Is there any association between the presence of biomarkers and apical periodontitis? A systematic review.

This systematic review aimed to verify whether there is evidence of an association between apical periodontitis and the presence of systemic biomarkers. This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses - PRISMA. For this, the acronym PECO was used; population (P) of adult humans exposed (E) to the presence of apical periodontitis, compared (C) to adult humans without apical periodontitis, and the outcome (O) of the presence of biomarkers was observed. The articles were searched in PubMed, Scopus, Web of Science, LILACS, Cochrane Library, OpenGray, and Google Scholar grey databases. Subsequently, studies were excluded based on title, abstract, and full article reading, following the eligibility criteria. The methodological quality of the selected studies was evaluated using the Newcastle-Ottawa qualifier. After exclusion, 656 studies were identified, resulting in 17 final articles that were divided into case-control, cross-sectional, and cohort studies. Eight studies were considered to have a low risk of bias, one had a medium risk of bias, and eight had a high risk of bias. In addition, 12 articles evaluated biomarkers in blood plasma, four evaluated them in saliva, and only one evaluated them in gingival crevicular fluid. The results of these studies indicated an association between apical periodontitis and the systemic presence of biomarkers. These markers are mainly related to inflammation, such as interleukins IL-1, IL-2, and IL-6, oxidative markers, such as nitric oxide and superoxide anions, and immunoglobulins IgG and IgM. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier (CRD42023493959).

Emerging and anticipated innovations in prostate cancer MRI and their impact on patient care.

Prostate cancer (PCa) remains the leading malignancy affecting men, with over 3 million men living with the disease in the US, and an estimated 288,000 new cases and almost 35,000 deaths in 2023 in the United States alone. Over the last few decades, imaging has been a cornerstone in PCa care, with a crucial role in the detection, staging, and assessment of PCa recurrence or by guiding diagnostic or therapeutic interventions. To improve diagnostic accuracy and outcomes in PCa care, remarkable advancements have been made to different imaging modalities in recent years. This paper focuses on reviewing the main innovations in the field of PCa magnetic resonance imaging, including MRI protocols, MRI-guided procedural interventions, artificial intelligence algorithms and positron emission tomography, which may impact PCa care in the future.

Physical training minimizes immunological dysfunction, oxidative stress and tissue destruction on experimental periodontitis in rats.

The objective of this study is to investigate the effects of a moderate intensity physical training protocol, on alveolar bone morphology of rats submitted to ligature-induced periodontitis. Twenty-eight male Wistar rats were divided into four groups, considering the presence/absence of periodontitis and presence/absence of training. The training protocol was performed on a treadmill, 30 min/day, 5 days a week, for 4 weeks. In the experimental periodontal breakdown, with/without training, ligatures were placed on the lower first molars on the 14th day of the experiment, and were followed until the end of the protocol. At the end of the experiment, animals were euthanized and samples of plasma and mandibles were collected for immunoenzymatic evaluation of interleukins (IL)-1ß, IL-6, TNF-α and IL-10, evaluation of serum concentrations of C-reactive protein, analysis of lipid peroxidation (LPO) and reduced glutathione, histological and microtomographic analyses were performed. Physical training resulted in a reduced levels of IL-1ß, IL-6, TNF-α C-reactive protein and LPO and an increase in the levels of IL-10 in rats with periodontitis (p<0.05); a reduction in the inflammatory infiltrate and decreased fiber degradation was identified in histological analysis. Additionally, it was shown a decrease in vertical bone loss and an increase in the bone volume/trabecular volume ratio was identified in periodontitis+physical training group (p<0.05). Based on the results, the practice of frequent physical exercise, at moderate intensity, can contribute to the reduction of damage related to the disproportionate inflammatory response in periodontitis.

Porto-sinusoidal Vascular Disease and Portal Hypertension.

Porto-sinusoidal vascular disease (PSVD) is the medical diagnosis for a patient who has portal hypertension in the absence of cirrhosis on liver biopsy. There are several specific histologic findings for PSVD, including obliterative portal venopathy, nodular regenerative hyperplasia, and incomplete septal fibrosis. Epidemiologic reports vary widely among regions; PSVD comprises less than 10% of causes of portal hypertension in Western countries but incidence has been found to be as high as 48% in India. There is an expansive list of etiologies that have been reported to cause PSVD.

