Use of antidepressants in the treatment of chronic orofacial pain caused by temporomandibular disorders: A randomized controlled clinical trial.

BACKGROUND AND OBJECTIVE: Temporomandibular disorders (TMDs) are a common pathology, associated with pain in the facial territory and with associated psychological disorders, such as anxiety and depression. The aim of this study was to evaluate the efficacy of antidepressants in the treatment of pain associated with TMD. MATERIALS AND METHODS: Sixty four patients suffering from chronic orofacial pain, randomly distributed in 3 groups: control group treated with night splint, group treated with 10mg/day of citalopram and group treated with 25mg/day of amitriptyline. Pain intensity was assessed, randomly, by a single blinded evaluator, according to the VAS at baseline and after one, three, six and nine weeks. RESULTS: All groups showed a reduction of pain throughout the period of time evaluated, however, the group treated with amitriptyline showed the best pain reduction results 3.3±1.5, 1.5±1.4 and 0.9±1.3 at 3, 6 and 9 weeks, respectively. CONCLUSIONS: Low doses of amitriptyline appear to be a good therapeutic option in patients with TMDs suffering from chronic orofacial pain.

Identification of Novel Molecular and Clinical Biomarkers of Survival in Glioblastoma Multiforme Patients: A Study Based on The Cancer Genome Atlas Data.

Glioblastoma multiforme (GBM) is the most prevalent type of brain tumour; although advancements in treatment have been made, the median survival time for GBM patients has persisted at 15 months. This study is aimed at investigating the genetic alterations and clinical features of GBM patients to find predictors of survival. GBM patients' methylation and gene expression data along with clinical information from TCGA were retrieved. The most overrepresented pathways were identified independently for each omics dataset. From the genes found in at least 30% of these pathways, one gene that was identified in both sets was further examined using the Kaplan-Meier method for survival analysis. Additionally, three groups of patients who started radio and chemotherapy at different times were identified, and the influence of these variations in treatment modality on patient survival was evaluated. Four pathways that seemed to negatively impact survival and two with the opposite effect were identified. The methylation status of PRKCB was highlighted as a potential novel biomarker for patient survival. The study also found that treatment with chemotherapy prior to radiotherapy can have a significant impact on patient survival, which could lead to improvements in clinical management and therapeutic approaches for GBM patients.

Surface Treatment of Dental Mini-Sized Implants and Screws: A Systematic Review with Meta-Analysis.

Miniscrews are devices that allow for absolute skeletal anchorage. However, their use has a higher failure rate (10-30%) than dental implants (10%). To overcome these flaws, chemical and/or mechanical treatment of the surface of miniscrews has been suggested. There is no consensus in the current literature about which of these methods is the gold standard; thus, our objective was to carry out a systematic review and meta-analysis of the literature on surface treatments of miniscrews. The review protocol was registered (PROSPERO CRD42023408011) and is in accordance with the PRISMA guidelines. A bibliographic search was carried out on PubMed via MEDLINE, Cochrane Library, Embase and Web of Science. The initial search of the databases yielded 1684 results, with 98 studies included in the review, with one article originating from the search in the bibliographic references of the included studies. The results of this systematic review show that the protocols of miniscrew surface treatments, such as acid-etching; sandblasting, large-grit and acid-etching; photofunctionalization with ultraviolet light; and photobiomodulation, can increase stability and the success of orthodontic treatment. The meta-analysis revealed that the treatment with the highest removal torque is SLA, followed by acid-etching. On the other hand, techniques such as oxidative anodization, anodization with pre-calcification and heat treatment, as well as deposition of chemical compounds, require further investigation to confirm their effectiveness.

A peripheral blood mononuclear cell-based in vitro model: A tool to explore indoleamine 2, 3-dioxygenase-1 (IDO1).

