Prevalence and Quality of Endodontic Treatment in Patients with Cardiovascular Disease and Associated Risk Factors.

This study aimed to determine the prevalence and quality of endodontic treatment, by radiographically assessing the periapical periodontitis and endodontic treatment status in patients with cardiovascular disease (CVD) and cardiovascular risk (CVR) factors. Patients who visited the Out Patient Department of Institute of Dental Sciences and Department of Cardiology, Institute of Medical Sciences and SUM Hospital, Siksha 'O' Anusandhan University, Bhubaneswar, from August 2021 to February 2022, for a check-up or dental problem were considered as participants in this study. After obtaining informed consent, the participants were enrolled on the Oral Infections and Vascular Disease Epidemiology Study (INVEST) IDS, BHUBANESWAR. After testing negative for COVID-19, patients' demographic details, such as age and gender were recorded, followed by a panoramic radiographic examination (OPG). A total sample of 408 patients were divided into three groups: Group 1/control (without any cardiovascular manifestation) consisting of 102 samples, group 2 of 222 CVR patients, and group 3 of 84 CVD cases. The CVR and CVD groups had a preponderance of elderly age groups between 60 to 70 years, with a significantly higher proportion of males. Co-morbidities such as diabetes mellitus, hypertension, and dyslipidemia were significantly associated with the CVR and CVD groups. From OPG interpretation, it was observed that the periapical radiolucency was greater in the CVR and CVD groups than in the control group (p = 0.009). The prevalence of endodontically treated teeth was higher in CVR and CVD than in the control group (p = 0.028). A high prevalence of dental caries, about 70%, was reported in all three groups (p = 0.356). The presence of dental restoration among all the groups was low (p = 0.079). The proportion of periodontal bone loss in the control group was significantly lower than CVR and CVD (p = 0.000). There was a strong association between periapical radiolucency, endodontically treated teeth, and periodontal bone loss in CVR and CVD patients. Notably, the associations reported herein do not reflect a cause-effect relationship; however, individuals with endodontic pathologies may accumulate additional risk factors predisposing them to hypertension or other CVDs. The results emphasize that eliminating local infections may decrease the systemic infection burden.

Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development.

The gene regulatory networks that coordinate the development of the cardiac and pulmonary systems are essential for terrestrial life but poorly understood. The T-box transcription factor Tbx5 is critical for both pulmonary specification and heart development, but how these activities are mechanistically integrated remains unclear. Here using Xenopus and mouse embryos, we establish molecular links between Tbx5 and retinoic acid (RA) signaling in the mesoderm and between RA signaling and sonic hedgehog expression in the endoderm to unveil a conserved RA-Hedgehog-Wnt signaling cascade coordinating cardiopulmonary (CP) development. We demonstrate that Tbx5 directly maintains expression of aldh1a2, the RA-synthesizing enzyme, in the foregut lateral plate mesoderm via an evolutionarily conserved intronic enhancer. Tbx5 promotes posterior second heart field identity in a positive feedback loop with RA, antagonizing a Fgf8-Cyp regulatory module to restrict FGF activity to the anterior. We find that Tbx5/Aldh1a2-dependent RA signaling directly activates shh transcription in the adjacent foregut endoderm through a conserved MACS1 enhancer. Hedgehog signaling coordinates with Tbx5 in the mesoderm to activate expression of wnt2/2b, which induces pulmonary fate in the foregut endoderm. These results provide mechanistic insight into the interrelationship between heart and lung development informing CP evolution and birth defects.

Disruption of a hedgehog-foxf1-rspo2 signaling axis leads to tracheomalacia and a loss of sox9+ tracheal chondrocytes.

Congenital tracheomalacia, resulting from incomplete tracheal cartilage development, is a relatively common birth defect that severely impairs breathing in neonates. Mutations in the Hedgehog (HH) pathway and downstream Gli transcription factors are associated with tracheomalacia in patients and mouse models; however, the underlying molecular mechanisms are unclear. Using multiple HH/Gli mouse mutants including one that mimics Pallister-Hall Syndrome, we show that excessive Gli repressor activity prevents specification of tracheal chondrocytes. Lineage tracing experiments show that Sox9+ chondrocytes arise from HH-responsive splanchnic mesoderm in the fetal foregut that expresses the transcription factor Foxf1. Disrupted HH/Gli signaling results in 1) loss of Foxf1 which in turn is required to support Sox9+ chondrocyte progenitors and 2) a dramatic reduction in Rspo2, a secreted ligand that potentiates Wnt signaling known to be required for chondrogenesis. These results reveal a HH-Foxf1-Rspo2 signaling axis that governs tracheal cartilage development and informs the etiology of tracheomalacia.