Açai (Euterpe oleracea Mart.) supplementation promotes histological and ultrastructural changes in rats' alveolar bone.

The açai juice contains high concentrations of phenolic compounds, including cyanidin-3-glucoside and others flavonoids. The aim of this study was to evaluate the impact of açai supplementation on healthy mandibular alveolar bone in male albino rats of the Wistar strain. 24 rats were divided into 3 groups, in which one group received a daily dose of saline solution and the other two groups were treated with daily doses of clarified açai juice for 14 or 28 days. After the experiment, hemimandibles were collected and analyzed using Scanning Electron Microscopy (SEM), histological assessments, and micro-CT. Results showed changes in the integrity of the alveolar bone as seen in SEM, increased osteocyte density and higher collagen matrix area in the açai group compared to the control group as seen in histological analysis, and increased bone volume, trabecular thickness and number, and cortical bone as seen in micro-CT analysis. The space between bone trabeculae showed no difference among the groups. These results suggest that açai supplementation may have a structural change effect on alveolar bone, but further research is needed to confirm these findings in humans and to determine the exact mechanisms behind these effects.

Is there any association between fluoride exposure and thyroid function modulation? A systematic review.

Numerous pre-clinical and observational studies have explored the potential effects of fluoride (F) at varying concentrations on diverse systems and organs. While some have assessed the endocrinological conditions of children and adults, a consensus regarding the interaction between F and the thyroid remains elusive. This systematic review aimed to gather primary evidence on the association between F and changes in the thyroid at optimal and high levels in water supply as stipulated by the World Health Organization. A search strategy, incorporating terms pertinent to the studies, was employed across PubMed, Scopus, Web of Science, Lilacs, and Google Scholar. Following the review of studies, data were extracted and analyzed using the Grading of Recommendations, Assessment, Development, and Evaluations to assess the quality of the evidence. Our results yielded 3,568 studies, of which seven met the inclusion criteria for this review. Five of the seven studies identified an association between high F exposure and thyroid function. In the analysis of methodological quality, every study was found to have major or minor methodological issues and significant risk of bias. The overall confidence in the evidence was deemed low for all outcomes in the seven studies. The evidence compiled in this review suggests a potential association between chronic high levels of F exposure and thyroid damage. Nonetheless, further studies with robust design and high methodological quality are required to provide evidence for policy makers and health care practitioners.

What does scientometry tell us about mercury toxicology and its biological impairments?

Mercury is a toxic pollutant that poses risks to both human and environmental health, making it a pressing public health concern. This study aimed to summarize the knowledge on mercury toxicology and the biological impairments caused by exposure to mercury in experimental studies and/or diagnosis in humans. The research was conducted on the main collection of Web of Science, employing as a methodological tool a bibliometric analysis. The selected articles were analyzed, and extracted data such as publication year, journal, author, title, number of citations, corresponding author's country, keywords, and the knowledge mapping was performed about the type of study, chemical form of mercury, exposure period, origin of exposure, tissue/fluid of exposure measurement, mercury concentration, evaluation period (age), mercury effect, model experiments, dose, exposure pathway, and time of exposure. The selected articles were published between 1965 and 2021, with Clarkson TW being the most cited author who has also published the most articles. A total of 38% of the publications were from the USA. These studies assessed the prenatal and postnatal effects of mercury, emphasizing the impact of methylmercury on neurodevelopment, including motor and cognitive evaluations, the association between mercury and autism, and an evaluation of its protective effects against mercury toxicity. In observational studies, the blood, umbilical cord, and hair were the most frequently used for measuring mercury levels. Our data analysis reveals that mercury neurotoxicology has been extensively explored, but the association among the outcomes evaluated in experimental studies has yet to be strengthened. Providing metric evidence on what is unexplored allows for new studies that may help governmental and non-governmental organizations develop guidelines and policies.

Physical training attenuates systemic cytokine response and tissue damage triggered by apical periodontitis.