BACKGROUND: Proinflammatory cytokines powerfully induce the rate-limiting enzyme indoleamine 2, 3-dioxygenase-1 (IDO-1) in dendritic cells (DCs) and monocytes, it converts tryptophan (Trp) into L-kynurenine (KYN), along the kynurenine pathway (KP). This mechanism represents a crucial innate immunity regulator that can modulate T cells. This work explores the role of IDO1 in lymphocyte proliferation within a specific pro-inflammatory milieu. METHODS: Peripheral blood mononuclera cells (PBMCs) were isolated from buffy coats taken from healthy blood donors and exposed to a pro-inflammatory milieu triggered by a double-hit stimulus: lipopolysaccharide (LPS) plus anti-CD3/CD28. The IDO1 mRNA levels in the PBMCs were measured by RT-PCR; the IDO1 activity was analyzed using the KYN/Trp ratio, measured by HPLC-EC; and lymphocyte proliferation was measured by flow cytometry. Trp and epacadostat (EP) were used as an IDO1 substrate and inhibitor, respectively. KYN, which is known to modulate Teffs, was tested as a positive control in lymphocyte proliferation. RESULTS: IDO1 expression and activity in PBMCs increased in an in vitro pro-inflammatory milieu. The lymphoid stimulus increased IDO1 expression and activity, which supports the interaction between the activated lymphocytes and the circulating myeloid IDO1-expressing cells. The addition of Trp decreased lymphocyte proliferation but EP, which abrogated the IDO1 function, had no impact on proliferation. Additionally, incubation with KYN seemed to decrease the lymphocyte proliferation. CONCLUSION: IDO1 inhibition did not change T lymphocyte proliferation. We present herein an in vitro experimental model suitable to measure IDO1 expression and activity in circulating myeloid cells.

Cx43 can form functional channels at the nuclear envelope and modulate gene expression in cardiac cells.

Classically associated with gap junction-mediated intercellular communication, connexin43 (Cx43) is increasingly recognized to possess non-canonical biological functions, including gene expression regulation. However, the mechanisms governing the localization and role played by Cx43 in the nucleus, namely in transcription modulation, remain unknown. Using comprehensive and complementary approaches encompassing biochemical assays, super-resolution and immunogold transmission electron microscopy, we demonstrate that Cx43 localizes to the nuclear envelope of different cell types and in cardiac tissue. We show that translocation of Cx43 to the nucleus relies on Importin-ß, and that Cx43 significantly impacts the cellular transcriptome, likely by interacting with transcriptional regulators. In vitro patch-clamp recordings from HEK293 and adult primary cardiomyocytes demonstrate that Cx43 forms active channels at the nuclear envelope, providing evidence that Cx43 can participate in nucleocytoplasmic shuttling of small molecules. The accumulation of nuclear Cx43 during myogenic differentiation of cardiomyoblasts is suggested to modulate expression of genes implicated in this process. Altogether, our study provides new evidence for further defining the biological roles of nuclear Cx43, namely in cardiac pathophysiology.

New Insights on Sperm Function in Male Infertility of Unknown Origin: A Multimodal Approach.

The global trend of rising (male) infertility is concerning, and the unidentifiable causes in half of the cases, the so-called unknown origin male infertility (UOMI), demands a better understanding and assessment of both external/internal factors and mechanisms potentially involved. In this work, it was our aim to obtain new insight on UOMI, specifically on idiopathic (ID) and Unexplained male infertility (UMI), relying on a detailed evaluation of the male gamete, including functional, metabolic and proteomic aspects. For this purpose, 1114 semen samples, from males in couples seeking infertility treatment, were collected at the Reproductive Medicine Unit from the Centro Hospitalar e Universitário de Coimbra (CHUC), from July 2018-July 2022. Based on the couples' clinical data, seminal/hormonal analysis, and strict eligibility criteria, samples were categorized in 3 groups, control (CTRL), ID and UMI. Lifestyle factors and anxiety/depression symptoms were assessed via survey. Sperm samples were evaluated functionally, mitochondrially and using proteomics. The results of Assisted Reproduction Techniques were assessed whenever available. According to our results, ID patients presented the worst sperm functional profile, while UMI patients were similar to controls. The proteomic analysis revealed 145 differentially expressed proteins, 8 of which were specifically altered in ID and UMI samples. Acrosin (ACRO) and sperm acrosome membrane-associated protein 4 (SACA4) were downregulated in ID patients while laminin subunit beta-2 (LAMB2), mannose 6-phosphate isomerase (MPI), ATP-dependent 6-phosphofructokinase liver type (PFKAL), STAR domain-containing protein 10 (STA10), serotransferrin (TRFE) and exportin-2 (XPO2) were downregulated in UMI patients. Using random forest analysis, SACA4 and LAMB2 were identified as the sperm proteins with a higher chance of distinguishing ID and UMI patients, and their function and expression variation were in accordance with the functional results. No alterations were observed in terms of lifestyle and psychological factors among the 3 groups. These findings obtained in an experimental setting based on 3 well-defined groups of subjects, might help to validate new biomarkers for unknown origin male infertility (ID and UMI) that, in the future, can be used to improve diagnostics and treatments.

