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Background: Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy characterized by uncontrolled proliferation and impaired differentiation of myeloid cells in the bone marrow. The tumor suppressor gene TP53 plays a crucial role in maintaining genomic integrity and preventing the development of cancer. TP53 mutations are frequently observed in AML (∼10% of patients) and are associated with aggressive disease behavior, resistance to therapy, and poor prognosis., Summary: Recent changes in classification of TP53-mutated myelodysplastic syndrome (MDS) have occurred related to the allelic status of TP53 and more importantly to harmonize MDS/AML patients as a homogeneous hematological malignancy. Current treatment regimens involve hypomethylating agents +/- venetoclax or intensive chemotherapy although unfortunately independent of treatment regimen the overall survival (OS) of this patient cohort is around 6 months with poor long-term outcomes after allogeneic stem-cell transplantation. Recent developments geared toward the treatment of TP53-mutated MDS/AML have focused on immunotherapies., Key Messages: Notably, there is optimism surrounding these new therapies that could provide breakthroughs with improving outcomes either as monotherapy or combined with established nonimmune therapies. This paper aims to provide an overview of TP53-mutated MDS/AML, including the underlying mechanisms, clinical implications, and emerging therapeutic strategies targeting this hematologic malignancy., (© 2023 S. Karger AG, Basel.)

Purpose: To evaluate the antiplaque effects for 0.454% bioavailable gluconate chelated stannous fluoride (SnF₂) dentifrices versus controls by clinical model, plaque index, tooth surface and tooth type in a pooled analysis., Methods: Randomized controlled trials (RCTs) were conducted to evaluate plaque effects of SnF₂ dentifrices from the same formulation family over the past 30 years. Forty-four 4-day and longer-term (≥ 2 weeks) RCTs conducted in six countries with 3,336 subjects using Turesky Modified Quigley-Hein Plaque Index, Rustogi Modification of the Navy Plaque Index, Digital Plaque Imaging Analysis, and Silness and Löe Plaque Index were included., Results: In 13 and 11 longer-term studies assessing SnF₂ dentifrice versus a negative or positive control, respectively, standardized differences in average plaque score of -1.15 (95% CI: -1.61, -0.69) and -0.74 (95% CI: -1.20, -0.28) were observed (P ≤ 0.011), favoring SnF₂. Reductions represented a 19% and 16% benefit versus the negative and positive control, respectively. In 18 and five 4-day studies assessing SnF₂ dentifrice versus a negative (NaF/SMFP) or positive (triclosan/chlorhexidine) control, respectively, differences in average 4-day plaque score of -0.27 (95% CI: -0.31, -0.23) and -0.15 (95% CI: -0.25, -0.06) were observed (P≤ 0.001) favoring SnF₂. Reductions represented a 14% and 11% benefit versus the negative and positive control, respectively. Significant antiplaque benefits for SnF₂ dentifrice were seen regardless of clinical model, plaque index, tooth surface or type, including brushed and unbrushed surfaces (P≤ 0.049)., Clinical Significance: Bioavailable gluconate chelated SnF₂ dentifrices showed consistent plaque inhibition versus negative and positive controls across all conditions evaluated. Importantly, the effect on unbrushed surfaces illustrated the significant plaque inhibition benefit of SnF₂ beyond mechanical plaque removal., Competing Interests: All authors are employees of The Procter & Gamble Company. This work was funded by The Procter & Gamble Company., (Copyright©American Journal of Dentistry.)