Capsulotomy in Unstable Slipped Capital Femoral Epiphysis and the Odds of AVN: A Meta-analysis of Retrospective Studies.

BACKGROUND: Unstable slipped capital femoral epiphysis (SCFE) may lead to avascular necrosis (AVN) in up to 60% of patients. The aim of this study was to assess the best clinical evidence to determine the effect of capsular decompression (CD) on odds of AVN in unstable SCFE. METHODS: Medline, Embase, and Cochrane databases were systematically searched for comparative studies investigating AVN rates in unstable SCFE treated with or without CD (aspiration, percutaneous, or open). Quality was evaluated by the Newcastle Ottawa Scale. A comparative analysis with pooled effect estimates using random-effects modeling was calculated. Secondary analysis pooled AVN rates from both comparative studies and case series. RESULTS: Comparative analysis included 17 retrospective studies with 453 hips (201 with CD, 252 without CD). Thirty-four of 201 (17%) hips with CD developed AVN, while 67 of 252 (27%) hips without CD developed AVN. The odds of AVN for patients treated with or without CD [odds ratio=0.80, 95% confidence interval (CI): 0.48-1.35] was not statistically different. Subanalysis on patients treated with in situ pinning or positional reduction and pinning showed no difference in AVN rates with or without CD (odds ratio=0.97, 95% CI: 0.44-2.10). In the secondary analysis of 17 comparative studies and 23 case series, the average rate of AVN was 17%, 0.17 (95% CI: 0.13-0.23) for patients treated with CD (60/447 hips) and 28%, 0.28 (95% CI: 0.22-0.35) for patients treated without CD (129/464 hips). CONCLUSIONS: There was no statistically significant decrease in odds of AVN with CD. However, studies were limited by their retrospective nature and inadequate documentation of CD techniques; the majority lacked femoral head blood flow monitoring to demonstrate adequate decompression. Future prospective studies with carefully documented complete decompression may help to elucidate the effect of CD on AVN risk. Although there was no statistically different odds of AVN with or without CD, even this large meta-analysis was underpowered, and one cannot conclude that there was truly no difference in odds of AVN without an appropriately powered study. Therefore, we recommend routine CD for all unstable SCFEs pending additional research, as CD adds little to the surgical procedure and may minimize the risk of a devastating insult to the femoral head.

Utilization of a Wide Array of Nonvalidated Outcome Scales in Pediatric Orthopaedic Publications: Can't We All Measure the Same Thing?

PURPOSE: Clinical changes are best evaluated with standardized, validated outcomes, including both patient-reported outcome measures and surgeon-reported outcome measures (PROMs and SROMs). The purpose of this study was to describe the spectrum of outcome measures used in pediatric orthopaedic publications over the past 10 years and to determine the proportion that are in fact age-appropriate, validated, and appropriately applied in terms of condition and population. METHODS: The Journal of Bone and Joint Surgery, The Bone and Joint Journal, Journal of Pediatric Orthopaedics A and B, and Journal of Children's Orthopaedics were systematically searched for studies including children aged 18 and below, over a 10-year period from January 2005 to December 2014. Economic evaluations, letters, editorials, review articles, and clinical guidelines were excluded. SROMs and PROMs used were extracted, as were details on subject age and condition for which they were used. Each outcome scale was assessed for validity, and the proportion of scales used appropriately was calculated. Cochrane-Armitage test of trend was used to determine changes in PROM and SROM utilization over the study period. RESULTS: A total of 4614 articles were identified, of which 2251 met inclusion and exclusion criteria. In total, 259 (11.5%) of studies used a PROM, whereas 326 (14.5%) used a SROM. A total of 230 different outcome scales were identified; 115 were patient reported and 115 were surgeon reported. However, only 18.7% of SROMs and 38.3% of PROMs were applied to an age and disease-appropriate demographic. Overall, there was a significant increase in the overall utilization of PROMs during the study period (P=0.004), but no corresponding increase in pediatric-validated PROMs (P=0.164). SROM utilization did not significantly change over the study period (P=0.337). CONCLUSIONS: Within the field of pediatric orthopaedics, an expansive variety of outcome scales are used, many of which have not been validated in children. Improved uniformity in reporting of outcomes and use of disease and age-validated outcomes scales is essential to improve multicenter research collaboration and data quality to generate appropriate evidence-based conclusions and treatment strategies in pediatric orthopaedics. LEVEL OF EVIDENCE: Level IV-systematic review.