Development of an in chemico high-throughput screening method for the identification of skin sensitization potential.

It is well established that chemical-peptide conjugation represents the molecular initiating event (MIE) in skin sensitization. This MIE has been successfully exploited in the development of in chemico peptide reactivity assays, with the Direct Peptide Reactivity Assay (DPRA) being validated as a screening tool for skin sensitization hazard as well as an OECD test guideline. This test relies on the use of a high-performance liquid chromatography/ultraviolet detection method to quantify chemical-peptide conjugation through measurement of the depletion of two synthetic peptides containing lysine or cysteine residues, which is labor-intensive and time-consuming. To improve assay throughput, sensitivity, and accuracy, we have developed a spectrophotometric assay for skin sensitization potential based on MIE measurement-the ProtReact assay. ProtReact is also a cheaper, faster, simpler, and more accessible alternative for the DPRA, giving comparable results. A set of 106 chemicals was tested with ProtReact and the peptide depletion values compared with those reported for the DPRA. The predictive capacity of both assays was evaluated with human reference data. ProtReact and DPRA assays show similar predictive capacities for hazard identification (75% and 74%, respectively), although ProtReact showed a higher specificity (86% versus 74%, respectively) and lower sensitivity (69% versus 73%). Overall, the results show that ProtReact assay described here represents an efficient, economic, and accurate assay for the prediction of skin sensitization potential of chemical haptens.

The Role of Apical Periodontitis Disease in the Development of Bisphosphonate-Related Osteonecrosis of the Jaw: An Animal Study.

BACKGROUND: Microorganisms and their by-products are responsible for establishing pulpal and periapical diseases. Healing is compromised in patients under bisphosphonate therapy, and the presence of periapical infections can potentially lead to the development of medication-related osteonecrosis of the jaw (MRONJ). This work aimed to evaluate if bisphosphonate therapy is a risk factor for MRONJ development in the presence of periapical lesions. METHODS: Two groups of 10 female Wistar rats were used. The experimental group received zoledronate (0.1 mg/kg) intraperitoneally, and the control received a saline solution, three times a week for three weeks. One week after the last injection, apical periodontitis was induced through pulpal exposure in the mandibular first molars. Twenty-one days later, the animals were intravenously injected with 99mTc-HMDP, and the radioactivity uptake by mandibular specimens was counted. In addition, sample radiographs and a histological examination were performed. RESULTS: The bone loss was higher in the control group when compared to the experimental group (p = 0.027). 99mTc-HMDP uptake in the control was reduced compared with the experimental group, although without statistical significance. CONCLUSIONS: In the presence of zoledronate therapy, apical periodontitis does not increase the risk of MRONJ development, and periapical lesions have lower bone resorption when compared to the control group.

One Step Nucleic Acid Amplification (OSNA) Lysate Samples Are Suitable to Establish a Transcriptional Metastatic Signature in Patients with Early Stage Hormone Receptors-Positive Breast Cancer.

The One Step Nucleic Acid Amplification (OSNA) is being adopted worldwide for sentinel lymph nodes (SLNs) staging in breast cancer (BC). As major disadvantage, OSNA precludes prognostic information based on structural evaluation of SLNs. Our aim is to identify biomarkers related to tumor-microenvironment interplay exploring gene expression data from the OSNA remaining lysate. This study included 32 patients with early stage hormone receptors-positive BC. Remaining OSNA lysates were prepared for targeted RNA-sequencing analysis. Identification of differentially expressed genes (DEGs) was performed by DESeq2 in R and data analysis in STATA. The results show that, in metastatic SLNs, several genes were upregulated: KRT7, VTCN1, CD44, GATA3, ALOX15B, RORC, NECTIN2, LRG1, CD276, FOXM1 and IGF1R. Hierarchical clustering analysis revealed three different clusters. The identified DEGs codify proteins mainly involved in cancer aggressiveness and with impact in immune response. The overexpression of the immune suppressive genes VTCN1 and CD276 may explain that no direct evidence of activation of immune response in metastatic SLNs was found. We show that OSNA results may be improved incorporating microenvironment-related biomarkers that may be useful in the future for prognosis stratification and immunotherapy selection. As OSNA assay is being implemented for SLNs staging in other cancers, this approach could also have a wider utility.