Objectives: To compare the effect of bioavailable gluconate-chelated stannous fluoride (SnF 2 ) toothpaste with control toothpastes for treatment of dentine hypersensitivity (DH) and enamel erosion., Data and Sources: A Procter & Gamble Oral Care archive of clinical studies was reviewed from 2000 to 2020. Eligible studies were Randomised Controlled Trials (RCTs) investigating bioavailable gluconate-chelated SnF 2 toothpaste efficacy compared to controls in adult participants measured following tactile (Yeaple force) and/or evaporative stimuli (Schiff score) in-vivo, duration <2 months (DH); or by erosive toothwear (profilometry) from in-situ samples, duration 10-15 days. Two authors independently assessed eligibility and resolved disagreements by discussion. A meta-analysis was undertaken and Risk of Bias (RoB) assessed using the Cochrane collaboration RoB tool for randomized parallel-group and cross-over trials., Results: Fourteen RCTs (1287 participants) assessed DH relief and Six RCTs (184 participants) enamel erosion protection. For DH SnF 2 toothpastes provided a 57 % (evaporative air) and 142 % (tactile) benefit versus negative controls (sodium fluoride/monofluorophosphate, 8 studies; p < 0.001). Compared to positive controls (potassium nitrate or arginine, 6 studies), a 22 % advantage (p = 0.036) was seen for evaporative air. In erosion studies, SnF 2 toothpastes provided an 83 % benefit versus control toothpastes (arginine or sodium fluoride; p < 0.001) with a change (95 %CI) in average surface profilometry level (μm) of -2.02(-2.85, -1.20)., Conclusions: The use of these bioavailable SnF 2 toothpastes, as part of a daily oral hygiene regimen, will provide patients with enamel erosion protection, combined with alleviation of DH pain when present, improving quality of life., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Aim: To estimate gingivitis effects of a bioavailable gluconate chelated 0.454% stannous fluoride (SnF 2 ) family of dentifrices in adult subjects versus positive (triclosan) and negative (NaF or MFP) controls when used ≤3 months., Materials and Methods: A meta-analysis evaluated bioavailable gluconate chelated SnF 2 dentifrices versus a negative or positive control for gingival bleeding., Results: In 18 randomized controlled trials (RCTs) with 2,890 subjects assessing SnF 2 paste versus a negative or positive control, the average number of bleeding sites was reduced by 51% and 31%, respectively. The average change (95% CI) in number of bleeding sites was -16.3 (-27.8, -4.9) versus the negative control and -3.6 (-5.4, -1.8) versus the positive control. Subjects with localized or generalized gingivitis had 3.7 times better odds (95% CI [2.8, 5.0]) of shifting to generally healthy using SnF 2 versus a negative control and 2.8 times better odds (95% CI [2.1, 3.9]) of shifting to generally healthy using SnF 2 versus a positive control. The individual study risk of bias was deemed to be low in all categories of bias., Conclusion: This meta-analysis demonstrates significant gingivitis benefits of bioavailable SnF 2 dentifrices when used ≤3 months versus positive (triclosan) and negative (NaF or MFP) controls., (© 2019 John Wiley & Sons A/S. published by John Wiley & Sons Ltd.)

Body condition scoring (BCS) provides a readily available technique that can be used by both veterinary professionals and owners to assess the body condition of cats, and diagnose overweight or underweight conditions. The objective of this study was to evaluate a five-point BCS system with half-point delineations using dual-energy x-ray absorptiometry (DXA). Four evaluators (a veterinarian, veterinary technician, trained scorer and untrained scorer) assessed 133 neutered adult cats. For all scorers, BCS score was more strongly correlated with percent body fat than with body weight. Percent body fat increased by approximately 7% within each step increase in BCS. The veterinarian had the strongest correlation coefficient between BCS and percent fat (r = 0.80). Mean body fat in cats classified as being in ideal body condition was 12 and 19%, for 3.0 and 3.5 BCS, respectively. Within BCS category, male cats were significantly heavier in body weight than females within the same assigned BCS category. However, DXA-measured percent body fat did not differ significantly between male and female cats within BCS category, as assigned by the veterinarian (P >0.13). Conversely, when assessed by others, mean percent body fat within BCS category was lower in males than females for cats classified as being overweight (BCS >4.0). The results of this study show that using a BCS system that has been validated within a range of normal weight to moderately overweight cats can help to differentiate between lean cats and cats that may not be excessively overweight, but that still carry a higher proportion of body fat., (© ISFM and AAFP 2014.)