Apical periodontitis (AP) is a condition characterized by inflammatory and infectious components in the tooth canal. AP affects periradicular tissues and has systemic repercussions. Physical exercise is a structured activity that requires cardiorespiratory function, and can modulate the inflammatory profile in pathological conditions. As a result, this study aimed to determine the effects of aerobic physical training (PT) on the alveolar bone with and without AP, and its systemic inflammatory repercussions. AP was induced in the mandibular first molars, and PT was performed on a treadmill for five consecutive days over four weeks, with progressive increases in speed and activity time. Blood samples were collected to determine serum cytokine levels using immunoassays, and alveolar bone samples were collected for histopathological evaluation, lesion volume and microarchitecture assessment using computed microtomography. Animals with AP had increased pro-inflammatory cytokines levels compared to those without AP; however, these levels were attenuated or restored by PT. Compared to the AP group, the AP + PT group had a smaller lesion volume and greater preservation of the bone trabeculae in the remaining alveolar bone surrounding the lesion. In overall, PT minimized the severity of AP proving to be a valid strategy for individuals undergoing endodontic treatment.

Physical training mitigates alveolar bone and blood enzymatic antioxidants defense impairment induced by binge ethanol consumption in rats.

We aimed to investigate the effectiveness of physical training as a protective strategy to mitigate alveolar bone damage and blood antioxidant defense caused by ethanol (EtOH) consumption in a binge-drinking pattern. Male Wistar rats aged approximately 90 days were divided into four groups: control, training, EtOH, and training + EtOH. The physical training protocol was conducted on a treadmill for four consecutive weeks, while the animals in the EtOH group were administered EtOH via orogastric gavage for three consecutive days each week, following the binge drink pattern. After the training period, blood and mandibles were collected for plasma oxidative biochemistry analysis, and the alveolar bone was subjected to physicochemical composition analysis, tissue evaluation, and microtomography evaluation. Our results showed that EtOH induced oxidative stress and physical exercise promoted the recovery of antioxidant action. Physical training minimized the damage to the mineral/matrix composition of the alveolar bone due to EtOH consumption and increased the density of osteocytes in the trained group treated with EtOH than in those exposed only to EtOH. Furthermore, physical training reduced damage to the alveolar bone caused by EtOH consumption. Our findings suggest that physical training can serve as an effective strategy to reduce systemic enzymatic oxidative response damage and alleviate alveolar bone damage resulting from alcohol consumption. Further investigations are warranted to elucidate the underlying mechanisms and explore, in addition to physical training, the potential effects of other activities with varying intensities on managing alcohol-induced bone damage.

Postoperative Imaging of Endometriosis.

Endometriosis is a highly prevalent disease that affects 10%-15% of women of reproductive age worldwide and is mainly associated with chronic pelvic pain and infertility. With the widespread use of imaging for the diagnosis and monitoring of endometriosis, combined with the ability of surgery to eradicate the disease and address infertility, there has been a significant increase in recent years in imaging examinations for postoperative evaluation of endometriosis. US and MRI are used not only to help diagnose and map endometriosis but also to evaluate refractory symptoms, residual lesions, and complications at posttreatment assessment. Knowledge of surgical techniques and recognition of expected postoperative imaging findings are crucial to differentiate postoperative changes from residual disease and/or recurrence. The authors discuss imaging aspects of postoperative endometriosis, with an emphasis on the imaging approach, comprehension of surgical techniques, recognition of the expected findings, possible complications, and analysis of residual disease or recurrence. ©RSNA, 2024 Test Your Knowledge questions for this article are available in the supplemental material. See the invited commentary by VanBuren in this issue. The slide presentation from the RSNA Annual Meeting is available for this article.

Multispecies comparative prostate anatomy by imaging: Implications for experimental models of prostatic disease.