The Fragility of Statistically Significant Results in Pediatric Orthopaedic Randomized Controlled Trials as Quantified by the Fragility Index: A Systematic Review.

BACKGROUND: The randomized controlled trial (RCT) is the gold standard study design allowing critical comparison of clinical outcomes while minimizing bias. Traditionally clinical trials are evaluated through statistical significance, expressed by P-values and confidence intervals. However, until recently, the robustness of a study's conclusions has been given little attention. A new metric, the fragility index, quantifies the number of patients theoretically required to switch outcomes in order to reverse the study conclusions. The primary aim of our work was to determine the fragility index of RCTs in the pediatric orthopaedic literature. The secondary aim was to determine study factors associated with lower fragility index. METHODS: Pubmed and Embase were systematically searched for pediatric orthopaedic RCTs published September 1, 2006 to September 1, 2016. Two independent reviewers screened titles, abstracts, and manuscripts to identify studies published in English involving 2 treatment arms. Trials without dichotomous primary or secondary outcomes or with patients >18 years were excluded. Data were extracted from each eligible article in duplicate and the fragility index was determined using Fisher exact test, with previously published methods. Univariate analysis was used to determine factors associated with lower fragility index. RESULTS: Seventeen trials were eligible for inclusion. The median treatment arm size was 58 and overall sample size was 116 patients. The median fragility index was 3 (range, 0 to 18). A fragility index of 3 means that just 3 patients would need to switch treatment outcomes in order for the trial results to become statistically nonsignificant. In 1 study, the number of patients lost to follow-up exceeded the fragility index, such that the study conclusions could be completely reversed purely depending on the outcomes of the patients lost to follow-up. Lower fragility index was associated with smaller patient sample sizes and greater P-values. CONCLUSIONS: The fragility index is a useful adjunct metric to the P-value and confidence intervals, allowing analysis of the robustness of study conclusions. RCTs in pediatric orthopaedics often have small sample sizes, many with low fragility indices. Future efforts could focus on encouraging institutional collaboration and patient recruitment with the ultimate goal of improving RCT sample sizes, and potentially improving the robustness of RCT results. LEVEL OF EVIDENCE: Level I.

Tumour associated tissue eosinophilia as a predictor of locoregional recurrence in oral squamous cell carcinoma.

OBJECTIVES: The increasing global burden of oral cancer has driven much of the focus of research to the determination of reliable prognostic markers which may have significant effects on survival and the control of post-treatment morbidity. This study was undertaken to evaluate tumour associated tissue eosinophilia (TATE) quantitatively in oral cancer specimens and observe for its possible association with tumour stage, patterns of locoregional recurrence and overall prognosis. STUDY DESIGN: 14 patients undergoing surgical resection for primary oral squamous cell carcinoma (OSCC) were subjected to grey scale ultrasonography (USG) to assess tumour dimensions. The findings were compared with the cTNM stage initially documented. TATE was evaluated along the invasive tumour front (ITF) using H & E stained sections of histopathological specimens for 10 continuous high power fields (HPF) and graded as mild, moderate or intense. Patients were followed up over 5 years and observed for patterns of recurrence. RESULTS: Loco regional recurrence was significantly associated with intense degree of TATE. (p<0.001) cTNM stage as well as USG stage did not correlate with the degree of TATE with p=0.419 and 0.772 respectively. None of the patients with mild/ moderate dysplasia developed locoregional recurrence within the period of follow up. CONCLUSIONS: Analysis of TATE in OSCC patients may provide an early indication of future locoregional recurrence. Identification of an appropriate biopsy site representing the ITF where TATE analysis can be performed may be a simple, inexpensive method of obtaining valuable prognostic information at the time of diagnosis. Key words:Tumour associated tissue eosinophilia, oral cancer, prognosis.

Ultrastructural and elemental analysis of sialoliths and their comparison with nephroliths.

