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Purpose: The existence of patients with multiple myeloma (MM) and light-chain (AL) amyloidosis who present with a monoclonal gammopathy of undetermined significance (MGUS)-like phenotype has been hypothesized, but methods to identify this subgroup are not standardized and its clinical significance is not properly validated., Patients and Methods: An algorithm to identify patients having MGUS-like phenotype was developed on the basis of the percentages of total bone marrow (BM) plasma cells (PC) and of clonal PC within the BM PC compartment, determined at diagnosis using flow cytometry in 548 patients with MGUS and 2,011 patients with active MM. The clinical significance of the algorithm was tested and validated in 488 patients with smoldering MM, 3,870 patients with active MM and 211 patients with AL amyloidosis., Results: Patients with smoldering MM with MGUS-like phenotype showed significantly lower rates of disease progression (4.5% and 0% at 2 years in two independent series). There were no statistically significant differences in time to progression between treatment versus observation in these patients. In active newly diagnosed MM, MGUS-like phenotype retained independent prognostic value in multivariate analyses of progression-free survival (PFS; hazard ratio [HR], 0.49; P = .001) and overall survival (OS; HR, 0.56; P = .039), together with International Staging System, lactate dehydrogenase, cytogenetic risk, transplant eligibility, and complete remission status. Transplant-eligible patients with active MM with MGUS-like phenotype showed PFS and OS rates at 5 years of 79% and 96%, respectively. In this subgroup, there were no differences in PFS and OS according to complete remission and measurable residual disease status. Application of the algorithm in two independent series of patients with AL predicted for different survival., Conclusion: We developed an open-access algorithm for the identification of MGUS-like patients with distinct clinical outcomes. This phenotypic classification could become part of the diagnostic workup of MM and AL amyloidosis.

Neuromorphic visual systems emulating biological retina functionalities have enormous potential for in-sensor computing, with prospects of making artificial intelligence ubiquitous. Conventionally, visual information is captured by an image sensor, stored by memory units, and eventually processed by the machine learning algorithm. Here, we present an optoelectronic synapse device with multifunctional integration of all the processes required for real time object identification. Ultraviolet-visible wavelength-sensitive MoS 2 FET channel with infrared sensitive PtTe 2 /Si gate electrode enables the device to sense, store, and process optical data for a wide range of the electromagnetic spectrum, while maintaining a low dark current. The device exhibits optical stimulation-controlled short-term and long-term potentiation, electrically driven long-term depression, synaptic weight update for multiple wavelengths of light ranging from 300 nm in ultraviolet to 2 μm in infrared. An artificial neural network developed using the extracted weight update parameters of the device can be trained to identify both single wavelength and mixed wavelength patterns. This work demonstrates a device that could potentially be used for realizing a multiwavelength neuromorphic visual system for pattern recognition and object identification.

Purpose: Undetectable measurable residual disease (MRD) is a surrogate of prolonged survival in multiple myeloma. Thus, treatment individualization based on the probability of a patient achieving undetectable MRD with a singular regimen could represent a new concept toward personalized treatment, with fast assessment of its success. This has never been investigated; therefore, we sought to define a machine learning model to predict undetectable MRD at the onset of multiple myeloma., Experimental Design: This study included 487 newly diagnosed patients with multiple myeloma. The training (n = 152) and internal validation cohorts (n = 149) consisted of 301 transplant-eligible patients with active multiple myeloma enrolled in the GEM2012MENOS65 trial. Two external validation cohorts were defined by 76 high-risk transplant-eligible patients with smoldering multiple myeloma enrolled in the Grupo Español de Mieloma(GEM)-CESAR trial, and 110 transplant-ineligible elderly patients enrolled in the GEM-CLARIDEX trial., Results: The most effective model to predict MRD status resulted from integrating cytogenetic [t(4;14) and/or del(17p13)], tumor burden (bone marrow plasma cell clonality and circulating tumor cells), and immune-related biomarkers. Accurate predictions of MRD outcomes were achieved in 71% of cases in the GEM2012MENOS65 trial (n = 214/301) and 72% in the external validation cohorts (n = 134/186). The model also predicted sustained MRD negativity from consolidation onto 2 years maintenance (GEM2014MAIN). High-confidence prediction of undetectable MRD at diagnosis identified a subgroup of patients with active multiple myeloma with 80% and 93% progression-free and overall survival rates at 5 years., Conclusions: It is possible to accurately predict MRD outcomes using an integrative, weighted model defined by machine learning algorithms. This is a new concept toward individualized treatment in multiple myeloma. See related commentary by Pawlyn and Davies, p. 2482., (©2022 American Association for Cancer Research.)