Normal percentile reference curves for skin ultrasound thickness and stiffness at Rodnan sites.

OBJECTIVES: Our primary objective was to establish preliminary normal reference curves for ultrasound-dermal thickness and skin stiffness in the 17 Rodnan skin sites, considering the effect of gender and age on these measures. As an exploratory objective, we investigated the effect of body mass index and the menopause on skin ultrasound measures. METHODS: A cross-sectional study was conducted involving 140 healthy volunteers, aged 20-79 years. Recruitment was stratified by gender and age (10-year categories). Ultrasound-dermal thickness and skin stiffness were assessed by high-frequency ultrasound and shear-wave elastography, respectively, at the 17 Rodnan skin sites. Outcomes were evaluated through a mixed linear model, univariate and multivariate regressions. Normal reference curves were derived for both ultrasound measures in each skin site. An online calculator of the percentiles of skin ultrasound measures was developed. RESULTS: Ultrasound-dermal thickness and stiffness measures were higher in men than women in all Rodnan skin sites (except in chest for ultrasound-dermal thickness). Age had also a significant impact in both ultrasound measures, but only in some skin sites. Gender and age percentile curves (97.5th, 95th, 75th, 50th, 25th, 5th, 2.5th) were plotted for each of the measures in each skin site. CONCLUSIONS: Gender and age are strongly associated with skin ultrasound parameters, imposing the need for gender-specific and age-specific reference values. Normal reference percentile curves are provided as a basis for future cooperative work to strengthen its evidence basis, representativeness and refinement regarding potentially influential factors.

Medium-Term Effect of Treatment with Intra-Articular Injection of Sodium Hyaluronate, Betamethasone and Platelet-Rich Plasma in Patients with Temporomandibular Arthralgia: A Retrospective Cohort Study.

Temporomandibular joint disorders are associated with pain and reduced jaw mobility. The aim of this study was to compare the long-term effect on pain of intra-articular TMJ injections of betamethasone, sodium hyaluronate and platelet-rich plasma. The sample was made up of 114 patients, who were randomly distributed into three groups at least three years ago and who achieved a total remission of pain after treatment. We found that the median number of months without pain was, according to each group, as follows: platelet-rich plasma: 33; sodium hyaluronate: 28; betamethasone: 19. Both platelet-rich plasma and sodium hyaluronate lead to significant pain-free time after treatment; when we compare bethametasone with the two other substances, it proved to be very ineffective.

Dopaminergic Gene Dosage Reveals Distinct Biological Partitions between Autism and Developmental Delay as Revealed by Complex Network Analysis and Machine Learning Approaches.

The neurobiological mechanisms underlying Autism Spectrum Disorders (ASD) remains controversial. One factor contributing to this debate is the phenotypic heterogeneity observed in ASD, which suggests that multiple system disruptions may contribute to diverse patterns of impairment which have been reported between and within study samples. Here, we used SFARI data to address genetic imbalances affecting the dopaminergic system. Using complex network analysis, we investigated the relations between phenotypic profiles, gene dosage and gene ontology (GO) terms related to dopaminergic neurotransmission from a polygenic point-of-view. We observed that the degree of distribution of the networks matched a power-law distribution characterized by the presence of hubs, gene or GO nodes with a large number of interactions. Furthermore, we identified interesting patterns related to subnetworks of genes and GO terms, which suggested applicability to separation of clinical clusters (Developmental Delay (DD) versus ASD). This has the potential to improve our understanding of genetic variability issues and has implications for diagnostic categorization. In ASD, we identified the separability of four key dopaminergic mechanisms disrupted with regard to receptor binding, synaptic physiology and neural differentiation, each belonging to particular subgroups of ASD participants, whereas in DD a more unitary biological pattern was found. Finally, network analysis was fed into a machine learning binary classification framework to differentiate between the diagnosis of ASD and DD. Subsets of 1846 participants were used to train a Random Forest algorithm. Our best classifier achieved, on average, a diagnosis-predicting accuracy of 85.18% (sd 1.11%) on the test samples of 790 participants using 117 genes. The achieved accuracy surpassed results using genetic data and closely matched imaging approaches addressing binary diagnostic classification. Importantly, we observed a similar prediction accuracy when the classifier uses only 62 GO features. This result further corroborates the complex network analysis approach, suggesting that different genetic causes might converge to the dysregulation of the same set of biological mechanisms, leading to a similar disease phenotype. This new biology-driven ontological framework yields a less variable and more compact domain-related set of features with potential mechanistic generalization. The proposed network analysis, allowing for the determination of a clearcut biological distinction between ASD and DD (the latter presenting much lower modularity and heterogeneity), is amenable to machine learning approaches and provides an interesting avenue of research for the future.