AIM: Sialoliths are common in the submandibular gland and its duct system, although their exact cause of formation is still a matter of debate. The aims of this study were to: (a) analyze sialoliths ultrastructurally, and to determine the role of foreign bodies or organic materials in the formation of sialolith nuclei; and (b) compare nephroliths with sialoliths ultrastructurally. METHODS: Three sialoliths and two nephroliths were analyzed ultrastructurally by a scanning electron microscope and X-ray diffractometer. RESULTS: The main structures of the sialoliths were found to be hydroxyapatite crystals. No organic cores were observed in the central parts of the sialoliths. In nephroliths, calcium oxalate, calcium phosphate, and struvite crystals were found. The energy-dispersive X-ray microanalysis found that sialoliths and nephroliths were predominantly composed of elements comprising calcium, phosphorous, magnesium, sodium, chloride, silicon, iron, and potassium. CONCLUSION: Sialoliths in the submandibular salivary glands might form secondary to sialadenitis, but not via a luminal organic nidus.

Dynamic Fluid Flow Mechanical Stimulation Modulates Bone Marrow Mesenchymal Stem Cells.

Osteoblasts are derived from mesenchymal stem cells (MSCs), which initiate and regulate bone formation. New strategies for osteoporosis treatments have aimed to control the fate of MSCs. While functional disuse decreases MSC growth and osteogenic potentials, mechanical signals enhance MSC quantity and bias their differentiation toward osteoblastogenesis. Through a non-invasive dynamic hydraulic stimulation (DHS), we have found that DHS can mitigate trabecular bone loss in a functional disuse model via rat hindlimb suspension (HLS). To further elucidate the downstream cellular effect of DHS and its potential mechanism underlying the bone quality enhancement, a longitudinal in vivo study was designed to evaluate the MSC populations in response to DHS over 3, 7, 14, and 21 days. Five-month old female Sprague Dawley rats were divided into three groups for each time point: age-matched control, HLS, and HLS+DHS. DHS was delivered to the right mid-tibiae with a daily "10 min on-5 min off-10 min on" loading regime for five days/week. At each sacrifice time point, bone marrow MSCs of the stimulated and control tibiae were isolated through specific cell surface markers and quantified by flow cytometry analysis. A strong time-dependent manner of bone marrow MSC induction was observed in response to DHS, which peaked on day 14. After 21 days, this effect of DHS was diminished. This study indicates that the MSC pool is positively influenced by the mechanical signals driven by DHS. Coinciding with our previous findings of mitigation of disuse bone loss, DHS induced changes in MSC number may bias the differentiation of the MSC population towards osteoblastogenesis, thereby promoting bone formation under disuse conditions. This study provides insights into the mechanism of time-sensitive MSC induction in response to mechanical loading, and for the optimal design of osteoporosis treatments.

Influence of atrial function and mechanical synchrony on LV hemodynamic status in heart failure patients on resynchronization therapy.

OBJECTIVES: The aim of this study was to evaluate atrial and ventricular function in patients undergoing cardiac resynchronization therapy (CRT). BACKGROUND: Right atrial pacing (AP) in CRT induces delays in electrical and mechanical activation of the left atrium. The influence of atrial sensing (AS) versus AP on ventricular performance in CRT and the mechanisms underlying the differences between AS and AP in CRT have not been fully elucidated. METHODS: Fifty-five patients with heart failure undergoing CRT for 9 ± 12.5 months and 22 control subjects without heart failure were enrolled. Conventional and tissue Doppler echocardiography was performed to examine atrial and ventricular mechanics and hemodynamic status. RESULTS: The optimal atrioventricular interval was shorter in AS compared with AP mode (126 ± 19 ms vs. 155 ± 20 ms, p < 0.0001). Left ventricular (LV) outflow tract time-velocity integral (22 ± 7 cm vs. 20 ± 7 cm, p < 0.001), diastolic filling period (468 ± 124 ms vs. 380 ± 93 ms, p < 0.001), and global strain (-32 ± 24% vs. -27 ± 22%, p = 0.001) were greater in AS compared with AP mode. Atrial strain was higher in AS compared with AP mode in the right atrium (-28.2 ± 8.6% vs. -22.6 ± 7.6%, p = 0.0007), interatrial septum (-17.1 ± 6.5% vs. -13.2 ± 5.4%, p = 0.002), and left atrium (-16.4 ± 11.0% vs. -13.6 ± 8.5%, p = 0.02). There was no difference in intraventricular dyssynchrony but significantly lower atrial dyssynchrony in AS compared with AP mode (31 ± 19 ms vs. 42 ± 24 ms, p = 0.0002). CONCLUSIONS: AS is associated with preserved atrial contractility and atrial synchrony, resulting in optimal LV diastolic filling, stroke volume, and LV systolic mechanics. This pacing mode maximizes LV performance and the hemodynamic benefit of CRT in patients with heart failure.