Optoelectronic synapses combine the functionalities of a non-volatile memory and photodetection in the same device, paving the path for the realization of artificial retina systems which can capture, pre-process, and identify images on the same platform. Graphene/Ta 2 O 5 /graphene phototransistor exhibits synapse characteristics when visible electromagnetic radiation of wavelength 405 nm illuminates the device. The photocurrent is retained after light withdrawal when positive gate voltage is applied to the device. The device exhibits distinct conductance states, modulated by different parameters of incident light, such as pulse width and number of pulses. The conductance state can be retained for 10 4  s, indicating long term potentiation (LTP), similar to biological synapses. By using optical and electrical pulses, the device shows optical potentiation and electrical LTD repeatably, implying their applicability in neural networks for pattern recognition., (© 2022. The Author(s).)

Background/purpose: The use of fluoride is known to reduce the risk of dental caries. There is limited information on the relationship between Streptococcus mutans ( S. mutans ) and fluoride exposure. This study investigated the association between the count of S. mutans on supragingival biofilm and fluoride exposure of scholar children., Materials and Methods: In this cross-sectional study, 56 children from 9 to 11 years of age were selected. Fluoride concentration in drinking water, urine and saliva of each participant were assessed. The count of S. mutans was estimated by calculating the DNA copy number through a quantitative real time polymerase chain reaction (qPCR) assay. Also, sociodemographic data, oral and general health information and variables related to caries risk were evaluated. A stepwise multiple linear regression was performed in all caries related predictor variables with the count of S. mutans as the dependent variable., Results: The multiple linear regression analysis showed that the concentration of fluoride in saliva (β = -3.029, p < 0.001) and urine (β = -2.057, p = 0.017), time of last visit to the dentist (β = 1.968, p = 0.001), plaque index (β = 1.637, p = 0.006) and number of surfaces with codes 3-6 (D 3-6 MFS) of ICDAS II criteria (β = 0.283, p = 0.076) were significantly associated with the count of S. mutans (Adjusted R square = 0.427, p < 0.001)., Conclusion: Fluoride levels in urine and saliva were negatively associated with the count of S. mutans in supragingival biofilm. Plaque index, D 3-6 MFS and time of last visit to the dentist showed a positive association., Competing Interests: The authors declare that they have no conflict of interest due to any relationship or financial support received., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequencing of paired diagnostic and MRD tumor cells, revealed greater clonal selection in patients with standard-risk CAs, higher genomic instability with acquisition of new mutations in high-risk MM, and no unifying genetic event driving MRD resistance. Conversely, RNA sequencing of diagnostic and MRD tumor cells uncovered the selection of MRD clones with singular transcriptional programs and reactive oxygen species-mediated MRD resistance in high-risk MM. Our study supports undetectable MRD as a treatment endpoint for patients with MM who have high-risk CAs and proposes characterizing MRD clones to understand and overcome MRD resistance. This trial is registered at www.clinicaltrials.gov as #NCT01916252., (© 2021 by The American Society of Hematology.)

Purpose: Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG)., Patients and Methods: In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10 -6 . Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial., Results: Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30; P < .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29; P < .001). Timing of undetectable MRD (after induction v intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%., Conclusion: The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.