Efficacy of different neoadjuvant treatment regimens in BRCA-mutated triple negative breast cancer: a systematic review and meta-analysis.

PURPOSE: Triple negative breast cancer (TNBC) is an aggressive breast cancer strongly associated with BRCA mutation. Standard neoadjuvant chemotherapy remains the standard of care for early stage TNBC, the optimal chemotherapy regimen is still a matter of discussion. Other agents, such as poly-ADP-ribosyl polymerase inhibitors (PARPi) and anti-vascular endothelial growth factor (VEGF) antibodies were evaluated in the neoadjuvant setting. This systematic review and meta-analysis intend to evaluate the impact of neoadjuvant treatments in pCR rates in TNBC gBRCA mutation, beyond traditional standard chemotherapy. METHODS: PubMed, Clinicaltrials.gov, Cochrane CENTRAL, Embase and key oncological meetings for trials were searched for studies reporting neoadjuvant chemo-immunotherapy in BRCA positive TNBC. RESULTS: Out of 1238 records reviewed, thirty-one trials were included, resulting in a total 619 BRCA-mutated TNBC patients. In BRCA mutated TNBC patients who received cisplatin in monotherapy the proportion of patients who achieved pCR was 0.53 (95%CI [0.30, 0.76]), and when treatment combined standard chemotherapy and platin derivatives the proportion of pCR increased to 0.62 (95% CI [0.48, 0.76]). The group of patients treated with platin derivatives, anthracyclines ± taxanes achieved the highest proportion of pCR, 0.66. Patients treated with PARPi alone show a pCR proportion of 0.55 (95% CI [0.30, 0.81]); and when standard chemotherapy and platin derivatives were combined with PARPi the proportion of pCR did not vary. CONCLUSIONS: Patients with BRCA mutated TNBC treated with cisplatin in monotherapy demonstrate inferior proportion in the pCR achievement when compared with standard chemotherapy plus platin derivates. The best pCR was achieved with platin derivates in association with anthracyclines ± taxanes. No difference in pCR was found between PARPi alone vs PARPi with standard chemotherapy.

Current Treatment of Cleft Patients in Europe from a Provider Perspective: A Cross-Sectional Survey.

The latest Eurocleft study reported several discrepancies in cleft care. Since then, no critical assessment has been performed. This study aimed to better understand the main strengths and inefficiencies of cleft care within Europe. The Google documents platform was used to create an online survey to investigate several aspects, i.e., provider characteristics, patient profile, services offered, and treatment protocols and complications. Descriptive statistics were calculated. The association between categorical variables was performed using Fisher's exact test. The significance level chosen was 0.05. A total of 69 individuals from 23 European countries completed the survey. Centralized care was the preferred system, and the majority of the countries have an association for cleft patients and professionals (53.6%). The largest percentage of patients was seen in the university hospital environment (Fisher's exact test p < 0.001). The majority of responders (98.6%) reported that an orthodontist was involved in cleft treatment, and 56.5% of them spend 76-100% of their time treating these patients. Despite cleft care having been reconfigured in Europe, a better consensus among the various centers regarding provider characteristics, services offered, and treatment protocols is still required. There is a need for better coordination between clinicians and national/international regulatory bodies.

Cleft Orthodontic Care in Europe: A Cross-Sectional Survey.

