2-year Studies Research Articles

Clinical outcomes following transtibial medial meniscal root repair are maintained at long-term follow-up.

To evaluate long-term outcomes of patients treated with posterior medial meniscal root tear (PMMRT) repair through assessment of functional outcome scores and to identify patient surgical and magnetic resonance imaging (MRI) characteristics associated with improved outcomes. This was a single-centre, retrospective study evaluating patients who had undergone a PMMR repair using a transtibial suture pullout technique with two locking cinch sutures. This was performed as a follow-up to previously published 2-year and 5-year outcome studies, using the same cohort. All patients from the prior short-term and midterm studies were invited to participate. Patient-reported outcome (PROs) scores, including the International Knee Documentation Committee (IKDC) and Lysholm scores, were collected. Previously collected demographic data were updated based on review of the electronic medical record. Patient outcomes were assessed preoperatively, as well as at 2-year, 5-yearand 8-yearpostoperatively. MRI outcome measurements were assessed at 2-year and 5-year follow-ups. All statistical analysis was performed using SPSS version 26. Seventeen patients of the original 18 patients (94.4%) were included in the final analysis. Additionally, three patients who had additional ipsilateral surgery were excluded from the analysis of PROs. The IKDC score significantly increased from 44.7 ± 11.6 at preoperative baseline to 71.2 ± 21.3 at 8-yearpost-operation (p = 0.001). There were no significant differences in IKDC score between 2-year and 8-year follow-ups (p = n.s.) or 5-year and 8-year follow-ups (p = n.s.). The Lysholm score significantly increased from 49.6 ± 7.3 at preoperative baseline to 76.4 ± 17.2 at 8-year follow-up (p < 0.001). There was no significant difference in Lysholm scores between 2-year and 8-year follow-ups (p = n.s.) or 5-year and 8-year follow-ups (p = n.s.). A linear regression analysis found that 5-year IKDC scores were significantly correlated with 8-year IKDC scores (β = 0.681, p = 0.038). At 8-year follow-up, four (23.5%) patients required additional procedures on their operative knee (one total knee arthroplasty conversion). Patients treated with repair of PMMRT had maintenance of clinical outcome improvements at long-term follow-up despite worsening MRI outcomes at short-term and medium-term follow-ups. While a high proportion of patients required additional procedures on their operative knee at 8-yearfollow-up, few of these patient's additional procedures were related to failure of their primary surgery. Providers and patients may expect durable clinical outcomes following the repair of PMMRT, irrespective of radiographic appearance. Level IV.

Predictors of Clinical Outcomes After Hip Arthroscopy: 10-Year Follow-up Analysis of 1038 Patients

Background: Although hip arthroscopy has been shown to have beneficial outcomes, there is a paucity of literature examining predictive factors of 10-year clinical outcomes. Purpose: (1) To identify predictive factors of 10-year outcomes of hip arthroscopy and (2) to compare these factors with those found in 2-year and 5-year studies. Study Design: Cohort study; Level of evidence, 3. Methods: Data were prospectively collected and retrospectively reviewed on all patients undergoing hip arthroscopy between February 2008 and June 2012. Patients were included if they had a minimum 10-year follow-up on 2 patient-reported outcome measures: Nonarthritic Hip Score (NAHS) and modified Harris Hip Score. Exclusion criteria included previous ipsilateral hip conditions. Using bivariate and multivariate analyses, that authors analyzed the effects of 37 pre- and intraoperative variables on the NAHS, modified Harris Hip Score, and conversion to total hip arthroplasty. Results: Of the 883 patients who met the inclusion criteria, 734 (83.1%) had follow-up data. The mean follow-up time was 124.4 months (range, 120.0-153.1 months). Six variables were significant predictors of NAHS in both multivariate and bivariate analyses: revision status, body mass index (BMI), duration of symptoms, preoperative NAHS, age at onset of symptoms, and need for acetabular microfracture. Positive predictors of 10-year survivorship included acute injury and gluteus medius repair, while negative predictors included revision arthroscopy, Tönnis grade, acetabular inclination, iliopsoas fractional lengthening, and notchplasty Conclusion: Multiple predictive factors including age, BMI, revision status, and preoperative outcome scores were identified for long-term survivorship and functional outcomes. These may prove useful to clinicians in refining indications and guiding patients on expected outcomes of hip arthroscopy.

Bis-(2-Chloroisopropyl) ether.