Background: Numerous factors have been linked to surgical career choice, including the quality of third-year surgical clerkship. The vast majority of studies also selectively evaluate one or only a few variables that link to surgical career choice, so relative impact cannot be assessed. This study simultaneously evaluates the majority of variables linked to surgical career choice in previous research so that the relative contributions of each of these variables with respect to surgical career choice can be determined., Study Design: Surveys before, during, and after the third-year surgical clerkship included student demographics, background, and values (eg, importance of money, controllable lifestyle), and student reactions to the third-year surgical clerkship. The dependent variables in this study included interest in surgery at the beginning and end of the clerkship and matching into a surgical residency., Results: Both univariate and multivariate analyses generally supported findings in the literature, but the strengths of these associations reported previously might not have been accurate. In this study, the surgical resident match odds ratio for students starting the clerkship already knowing they wanted to be a surgeon was 22.46; the next highest associations were 4.65 and 3.37, which corresponded to earlier exposure to a surgical specialty and earlier exposure to general surgery, respectively. Differences in career choice for general surgeons and surgical specialists were also explored., Conclusions: Although the experience of the clerkship is related to career choice, the largest impact of the clerkship is for those already interested in a surgical career. Interest in a surgical career largely develops before the third-year clerkship. Implications of the results for recruiting greater numbers of students into surgical careers are discussed., (Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background and Aim of the Study: There is paucity of data relating to the geographic variation in mitral valve (MV) repair trends and outcomes of patients undergoing MV surgery., Methods: Using the 2005-2008 Nationwide Inpatient Sample (NIS) Database, the four geographic regions of the US (Northeast, Midwest, South, and West) were compared with respect to baseline characteristics, mitral procedure selection, and hospital mortality of patients undergoing either MV repair (ICD-9CM code 35.12) or replacement (ICD-9-CM codes 35.23 and 35.24)., Results: Patient age was similar across regions. The Midwest had the highest proportion of whites, while patients in the South were the least affluent. The Northeast had the highest proportion of patients presenting non-electively. The West and Midwest had more women and patients with private insurance compared to the South, but the proportion of patients on Medicaid was similar across all regions. The Northeast and the South had a higher Charlson Comorbidity Index compared to the West. The overall repair rate was 47%; the Midwest had the highest rate (50%), and the South the lowest (42%) (p = NS). Following adjustment for baseline characteristics, hospital mortality was similar among regions for patients undergoing MV replacement. For the subset undergoing MV repair, hospital mortality was more than 2.5-fold higher in the South than in the Northeast (OR = 2.88, 95% CI 1.45-5.71)., Conclusion: MV repair is utilized in less than half of all mitral procedures nationwide. Repair rates and hospital mortality are comparable across all four regions in the US. Hospital mortality for isolated MV surgery is low. The higher adjusted mortality for patients undergoing MV repair in the South identifies an important area for future improvement in the care of patients with valvular heart disease.

Although evidence-based practice guidelines have been developed to achieve greater consistency and quality in mental health care, insufficient research exists on implementing these guidelines among different racial/ethnic groups and the impact of guideline adherence on treatment outcomes. This study compared mental health care received by community dwelling Latino and non-Latino White Medicaid enrollees in Florida with a diagnosis of major depressive disorder (MDD) and examined predictors of adherence to American Psychiatric Association (APA) guidelines for the treatment of MDD. Latinos were more likely than Whites to receive guideline adherent treatment (OR = 1.21, P < .0001). Enrollees receiving combination drug therapy were most likely to receive treatment consistent with APA guidelines (OR = 4.25, P < .0001). Despite research demonstrating the efficacy of evidence-based practices, many study participants did not receive guideline adherent treatment. Policies and practices targeted at increasing adherence to approved guidelines and improving treatment outcomes are recommended.

The binding of Ab (IgG)-opsonized particles by FcgammaRs on macrophages results in phagocytosis of the particles and generation of a respiratory burst. Both IgG-stimulated phagocytosis and respiratory burst involve activation of protein kinase C (PKC). However, the specific PKC isoforms required for these responses have yet to be identified. We have studied the involvement of PKC isoforms in IgG-mediated phagocytosis and respiratory burst in the mouse macrophage-like cell line, RAW 264.7. Like primary monocyte/macrophages, their IgG-mediated phagocytosis was calcium independent and diacylglycerol sensitive, consistent with novel PKC activation. Respiratory burst in these cells was Ca2+ dependent and inhibited by staurosporine and calphostin C as well as by the classic PKC-selective inhibitors Gö 6976 and CGP 41251, suggesting that classic PKC is required. In contrast, phagocytosis was blocked by general PKC inhibitors but not by the classic PKC-specific drugs. RAW 264.7 cells expressed PKCs alpha, betaI, delta, epsilon, and zeta. Subcellular fractionation demonstrated that PKCs alpha, delta, and epsilon translocate to membranes during phagocytosis. In Ca2+-depleted cells, only novel PKCs delta and epsilon increased in membranes, and the time course of their translocation was consistent with phagosome formation. Confocal microscopy of cells transfected with green fluorescent protein-conjugated PKC alpha or epsilon confirmed that these isoforms translocated to the forming phagosome in Ca-replete cells, but only PKC epsilon colocalized with phagosomes in Ca2+-depleted cells. Taken together, these results suggest that the classic PKC alpha mediates IgG-stimulated respiratory burst in macrophages, whereas the novel PKCs delta and/or epsilon are necessary for phagocytosis.