(1) Background: Orthodontists have an important role in cleft care. Over the two decades since the Eurocleft studies, a significant improvement in healthcare systems has been achieved but there has been no critical assessment regarding the establishment of proposed standard protocols. This study aimed to describe the current provider characteristics, orthodontic appliances, services offered, orthodontic complications, and cost analysis of cleft treatment in Europe. (2) Methods: A cross-sectional 22-question online survey, accessible from January 2021 to July 2021, was sent to 214 practitioners, pertaining to provider characteristics, orthodontic appliances, services offered, orthodontic complications, and cost analysis. Descriptive statistics were calculated for each question. Fisher's exact test was used to assess the association between categorical variables. (3) Results: A total of 79 responses from 23 European countries completed the survey (response rate = 37%), with 69 surveys being assessed after the exclusion of incomplete surveys. Rapid maxillary expansion was the preferred expansion protocol (45%). Distraction osteogenesis was the most reported alternative treatment to secondary bone grafts (19%), with private practitioners being less likely to perform these treatments (Fisher's exact test, p = 0.001). Orthodontic services offered were, however, rather similar in the various locations of provision (hospital and/or university, private). Compromised oral hygiene (77%) was the most reported orthodontic complication. The National Health Services support the majority of cleft orthodontic care (67%) in Europe. (4) Conclusion: An apparent improvement in orthodontic healthcare provision has been achieved within Europe in the last two decades, but there are several discrepancies, namely regarding treatment timing and the appliances offered.

Integrated Multi-Omics Signature Predicts Survival in Head and Neck Cancer.

Head and Neck Cancer (HNC) is characterized by phenotypic, biological, and clinical heterogeneity. Despite treatment modalities, approximately half of all patients will die of the disease. Several molecular biomarkers have been investigated, but until now, without clinical translation. Here, we identified an integrative nine-gene multi-omics signature correlated with HNC patients' survival independently of relapses or metastasis development. This prognosis multi-omic signature comprises genes mapped in the chromosomes 1q, 3p, 8q, 17q, 19p, and 19q and encompasses alterations at copy number, gene expression, and methylation. Copy number alterations in LMCD1-A1S and GRM7, the methylation status of CEACAM19, KRT17, and ST18, and the expression profile of RPL29, UBA7, FCGR2C, and RPSAP58 can predict the HNC patients' survival. The difference higher than two years observed in the survival of HNC patients that harbor this nine-gene multi-omics signature can represent a significant step forward to improve patients' management and guide new therapeutic targets development.

A Pilot Randomized Controlled Clinical Trial Comparing Piezo Versus Conventional Rotary Surgery for Removal of Impacted Mandibular Third Molars.

BACKGROUND: The extraction of impacted mandibular third molars is a frequent dental surgery, interfering with patients' quality of life. Ultrasonic surgery is an alternative to osteotomy with conventional rotary instruments. This study compares postoperative signals and symptoms after extracting impacted mandibular third molars using ultrasonic surgery or conventional rotary osteotomy. METHODS: A pilot randomized controlled clinical trial was conducted. Thirty patients were randomly divided into the test group (ultrasonic technique) and a control group (conventional rotatory technique). All surgeries were timed. Swelling parameters, trismus and paraesthesia were evaluated on the day of surgery and the third, fifth and seventh postoperative days. Intraoperative bleeding was evaluated during surgery. Postoperative pain was evaluated daily by the patient through a visual analogue scale and the number of ingested analgesics. RESULTS: Pain, swelling and trismus present beneficial results with the ultrasonic technique but without statistical significance. Intraoperative bleeding was significantly lower with ultrasonic surgery (t(28) = 3.258; p = 0.003). Operating time was significantly higher in extractions involving osteotomy and cutting crown and roots either with the conventional technique (p = 0.020) or ultrasonic technique (p = 0.039). Regardless of the surgical difficulty, no statistically significant results were detected between techniques regarding the procedure duration. CONCLUSIONS: The beneficial postoperative signs and symptoms make ultrasonic surgery a favourable therapeutic option, especially when the integrity of noble anatomical structures is the most important risk factor. Further studies with larger samples are needed to support the use of piezosurgery as a valid option for impacted mandibular third molar extraction.

Putative Biomarkers in Tears for Diabetic Retinopathy Diagnosis.