Bis-(2-Chloroisopropyl) ether (BCIPE) was used as a solvent for fats, greases, paint, varnish removers, and in spotting and cleaning solutions. However, BCIPE has not been commercially manufactured or used for numerous years. In experimental animal studies, BCIPE is moderately toxic following acute oral, dermal, and inhalation routes of exposure. BCIPE is a severe eye irritant but not a dermal irritant or dermal sensitizer. BCIPE was not genotoxic or mutagenic in in vitro and in vivo assays; it was not toxic in a 3-generation reproductive dietary study in rats. Short-term, repeated inhalation and oral exposure in rats produced increased liver and kidney weights and congestion; dermal exposure in rabbits did not produce any observable adverse effects. BCIPE did not produce a statistically significant increase in tumors in two different 2-year dietary studies in mice and rats. In mice, technical grade BCIPE produced increased incidences of alveolar/bronchiolar adenomas in females, hepatocellular carcinomas in males, and a low incidence of forestomach hyperplasia (in both sexes at the high-dose). Further investigation with technical grade BCIPE concluded that these effects were species- and dose-specific with limited, if any, relevance to humans. The NOAEL of 400 ppm (15 mg/kg/day) from the 2-year dietary study in female rats was considered the point of departure for the health-based WEEL derivation. After adjustment for duration of exposure, interindividual variability, and intraindividual variability, an 8-h time-weighted average (TWA) WEEL value of 3 ppm (21 mg/m3) was derived. This exposure limit is expected to provide a significant margin of safety against any potential adverse health effects in workers.

ICH S1 prospective evaluation study: weight of evidence approach to predict outcome and value of 2-year rat carcinogenicity studies. A report from the regulatory authorities subgroup.

Introduction: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) initiated a process in 2012 to revise the S1B Guideline "Testing for Carcinogenicity of Pharmaceuticals". Previous retrospective analysis indicated the importance of histopathological risk factors in chronic toxicity studies, evidence of endocrine perturbation, and positive genetic toxicology results as potentially predictive indicators of carcinogenic risk. In addition, a relationship between pharmacodynamic activity and carcinogenicity outcome in long-term rodent studies has been reported. It was postulated that these factors could be evaluated in a Weight-of-Evidence (WoE) approach to predict the outcome of a 2-year rat study. Methods: The ICH S1B(R1) Expert Working Group (EWG) conducted a Prospective Evaluation Study (PES) to determine the regulatory feasibility of this WoE approach. Drug Regulatory Authorities (DRAs) evaluated 49 Carcinogenicity Assessment Documents (CADs), which describe the WoE for submitted pharmaceutical compounds. Each compound was categorized into a carcinogenic risk category including a statement of the value of the 2-year rat study. The outcome of the completed 2-year rat studies was evaluated in relation to the prospective CAD to determine the accuracy of predictions. Results: Based on the results of the PES, the EWG concluded that the evaluation process for assessing human carcinogenic risk of pharmaceuticals described in ICH S1B could be expanded to include a WoE approach. Approximately 27% of 2-year rat studies could be avoided in cases where DRAs and sponsors unanimously agreed that such a study would not add value. Discussion: Key factors supporting a WoE assessment were identified: data that inform carcinogenic potential based on drug target biology and the primary pharmacologic mechanism of the parent compound and major human metabolites; results from secondary pharmacology screens for this compound and major human metabolites that inform carcinogenic risk; histopathology data from repeated-dose toxicity studies; evidence for hormonal perturbation; genotoxicity data; and evidence of immune modulation. The outcome of the PES indicates that a WoE approach can be used in place of conducting a 2-year rat study for some pharmaceuticals. These data were used by the ICH S1B(R1) EWG to write the R1 Addendum to the S1B Guideline published in August 2022.

Does Aid Matter? A Systematic Review and Meta-Analysis of the Effects of Grant Aid on College Student Outcomes

The College Board reported that, in 2022–2023, about two thirds of $177 billion in U.S. financial assistance awarded to undergraduates through programs sponsored by the federal government, state governments, colleges and universities, philanthropic organizations, and other entities was in the form of grants. While researchers have examined the effects of individual grant aid programs on particular college student outcomes, results have indicated varied effects. Moreover, individual study findings have not been widely synthesized or examined to understand why some programs succeed where others do not. We conducted a comprehensive systematic review and meta-analysis to provide structure to this varied field and better understand programmatic effects. The results of the systematic searching and screening yielded 86 studies, across seven outcome domains, and the meta-analysis synthesized findings from 709 effect sizes from study samples representing 7,656,062 individuals. The meta-analytic results found small but meaningful positive average effects on college enrollment, credit accumulation, persistence, and completion. We cannot conclude from available studies that grant aid increased academic achievement or postcollege labor market outcomes. We also found that grants had larger positive effects on credit accumulation for studies with samples of students at 2-year institutions and studies that combined samples of 2- and 4-year students than for studies with samples of students at 4-year institutions only. Using a relatively new method called an evidence gap map, we illustrate where researchers should focus on producing new evidence.

