachments for the rehabilitation of partially edentulous arches.

Evaluating bioanalytical capabilities of paper spray ionization for abiraterone drug quantification in patient plasma.

Paper spray ionization (PSI) is a direct, fast, and low-cost ambient ionization technique which may have clinical utility for qualitative and quantitative analysis of therapeutic drugs and metabolites from patient specimens. We developed and validated a PSI-mass spectrometry (PSI-MS/MS) method according to the US-FDA guidelines for bioanalytical studies to measure the prostate cancer drug abiraterone directly from patient plasma. The established linearity range was 3.1-156.8 ng/mL with a precision (%CV) and an accuracy (%) range of 0.5-10.7 and 93.5-103.2, respectively. The mean internal standard normalized matrix factor for abiraterone was just below 1 with highest %CV of 10.2 at the low-level quality control. In benchmarking the performance of this assay against a published LC-MS/MS assay, we showed they were mostly equivalent, with the exception of accuracy with clinical samples. We found the quantitative values observed for abiraterone measured directly from patient plasma using PSI-MS/MS showed positive bias. Upon investigation, we concluded the increased values were due to summed quantitation of isomeric abiraterone conjugates and metabolites which are separable by LC-MS/MS, but not with the current PSI-MS/MS configuration. Despite demonstrating the utility of PSI-MS/MS for rapid bioanalysis, this study also highlighted a limitation encountered with the direct analysis of abiraterone in clinical samples.

Efficacy of different lasers of various wavelengths in treatment of peri-implantitis and peri-implant mucositis: A systematic review and meta-analysis.

AIM: Peri implant diseases lead to pathological changes in the peri implant tissues and loss of osseointegration. The purpose of this analysis is to evaluate the effect of various lasers and photodynamic therapy (PDT) on peri implant diseases compared to conventional procedures. SETTING AND DESIGN: This meta analysis was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. MATERIALS AND METHODS: A systematic search of the electronic databases such as PubMed, ICTRP, CT.gov, Embase, and Cochrane Library was done additional to manual search of peer review article on peri-implant diseases. Eleven randomized control clinical trials were included in which laser therapy and PDT were used as an interventional procedure. RESULTS AND STATISTICAL ANALYSIS USED: Review Manager 5.03 (RevMan, Nordic Cochrane Center, Copenhagen, Denmark), and random effects model were used to assess mean difference (MD). Bivariate differential mean statistic was used in intergroup estimate with 95% confidence interval (CI). I2 test statistics was applied for heterogenity and P < 0.05 was considered significant statistically. The literature search yielded a total of 113 articles among which 11 articles were included for quantitative analysis. The selected outcome PD reported MD -0.01 with 95% CI (-0.13, 0.16), P = 0.84, and CAL reported MD -0.09 with 95% CI (-0.32, 0.14), P = 0.45, respectively. CONCLUSION: Laser treatment as an adjunctive therapy or monotherapy in peri implantitis does not show any superior effects than conventional measures as per evidence. However, cases with peri implant mucositis have shown far more promising results with laser therapy compared to peri implantitis.

Bioanalytical evaluation of dried plasma spots for monitoring of abiraterone and ∆(4)-abiraterone from cancer patients.

Abiraterone acetate is an approved prodrug administered orally in a fixed dose format for the treatment of metastatic castration-resistant prostate cancer (mCRPC). In vivo, the prodrug is readily metabolized to abiraterone and its active metabolite Δ(4)-abiraterone (D4A) which selectively and irreversibly inhibit the 17α-hydroxylase/17,20-lyase (CYP17A1) enzyme and the androgen receptor, respectively. Therapeutic drug monitoring (TDM) of abiraterone and its metabolites may be beneficial as significant pharmacokinetic variability has been observed. Dried plasma spots (DPS) represent an attractive, yet under-utilised approach for TDM analysis with desired features including easy collection, transport, storage and overcomes the issues of blood hematocrit levels known in dried blood spot analysis. In this study we developed and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for the simultaneous quantification of abiraterone and D4A with deuterated internal standard (abiraterone D4) from DPS using a high-resolution benchtop mass spectrometer. Calibration curves were linear over a wide and clinically-relevant concentration range (0.132-196.0 ng/mL for abiraterone and 0.110-39.17 ng/mL for D4A) with high accuracy (93-104% for abiraterone and 96-108% for D4A) and precision (%CV ≤ 12.5). As expected, the levels of abiraterone and D4A obtained from DPS from mCRPC patients varied substantially (1.5-31.4 ng/mL for abiraterone and 0.1-5.2 ng/mL for D4A; n = 22). Detailed benchmarking of the DPS method to a pre-validated liquid plasma method showed that the techniques generate quantitative indistinguishable data. Collectively, this demonstrates the potential of using LC-MS/MS in combination with DPS for TDM of abiraterone and D4A from patients.

Inter- and intra-patient variability in pharmacokinetics of abiraterone acetate in metastatic prostate cancer.

PURPOSE: This study examined the inter- and intra-patient variability in pharmacokinetics of AA and its metabolites abiraterone and Δ(4)-abiraterone (D4A), and potential contributing factors. METHODS: AA administered daily for ≥4 weeks concurrently with androgen deprivation therapy (ADT) for mCRPC were included. Pharmacokinetic evaluation was performed at two consecutive visits at least 4 weeks apart. Plasma samples were collected 24 h after last dose of AA to obtain drug trough level (DTL) of two active metabolites, abiraterone and D4A. RESULTS: 39 plasma samples were obtained from 22 patients, with 17 patients had repeat DTL measurement. Considerable inter-patient variability in DTL was seen, with initial DTL for abiraterone ranging between 1.5 and 25.4 ng/ml (CV 61%) and for D4A between 0.2 and 2.5 ng/ml (CV 61%). Intra-patient variability in DTL for abiraterone varied between 0.85 and 336% and for D4A between 1.14 and 199%. There was no increase in AA exposure with use of dexamethasone (n = 5; DTL 13.9) compared with prednisone (n = 17; DTL 11.0 p = 0.5), dosing in fasted state (n = 13, DTL 12.1) compared to dosing in fed state (n = 9; DTL 11.1, p = 0.8), or chemotherapy-exposed (n = 10; DTL 8.9) compared to chemotherapy naïve (n = 12; DTL 14.0, p = 0.1). CONCLUSIONS: Our cohort demonstrated high inter- and intra-patient variability in both abiraterone and D4A with fixed dosing of AA, with no effect from choice of corticosteroids, prior use of chemotherapy, or dosing in fasting state. Monitoring DTL of AA may be necessary to minimise risk of patients being under-dosed and earlier development of resistance.