Purpose: Tear fluid biomarkers may offer a non-invasive strategy for detecting diabetic patients with increased risk of developing diabetic retinopathy (DR) or increased disease progression, thus helping both improving diagnostic accuracy and understanding the pathophysiology of the disease. Here, we assessed the tear fluid of nondiabetic individuals, diabetic patients with no DR, and diabetic patients with nonproliferative DR (NPDR) or with proliferative DR (PDR) to find putative biomarkers for the diagnosis and staging of DR. Methods: Tear fluid samples were collected using Schirmer test strips from a cohort with 12 controls and 54 Type 2 Diabetes (T2D) patients, and then analyzed using mass spectrometry (MS)-based shotgun proteomics and bead-based multiplex assay. Tear fluid-derived small extracellular vesicles (EVs) were analyzed by transmission electron microscopy, Western Blotting, and nano tracking. Results: Proteomics analysis revealed that among the 682 reliably quantified proteins in tear fluid, 42 and 26 were differentially expressed in NPDR and PDR, respectively, comparing to the control group. Data are available via ProteomeXchange with identifier PXD033101. By multicomparison analyses, we also found significant changes in 32 proteins. Gene ontology (GO) annotations showed that most of these proteins are associated with oxidative stress and small EVs. Indeed, we also found that tear fluid is particularly enriched in small EVs. T2D patients with NPDR have higher IL-2/-5/-18, TNF, MMP-2/-3/-9 concentrations than the controls. In the PDR group, IL-5/-18 and MMP-3/-9 concentrations were significantly higher, whereas IL-13 was lower, compared to the controls. Conclusions: Overall, the results show alterations in tear fluid proteins profile in diabetic patients with retinopathy. Promising candidate biomarkers identified need to be validated in a large sample cohort.

The accuracy of magnetic resonance imaging in predicting the size of pure ductal carcinoma in situ: a systematic review and meta-analysis.

Ductal carcinoma in situ (DCIS) is a putative precursor of invasive breast cancer and MRI is considered the most sensitive imaging technique for its detection. This study aims to evaluate the accuracy of MRI measuring the pure DCIS size, against pathology, to better understand the role of MRI in the management of this intraductal neoplasm.Potentially eligible studies in MEDLINE, Embase and Google Scholar, up to January 2021 were considered, and a systematic review and meta-analysis according to the published protocol (Prospero-CRD42021232228) was performed. Outcomes of mean differences and accuracy rates were analysed using IBM® SPSS® v26 and random-effect models in platform R v3.3.Twenty-two cross-sectional studies were selected and 15 proceeded to meta-analysis. MRI accurately predicted 55% of the tumours' sizes and, according to Bland-Altman plots, concordance between MRI and pathology was greater for smaller tumours. In the meta-analysis, difference of the means between MRI and pathology was 3.85 mm (CI 95% [-0.92;8.60]) with considerable heterogeneity (I2 = 96.7%). Subgroup analysis showed similar results for sizes between different MRI fields, temporal resolution, slice thickness and acquisition times, but lower heterogeneity in studies using 3-T MRI (I2 = 57.2%). Results were concordant with low risk of bias studies (2.46, CI 95% [0.57-4.36]), without heterogeneity (I2 = 0%).Therefore, MRI is shown to be an accurate method in pure DCIS size assessment. Once the best MRI protocol is established, evaluation of the impact of pure DCIS size in predicting treatment outcomes will contribute to clarifying current issues related to intraductal breast carcinoma.

Condylar Changes after Maxillary Expansion in Children with Cleft Lip and Palate-A Three-Dimensional Retrospective Study.

BACKGROUND: The presence of posterior crossbite can trigger aesthetic and functional changes as mandibular asymmetry in individuals, contributing to asymmetrical muscle function. Mandibular asymmetry and respective condyle adaptation may be an etiological factor in temporomandibular disorder. This study aims to evaluate the effects of maxillary expansion on the position and angulation of the condyles as well as the intercondylar distance in children with cleft lip and palate. METHODS: Twenty-five individuals with cleft lip and palate who underwent maxillary expansion were selected. Condylar changes were evaluated by cone beam computed tomography using the Pullinger and Hollender formula. To determine the statistically significant differences between the variables, the Student t-test and the Benjamini-Hochberg correction method for multiple comparisons were used. RESULTS: No statistically significant differences between angulation and condylar position before and after maxillary expansion were found. The intercondylar distance tended to increase in growing individuals with cleft lip and palate after maxillary expansion. CONCLUSIONS: Intercondylar distance shows a tendency to increase after expansion regardless of the cleft phenotype. No differences were found in angulation and condylar position with the changes in occlusion resulting from maxillary expansion.