Asymptomatic Plasmodium falciparum carriage at the end of the dry season is associated with subsequent infection and clinical malaria in Eastern Gambia.

Chronic carriage of asymptomatic low-density Plasmodium falciparum parasitaemia in the dry season may support maintenance of acquired immunity that protects against clinical malaria. However, the relationship between chronic low-density infections and subsequent risk of clinical malaria episodes remains unclear. In a 2-years study (December 2014 to December 2016) in eastern Gambia, nine cross-sectional surveys using molecular parasite detection were performed in the dry and wet season. During the 2016 malaria transmission season, passive case detection identified episodes of clinical malaria. Among the 5256 samples collected, 444 (8.4%) were positive for P. falciparum. A multivariate model identified village of residence, male sex, age ≥ 5 years old, anaemia, and fever as independent factors associated with P. falciparum parasite carriage. Infections did not cluster over time within the same households or recurred among neighbouring households. Asymptomatic parasite carriage at the end of dry season was associated with a higher risk of infection (Hazard Ratio, HR = 3.0, p < 0.0001) and clinical malaria (HR = 1.561, p = 0.057) during the following transmission season. Age and village of residence were additional predictors of infection and clinical malaria during the transmission season. Chronic parasite carriage during the dry season is associated with an increased risk of malaria infection and clinical malaria. It is unclear whether this is due to environmental exposure or to other factors.

Translational Insights into Molecular Mechanisms of Chemical Hepatocarcinogenesis for Improved Human Risk Assessment

Background: Hepatocellular carcinoma (HCC) is a prevalent liver cancer with major risk factors being hepatitis viral infections, alcohol, non-alcoholic fatty liver disease, and aflatoxin exposure. Both genotoxic and non-genotoxic agents can induce HCC through mechanisms involving DNA damage, oxidative stress, chronic inflammation, and disrupted signaling pathways like MAPK/ERK, PI3K/AKT, WNT/β-catenin and PPARα. While rodent assays are utilized to detect potential chemical hepatocarcinogens, species differences in pathways like PPARα and CAR/PXR activation impact human risk assessment. Purpose: This analysis provides an updated, critical examination of species concordance in mechanisms of hepatic carcinogenesis to inform human safety assessment of rodent liver tumor findings. Main Body: Rodent assays including 2-year bioassays, transgenic models, and short-term studies detect liver tumors through lifetime exposure or early biomarkers. However, rodent-specific PPARα and CAR/PXR activation, along with human risk factors like hepatitis, highlight key interspecies differences. Determining mode of action relevance requires evaluating mechanistic validity and pivotal key events leading to tumors across species. Non-genotoxic compounds eliciting rodent liver tumors can activate PPARα, CAR/PXR, and other pathways triggering increased cell replication; but downstream signaling may differ in human liver. Understanding applicability of these mechanisms in humans as well as incorporating human risk factors into experimental models is critical for accurate risk assessment. Conclusion: In summary, elucidating conserved versus divergent molecular mechanisms of hepatic carcinogenesis between rodents and humans is essential for appropriately interpreting rodent findings and safeguarding human health through science-based risk assessment frameworks and regulatory decision-making processes around potential chemical hazards.

The influence of microelements on the yield and its quality of wheat grown under drought conditions on soil with different phosphorus supplies

The results of 2-year vegetation studies devoted to the study of the existing prerequisites for treating seeds (PTS) with solutions of flax selenium, vanadium, tungsten and iodine on the yield and its structure, as well as indicators of the quality of wheat grain are presented. The experimental crop was grown on soil with different supplies of available phosphorus and was grown in an artificially created drought. The effectiveness of microelements was most realized under conditions of low phosphate content in the soil. The use of solutions of sodium selenite, ammonium vanadate, ammonium tungstate and potassium iodide helps to increase the weight of wheat grain by 14, 11, 13 and 7% relative to seed treatment with distilled water. Under stress conditions, persistent sodium selenite has the best effectiveness - grain increase of 11%.