BACKGROUND: There is an increasing interest in using preclinical models for development and assessment of medical devices and imaging techniques for prostatic disease care. Still, a comprehensive assessment of the prostate's radiological anatomy in primary preclinical models such as dogs, rabbits, and mice utilizing human anatomy as a reference point remains necessary with no optimal model for each purpose being clearly defined in the literature. Therefore, this study compares the anatomical characteristics of different animal models to the human prostatic gland from the imaging perspective. METHODS: We imaged five Beagle laboratory dogs, five New Zealand White rabbits, and five mice, all sexually mature males, under Institutional Animal Care and Use Committee (IACUC) approval. Ultrasonography (US) was performed using the Vevo® F2 for mice (57 MHz probe). Rabbits and dogs were imaged using the Siemens® Acuson S3000 (17 MHz probe) and endocavitary (8 MHz) probes, respectively. Magnetic resonance imaging (MRI) was also conducted with a 7T scanner in mice and 3T scanner in rabbits and dogs. RESULTS: Canine transrectal US emerged as the optimal method for US imaging, depicting a morphologically similar gland to humans but lacking echoic zonal differentiation. MRI findings in canines indicated a homogeneously structured gland similar to the human peripheral zone on T2-weighted images (T2W) and apparent diffusion coefficient (ADC). In rabbits, US imaging faced challenges due to the pubic symphysis, whereas MRI effectively visualized all structures with the prostate presenting a similar aspect to the human peripheral gland on T2W and ADC maps. Murine prostate assessment revealed poor visualization of the prostate glands in ultrasound due to its small size, while 7T MRI delineated the distinct prostates and its lobes, with the lateral and dorsal prostate resembling the peripheral zone and the anterior prostate the central zone of the human gland. CONCLUSION: Dogs stand out as superior models for advanced preclinical studies in prostatic disease research. However, mice present as a good model for early stage studies and rabbits are a cost-effective alternative and serve as valuable tools in specific research domains when canine research is not feasible.

Ethanol binge drinking exposure during adolescence displays long-lasting motor dysfunction related to cerebellar neurostructural damage even after long-term withdrawal in female Wistar rats.

Ethanol is one of the psychoactive substances most used by young individuals, usually in an intermittent and episodic manner, also called binge drinking. In the adolescent period, brain structures undergo neuromaturation, which increases the vulnerability to psychotropic substances. Our previous studies have revealed that ethanol binge drinking during adolescence elicits neurobehavioral alterations associated with brain damage. Thus, we explored the persistence of motor function impairment and cerebellum damage in the context of ethanol withdrawal periods (emerging adulthood and adult life) in adolescent female rats. Female Wistar rats (35 days old) received orally 4 cycles of ethanol (3.0 g/kg/day) or distilled water in 3 days on-4 days off paradigm (35th until 58th day of life). Motor behavioral tests (open field, grip strength, beam walking, and rotarod tests) and histological assays (Purkinje's cell density and NeuN-positive cells) were assessed on the 1-, 30-, and 60-days of binge alcohol exposure withdrawal. Our findings demonstrate that the adolescent binge drinking exposure paradigm induced cerebellar cell loss in all stages evaluated, measured through the reduction of Purkinje's cell density and granular layer neurons. The cerebellar tissue alterations were accompanied by behavioral impairments. In the early withdrawal, the reduction of spontaneous movement, incoordination, and unbalance was seen. However, the grip strength reduction was found at long-term withdrawal (60 days of abstinence). The cerebellum morphological changes and the motor alterations persisted until adulthood. These data suggest that binge drinking exposure during adolescence causes motor function impairment associated with cerebellum damage, even following a prolonged withdrawal, in adult life.

PI-RADS Upgrading Rules: Impact on Prostate Cancer Detection and Biopsy Avoidance of MRI-Directed Diagnostic Pathways.