Objective: The objective of this study was to determine dental caries frequency and to analyze salivary and bacterial factors associated with active and inactive systemic lupus erythematous (SLE) patients. Also, a proposal to identify dental caries by a surface, teeth, and the patient was developed., Material and Methods: A cross-sectional, blinded study that included 60 SLE patients divided into two groups of 30 subjects each, according to the Activity Index for Diagnosis of Systemic Lupus Erythematous (SLEDAI). The decayed, missing, and filled teeth (DMFT) index and Integrative Dental Caries Index (IDCI) were used for analyzing dental caries. The saliva variables recorded were: flow, pH, and buffer capacity. The DNA copies of Streptococcus mutans and Streptococcus sobrinus were estimated by real-time PCR., Results: The caries frequency was 85% for SLE subjects (73.3% for inactive systemic lupus erythematous (ISLE) and 100% for active systemic lupus erythematous (ASLE)); DMFT for the SLE group was 12.6 ± 5.7 and the IDCI was (9.8 ± 5.9). The ASLE group showed a salivary flow of 0.65 compared with 0.97 ml/1 min from the ISLE group; all variables mentioned above showed a statistical difference (p < 0.05). The salivary pH was 4.6 (6.06 for ISLE and 3.9 for ASLE). The DNA copies of S. mutans and S. sobrinus were high; all variables mentioned above show a significant statistical difference (p < 0.05) between groups., Conclusion: SLE patients had high DMFT and IDCI scores that were associated with a decrease in salivary flow, pH, and buffer capacity. There were high counts of S. sobrinus and S. mutans species, and IDCI is a useful tool to provide more detail about dental caries in epidemiological studies., (© The Author(s) 2016.)

Meclofenamic acid is a nonsteroidal anti-inflammatory drug that has shown therapeutic potential for different types of cancers, including androgen-independent prostate neoplasms. The antitumor effect of diverse nonsteroidal anti-inflammatory drugs has been shown to be accompanied by histological and molecular changes that are responsible for this beneficial effect. The objective of the present work was to analyze the histological changes caused by meclofenamic acid in androgen-independent prostate cancer. Tumors were created in a nude mouse model using PC3 cancerous human cells. Meclofenamic acid (10 mg/kg/day; experimental group, n=5) or saline solution (control group, n=5) was administered intraperitoneally for twenty days. Histological analysis was then carried out on the tumors, describing changes in the cellular architecture, fibrosis, and quantification of cellular proliferation and tumor vasculature. Meclofenamic acid causes histological changes that indicate less tumor aggression (less hypercellularity, fewer atypical mitoses, and fewer nuclear polymorphisms), an increase in fibrosis, and reduced cellular proliferation and tumor vascularity. Further studies are needed to evaluate the molecular changes that cause the beneficial and therapeutic effects of meclofenamic acid in androgen-independent prostate cancer.

Background: Bacterial resistance to antibiotics is a health problem in many parts of the world. The aim of this study was to identify bacteria from dental infections and determine bacterial resistance to antibiotics used in dental care in the primary dentition., Methods: This cross-sectional study comprised 60 children who presented for dental treatment for active dental infections in the primary dentition. Samples from dental infections were collected and bacteria were identified by polymerase chain reaction (PCR) assay. Bacterial resistance to antibiotics was determined by colony forming units on agar plates containing amoxicillin, clindamycin and amoxillicin-clavulanic acid (A-CA) tested at 8 μg/ml or 16 μg/ml., Results: Clindamycin in both concentrations tested (8 μg/ml and 16 μg/ml) showed the highest bacterial resistance (85.9%), followed by amoxicillin (43.7%) and A-CA (12.0%). All comparisons among the three antibiotics used in the study exhibited statistical significance (p = <0.05) in both concentrations tested (8 μg/ml and 16 μg/ml), and under aerobic and anaerobic conditions. The most prevalent resistant species identified by PCR in primary dentition infections were: Streptococcus oralis and Prevotella intermedia (75.0%); Treponema denticola and Porphyromonas gingivalis (48.3%); Streptococcus mutans (45.0%); Campylobacter rectus; and Streptococcus salivarius (40%)., Conclusions: This study demonstrated that A-CA exhibited the lowest bacterial resistance for clinical isolates in primary dentition infections., (© 2014 Australian Dental Association.)