The Bilateral Tap-Block Ultrasound-Guided in Laparoscopic Abdominal Surgery: Evaluation of a Curare-Free Anaesthetic Protocol

Introduction: The transverse abdominal plane block or TAP block consists of injecting a local anaesthetic between the internal oblique and transverse muscles. Its contribution to muscle relaxation during laparoscopic surgery has been little studied. Material and Method: We carried out a 2-years prospective, descriptive and analytical randomised study blinded to the surgeon conducted in the operating theatre of the Saint Louis Regional Hospital Centre. Patients were randomised into two groups: those who received vecuronium after rapid sequence induction (group V) and those who received bilateral TAP block without curares (group T). Anamnestic, clinical, anaesthetic, surgical and evolutionary aspects were collected and analysed. The main evaluation criteria were: pneumoperitoneum pressure, exhaled CO2, respiratory motor pressure and surgeon satisfaction scale. Results: We collected 61 patients admitted for laparoscopic abdominal surgery. The mean age was 32.9 years with a standard deviation of 14.5. Appendicitis was the indication in 55% of cases. The Propofol-celocurine-TAP-block anaesthetic protocol was used in 25 patients, i.e. in 41% of cases, and 59% of patients had undergone a conventional induction using vecuronium. The mean pressure of the pneumoperitoneum was 11.3 mmHg for the conventional induction group and 12.6 mmHg for the TAP-block group. The mean respiratory motor pressures were 12 cmH2O for the conventional induction group and 13.7 cmH2O for the TAP-block group. The mean value of exhaled CO2 was 37.5 mmHg. Fentanyl reinjections were more frequent in the conventional induction group in 55.6% of cases. The mean VAS at 6 hours post-op was 4.5 for the conventional induction group and 3 for the TAP-block group. Discussion/Conclusion: The ultrasound-guided trans-abdominal-pelvic block remains an effective, durable and reproducible technique. Its advantages in terms of postoperative analgesia are well known. In addition, its selective effects on muscle ......

Carcinogenicity testing in drug development: Getting it right

For a pharmaceutical drug, carcinogenicity testing occurs in rodents to identify its tumorigenic potential to allow assessment of the risk from its use in humans. Testing takes the form of 2-year studies in mice and rats and/or more recently, a 6-month study in transgenic mice. This paper examines the process of regulatory interaction regarding carcinogenicity testing, notably through the United States (US) Food and Drug Administration (FDA) Special Protocol Assessment (SPA) process to seek Executive Carcinogenicity Assessment Committee (ECAC) approval. The content of 37 submissions to CAC were examined. The paper also examines the outcome from such agency engagement, notably around study dose level selection as well as looking at the design of proposed carcinogenicity study protocols used in submissions (including numbers of animals, control group aspects and toxicokinetic [TK] evaluation). Overall, it was shown that the current process of regulatory interaction allows for studies acceptable to support eventual drug approval and marketing. However, it was established that areas exist to improve the content of submission documents and study design aspects.

Analyses of transcutaneous oxygen pressure values stratified for foot angiosomes to predict diabetic foot ulcer healing

AimsPrevious research suggested that diabetic foot ulcer (DFU) location could affect transcutaneous oxygen pressure (TcPO2) values following the angiosome concept. Up to our knowledge no studies have yet analyzed if the location of a diabetic foot ulcer can be a confounding factor that modifies TcPO2 values. The primary aim of this study was to compare the potential healing prognosis of TcPO2 differentiated for diabetic foot ulcers in different angiosome locations. Methodsa 2-years observational cohort prospective study was performed in 81 patients with diabetic foot ulcers. Transcutaneous oxygen pressure measurements were performed at baseline by placing the electrode on two different angiosomes: dorsal zone of the foot (dorsalis pedis angiosome) and between the navicular bone and the tibial malleolus (posterior tibial angiosome). The main outcome was establishing the effectiveness of TcPO2 measurements (dorsalis pedis angiosome and posterior tibial angiosome) for predicting DFU healing. ResultsTranscutaneous oxygen pressure probe placed in the dorsum of the foot (dorsalis pedis angiosome) yielded a sensitivity (S) of 95 % and specificity (SP) of 73 %, and an area under the curve (AUC) of 0.902 (p < 0.001 [0.84–0.96]) for ulcers located in the forefoot and toes; while TcPO2 placed in the posterior tibial angiosome yielded an S of 100 % and SP of 85 % and an AUC of 0.894 (p < 0.001 [0-822-0.966]) for DFU located in the midfoot and heel. ConclusionThis study suggests that angiosome-guided TcPO2 contributes to a prognosis of successful foot ulcer healing.