The majority of cell surface receptors involved in antigen recognition by T cells and in the orchestration of the subsequent cell signalling events are glycoproteins. The length of a typical N-linked sugar is comparable with that of an immunoglobulin domain (30 A). Thus, by virtue of their size alone, oligosaccharides may be expected to play a significant role in the functions and properties of the cell surface proteins to which they are attached. A databank of oligosaccharide structures has been constructed from NMR and crystallographic data to aid in the interpretation of crystal structures of glycoproteins. As unambiguous electron density can usually only be assigned to the glycan cores, the remainder of the sugar is then modelled into the crystal lattice by superimposing the appropriate oligosaccharide from the database. This approach provides insights into the roles that glycosylation might play in cell surface receptors, by providing models that delineate potential close packing interactions on the cell surface. It has been proposed that the specific recognition of antigen by T cells results in the formation of an immunological synapse between the T cell and the antigen-presenting cell. The cell adhesion glycoproteins, such as CD2 and CD48, help to form a cell junction, providing a molecular spacer between opposing cells. The oligosaccharides located on the membrane proximal domains of CD2 and CD48 provide a scaffold to orient the binding faces, which leads to increased affinity. In the next step, recruitment of the peptide major histocompatibility complex (pMHC) by the T-cell receptors (TCRs) requires mobility on the membrane surface. The TCR sugars are located such that they could prevent non-specific aggregation. Importantly, the sugars limit the possible geometry and spacing of TCR/MHC clusters which precede cell signalling. We postulate that, in the final stage, the sugars could play a general role in controlling the assembly and stabilisation of the complexes in the synapse and in protecting them from proteolysis during prolonged T-cell engagement., (Copyright 1999 Academic Press.)

This double-blind, placebo-controlled study was undertaken to determine 1) the efficacy of oral risedronate for prevention of bone loss in healthy, early postmenopausal patients with normal bone mass, 2) the effect on bone mass when treatment was stopped, and 3) the safety and tolerance of risedronate in this population. A group of 111 patients were randomized to oral placebo, risedronate 5 mg daily, or risedronate 5 mg cyclically, for 2 yr followed by 1 yr off treatment. Measurements included percentage change from baseline in lumbar spine bone mineral density (BMD) at 24 months; percentage change from baseline in BMD of the femoral neck, trochanteric region, and Ward's triangle region of the proximal femur; and changes in biochemical markers of bone turnover. After 2 yr, there was a mean increase in BMD of the lumbar spine of 1.4% from baseline and of 5.7% vs. placebo in the risedronate 5 mg daily group. There were decreases from baseline in BMD of 1.6% and 4.3% in the risedronate 5 mg cyclic and placebo groups, respectively. By the end of 24 months, trochanteric bone mass at the hip increased by 5.4% in the risedronate 5 mg daily group and by 3.3% in the risedronate 5 mg cyclic group vs. placebo. Bone mass was maintained at the femoral neck in the 2 active-treatment groups vs. a 2.4% mean loss with placebo. During the treatment-free follow-up, bone turnover increased toward baseline in both risedronate groups. By the end of that year, lumbar spine bone mass in all 3 groups was lower than at baseline. Oral risedronate was well tolerated. We conclude that risedronate (5 mg daily) increases bone mass and risedronate (5 mg cyclic) appears to prevent bone loss in early postmenopausal women with normal BMD.