BACKGROUND. PI-RADS incorporates rules by which ancillary sequence findings upgrade a dominant score to a higher final category. Evidence on the upgrading rules' impact on diagnostic pathways remains scarce. OBJECTIVE. The purpose of this article was to evaluate the clinical net benefit of the PI-RADS upgrading rules in MRI-directed diagnostic pathways. METHODS. This study was a retrospective analysis of a prospectively maintained clinical registry. The study included patients without known prostate cancer who underwent prostate MRI followed by prostate biopsy from January 2016 to May 2020. Clinically significant prostate cancer (csPCa) was defined as International Society of Urological Pathology (ISUP) grade group 2 and higher. csPCa detection was compared between dominant (i.e., no upgrade rule applied) and upgraded lesions. Decision-curve analysis was used to compare the net benefit, considering the trade-off of csPCa detection and biopsy avoidance, of MRI-directed pathways in scenarios considering and disregarding PI-RADS upgrading rules. These included a biopsy-all pathway, MRI-focused pathway (no biopsy for PI-RADS ≤ 2), and risk-based pathway (use of PSA density ≥ 0.15 ng/mL2 to select patients with PI-RADS ≤ 3 for biopsy). RESULTS. The sample comprised 716 patients (mean age, 64.9 years; 93 with a PI-RADS ≤ 2 examination, 623 with total of 780 PI-RADS ≥ 3 lesions). Frequencies of csPCa were not significantly different between dominant and upgraded PI-RADS 3 transition zone lesions (20% vs 19%, respectively), dominant and upgraded PI-RADS 4 transition zone lesions (33% vs 26%), and dominant and upgraded PI-RADS 4 peripheral zone lesions (58% vs 45%) (p > .05). In the biopsy-all, per-guideline MRI-focused, MRI-focused disregarding upgrading rules, per-guideline risk-based, and risk-based disregarding upgrading rules pathways, csPCa frequency was 53%, 52%, 51%, 52%, and 48% and biopsy avoidance was 0%, 13%, 16%, 19%, and 25%, respectively. Disregarding upgrading rules yielded 5.5 and 1.9 biopsies avoided per missed csPCa for MRI-focused and risk-based pathways, respectively. At probability thresholds for biopsy selection of 7.5-30.0%, net benefit was highest for the per-guideline risk-based pathway. CONCLUSION. Disregarding PI-RADS upgrading rules reduced net clinical bene fit of the risk-based MRI-directed diagnostic pathway when considering trade-offs between csPCa detection and biopsy avoidance. CLINICAL IMPACT. This study supports the application of PI-RADS upgrading rules to optimize biopsy selection, particularly in risk-based pathways.

Artificial intelligence applications in prostate cancer.

Artificial intelligence (AI) applications have enabled remarkable advancements in healthcare delivery. These AI tools are often aimed to improve accuracy and efficiency of histopathology assessment and diagnostic imaging interpretation, risk stratification (i.e., prognostication), and prediction of therapeutic benefit for personalized treatment recommendations. To date, multiple AI algorithms have been explored for prostate cancer to address automation of clinical workflow, integration of data from multiple domains in the decision-making process, and the generation of diagnostic, prognostic, and predictive biomarkers. While many studies remain within the pre-clinical space or lack validation, the last few years have witnessed the emergence of robust AI-based biomarkers validated on thousands of patients, and the prospective deployment of clinically-integrated workflows for automated radiation therapy design. To advance the field forward, multi-institutional and multi-disciplinary collaborations are needed in order to prospectively implement interoperable and accountable AI technology routinely in clinic.

Assessing the Potential of a Deep Learning Tool to Improve Fracture Detection by Radiologists and Emergency Physicians on Extremity Radiographs.

RATIONALE AND OBJECTIVES: To evaluate the standalone performance of a deep learning (DL) based fracture detection tool on extremity radiographs and assess the performance of radiologists and emergency physicians in identifying fractures of the extremities with and without the DL aid. MATERIALS AND METHODS: The DL tool was previously developed using 132,000 appendicular skeletal radiographs divided into 87% training, 11% validation, and 2% test sets. Stand-alone performance was evaluated on 2626 de-identified radiographs from a single institution in Ohio, including at least 140 exams per body region. Consensus from three US board-certified musculoskeletal (MSK) radiologists served as ground truth. A multi-reader retrospective study was performed in which 24 readers (eight each of emergency physicians, non-MSK radiologists, and MSK radiologists) identified fractures in 186 cases during two independent sessions with and without DL aid, separated by a one-month washout period. The accuracy (area under the receiver operating curve), sensitivity, specificity, and reading time were compared with and without model aid. RESULTS: The model achieved a stand-alone accuracy of 0.986, sensitivity of 0.987, and specificity of 0.885, and high accuracy (> 0.95) across stratification for body part, age, gender, radiographic views, and scanner type. With DL aid, reader accuracy increased by 0.047 (95% CI: 0.034, 0.061; p = 0.004) and sensitivity significantly improved from 0.865 (95% CI: 0.848, 0.881) to 0.955 (95% CI: 0.944, 0.964). Average reading time was shortened by 7.1 s (27%) per exam. When stratified by physician type, this improvement was greater for emergency physicians and non-MSK radiologists. CONCLUSION: The DL tool demonstrated high stand-alone accuracy, aided physician diagnostic accuracy, and decreased interpretation time.

Spatiotemporal knowledge teacher-student reinforcement learning to detect liver tumors without contrast agents.