Introduction: A high-fat diet and male obesity are aspects associated with germinal epithelial alterations and male infertility. Some reports have shown that certain tetracyclines can protect the germinal epithelium from toxic drugs. The aim of the present study design was to evaluate the possible effect of doxycycline on testicular germ cells in individuals fed a Western diet (atherogenic), using a murine model., Methods: Two groups of male mice (BALB/c) were fed a high-fat Western diet (HFD). One of these two groups was given doxycycline at a dose of 10 mg/kg/day (HFD+Dox). A third group was fed a standard rodent diet (SD group). After 6 months, the mice were euthanized and morphologic and histopathologic analyses were performed., Results: Germinal epithelial height was similar between the SD group (54 μm) and the HFD+Dox group (53 μm) (p = 0.26), and it was significantly reduced in the HFD group (47 μm) (p = 0.0001). The degree of germinal epithelial loss (DGEL) was significantly lower in the SD (10) and HFD+Dox (12.5) groups than in the HFD group (30) (p = 0.0001 and =0.007, respectively). There were no differences in the DGEL between the SD and HFD+Dox groups (p = 0.42)., Conclusions: Doxycycline administration was shown to prevent germinal epithelial loss in the testes of mice fed a high-fat diet. Future studies are necessary to evaluate the clinical usefulness of doxycycline or its analogs in persons with a habitual high-fat diet.

Unlabelled: The aim of this study was to characterize the main periodontal bacterial species in Down syndrome (DS) patients with and without periodontitis., Method: This cross-sectional study involved 75 DS patients, 45 with and 30 without periodontitis. Informed consent, health and dental questionnaires and periodontitis diagnosis were performed PCR and LAMP assays were performed on subgingival dental plaque sample., Results: Tannerella forsythia was the most frequent bacteria detected in the group with and without periodontitis (95.5 and 63.3%) followed by Treponema denticola (88.8 and 50%) and Porphyromonas gingivalis (53.3 and 25% respectively). There were statistical differences between groups (p < 0.05). Pg fimA type I was the most frequent Porphyromonas gingivalis genotype. Two different sets of primers (Aa-F/Aa-R and ltx3/ltx4) were used to detect Aggregatibacter actinomycetemcomitans and different frequencies were obtained, (68% and 14.6% respectively), they had a weak correlation (Cohen Kappa = 0.16). After sequencing of PCR products, ltx3/ltx4 showed more specificity. JP2 clone of A. actinomycetemcomitans was not detected in any sample., Conclusions: The composition of oral biofilm is fundamental for the development of periodontal disease independently of immunological alterations associated with DS. The frequency of detection of A. actinomycetemcomitans reported in the literature has a wide range, because the primers and probes applied

Purpose: Prostate cancer is a worldwide public health problem and its treatment continues to be a therapeutic challenge especially in patients with metastatic androgen-independent cancer. Inflammation is a process that has been involved in the origin of this cancer and its inhibition has been postulated as a prophylactic and therapeutic strategy. The present study evaluated two non-steroidal anti-inflammatory drugs (meclofenamic acid and mefenamic acid) that have been studied very little in regard to cancer treatment., Methods: In vitro, the cytotoxic effects of meclofenamic acid and mefenamic acid were determined in human prostate cancer cell lines (LNCaP: androgen-dependent; and PC3: androgen-independent). In vivo trials were divided into two phases; meclofenamic acid toxicity was initially determined at different doses (0, 5, 10 and 20 mg/kg/day/25 days) in BALB/c mice, after which a trial using non-toxic doses was carried out to evaluate the antitumor efficacy of the drug in a PC3/nude-mouse model of human androgen-independent prostate cancer., Results: In vitro trials showed that only meclofenamic acid is highly cytotoxic in neoplastic prostate cells. The 5 and 10 mg/kg/day/25 day doses did not cause relevant toxicity in the BALB/c mouse trial, and so both doses were used in the nude-mouse model of cancer trial. This latter trial showed that meclofenamic acid significantly reduces tumor growth, prolongs survival, and is even capable of generating total tumor regression in up to 25% of mice treated at high dose., Conclusions: Meclofenamic acid was shown to be a potential antineoplastic agent for both androgen-dependent and androgen-independent prostate cancer.

We describe a six year old Mexican girl whose clinical picture (short stature with delayed bone age, language difficulties and triangular face with prominent nose) was compatible with the diagnosis of Floating-Harbor Syndrome (FHS). A neuropsychological evaluation disclosed a mild mental retardation, a constructive apraxia, a comprehensive and expressive language impairment. The analysis of the present case and sixteen patients previously described establishes that the FHS is mainly characterized by proportionate short stature with significantly delayed bone age, delayed expressive language and peculiar face.