Detecting Liver tumors without contrast agents (CAs) has shown great potential to advance liver cancer screening. It enables the provision of a reliable liver tumor-detecting result from non-enhanced MR images comparable to the radiologists' results from CA-enhanced MR images, thus eliminating the high risk of CAs, preventing an experience gap between radiologists and simplifying clinical workflows. In this paper, we proposed a novel spatiotemporal knowledge teacher-student reinforcement learning (SKT-RL) as a safe, speedy, and inexpensive contrast-free technology for liver tumor detection. Our SKT-RL builds a teacher-student framework to realize the exploring of explicit liver tumor knowledge from a teacher network on clear contrast-enhanced images to guide a student network to detect tumors from non-enhanced images directly. Importantly, our STK-RL enables three novelties in aspects of construction, transferring, and optimization to tumor knowledge to improve the guide effect. (1) A new spatiotemporal ternary knowledge set enables the construction of accurate knowledge that allows understanding of DRL's behavior (what to do) and reason (why to do it) behind reliable detection within each state and between their related historical states. (2) A novel pixel momentum transferring strategy enables detailed and controlled knowledge transfer ability. It transfers knowledge at a pixel level to enlarge the explorable space of transferring and control how much knowledge is transferred to prevent over-rely of the student to the teacher. (3) A phase-trend reward function designs different evaluations according to different detection phases to optimal for each phase in high-precision but also allows reward trend to constraint the evaluation to improve stability. Comprehensive experiments on a generalized liver tumor dataset with 375 patients (including hemangiomas, hepatocellular carcinoma, and normal controls) show that our novel SKT-RL attains a new state-of-the-art performance (improved precision by at least 4% when comparing the six recent advanced methods) in the task of liver tumor detection without CAs. The results proved that our SKT-DRL has greatly promoted the development and deployment of contrast-free liver tumor technology.

Delta radiomic patterns on serial bi-parametric MRI are associated with pathologic upgrading in prostate cancer patients on active surveillance: preliminary findings.

Objective: The aim of this study was to quantify radiomic changes in prostate cancer (PCa) progression on serial MRI among patients on active surveillance (AS) and evaluate their association with pathologic progression on biopsy. Methods: This retrospective study comprised N = 121 biopsy-proven PCa patients on AS at a single institution, of whom N = 50 at baseline conformed to the inclusion criteria. ISUP Gleason Grade Groups (GGG) were obtained from 12-core TRUS-guided systematic biopsies at baseline and follow-up. A biopsy upgrade (AS+) was defined as an increase in GGG (or in number of positive cores) and no upgrade (AS-) was defined when GGG remained the same during a median period of 18 months. Of N = 50 patients at baseline, N = 30 had MRI scans available at follow-up (median interval = 18 months) and were included for delta radiomic analysis. A total of 252 radiomic features were extracted from the PCa region of interest identified by board-certified radiologists on 3T bi-parametric MRI [T2-weighted (T2W) and apparent diffusion coefficient (ADC)]. Delta radiomic features were computed as the difference of radiomic feature between baseline and follow-up scans. The association of AS+ with age, prostate-specific antigen (PSA), Prostate Imaging Reporting and Data System (PIRADS v2.1) score, and tumor size was evaluated at baseline and follow-up. Various prediction models were built using random forest (RF) classifier within a threefold cross-validation framework leveraging baseline radiomics (Cbr), baseline radiomics + baseline clinical (Cbrbcl), delta radiomics (CΔr), delta radiomics + baseline clinical (CΔrbcl), and delta radiomics + delta clinical (CΔrΔcl). Results: An AUC of 0.64 ± 0.09 was obtained for Cbr, which increased to 0.70 ± 0.18 with the integration of clinical variables (Cbrbcl). CΔr yielded an AUC of 0.74 ± 0.15. Integrating delta radiomics with baseline clinical variables yielded an AUC of 0.77 ± 0.23. CΔrΔclresulted in the best AUC of 0.84 ± 0.20 (p < 0.05) among all combinations. Conclusion: Our preliminary findings suggest that delta radiomics were more strongly associated with upgrade events compared to PIRADS and other clinical variables. Delta radiomics on serial MRI in combination with changes in clinical variables (PSA and tumor volume) between baseline and follow-up showed the strongest association with biopsy upgrade in PCa patients on AS. Further independent multi-site validation of these preliminary findings is warranted.