Exposure of Rats to Multi-Walled Carbon Nanotubes: Correlation of Inhalation Exposure to Lung Burden, Bronchoalveolar Lavage Fluid Findings, and Lung Morphology.

To evaluate lung toxicity due to inhalation of multi-walled carbon nanotubes (MWCNTs) in rats, we developed a unique MWCNT aerosol generator based on dry aerosolization using the aerodynamic cyclone principle. Rats were exposed to MWNT-7 (also known as Mutsui-7 and MWCNT-7) aerosolized using this device. We report here an analysis of previously published data and additional unpublished data obtained in 1-day, 2-week, 13-week, and 2-year inhalation exposure studies. In one-day studies, it was found that approximately 50% of the deposited MWNT-7 fibers were cleared the day after the end of exposure, but that clearance of the remaining fibers was markedly reduced. This is in agreement with the premise that the rapidly cleared fibers were deposited in the ciliated airways while the slowly cleared fibers were deposited beyond the ciliated airways in the respiratory zone. Macrophage clearance of MWNT-7 fibers from the alveoli was limited. Instead of macrophage clearance from the alveoli, containment of MWNT-7 fibers within induced granulomatous lesions was observed. The earliest changes indicative of pulmonary toxicity were seen in the bronchoalveolar lavage fluid. Macrophage-associated inflammation persisted from the one-day exposure to MWNT-7 to the end of the two-year exposure period. Correlation of lung tumor development with MWNT-7 lung burden required incorporating the concept of area under the curve for the duration of the study; the development of lung tumors induced by MWNT-7 correlated with lung burden and the duration of MWNT-7 residence in the lung.

(394) Effects of Age, Body Mass Index (BMI) and Diabetic Status on Testosterone Levels, Testosterone Dosing and Safety in Hypogonadal Men Treated with an Oral Testosterone Undecanoate (JATENZO)

Abstract Introduction A novel oral testosterone replacement therapy (TRT), testosterone undecanoate (TU, JATENZO) has been shown in 1- and 2-year studies to have durable efficacy and safety. Hypogonadal men are heterogeneous with respect to age, body mass index (BMI), and diabetic status. These factors have been shown to affect the hypothalamic-pituitary-gonadal axis. Objective The purpose of this study is to investigate the role of baseline age, BMI, and diabetic status on change in T levels, final TU dose, and safety. Methods Hypogonadal men, ages 18 – 65 y/o, were recruited into a randomized, open-label, multicenter, dose-titration trial. 222 subjects were randomized to BID TU (n = 166) or testosterone gel (n = 56). Subjects had dose adjustments based on plasma T levels (Cavg). Safety was assessed by standard clinical measures. Post hoc safety, efficacy, and dosing analyses were conducted on subjects who were stratified by age, BMI, and diabetes status. The age groups were &amp;lt;= 44 y/o, 45 – 54 y/o, and =&amp;gt; 55 y/o; the BMI groups were &amp;lt; 30 kg/m^2, 30 – 35 kg/m^2, and &amp;gt; 35 kg/m^2; and the subjects were grouped as non-diabetic, pre-diabetic, or diabetic. Results Overall, serum total T Cavg for the oral TU group was 489 ± 12.6 ng/dL (mean ± SE). For all groups, the mean total T was in the eugonadal range. Age, BMI, or diabetes status did not affect key efficacy variables, such as total T or calculated free T, nor key safety variables, such as hematocrit, PSA, liver transaminases, systolic BP, diastolic BP, HDL-C, or LDL-C. There were no differences in the final TU dose among the age categories. In contrast, the final TU dose was significantly different among BMI categories (p=0.0003), and the diabetic status (p &amp;lt; 0.0001). The higher BMI groups need a significantly higher oral TU dose. Those in the pre-diabetic or diabetic groups needed a significantly higher dose than the non-diabetic group. Because the pre-diabetic and diabetic groups had significantly higher BMI, it is difficult to determine if it was diabetes status or BMI that influenced the final dose [baseline BMI: non-diabetic 30.5 ± 0.52 (mean ± SEM), pre-diabetic 32.7 ± 0.54 (p = 0.003 vs the non-diabetic group), diabetic 32.5 ± 0.56 (p = 0.0175 vs the non-diabetic group)]. BMI had a greater effect on the final dose in the non-diabetic group, and its effect appeared to decrease in the pre-diabetic and diabetic groups. See figure for the final mean doses. Although the final total T values were in the eugonadal range, there was also a significantly smaller change from baseline in total T comparing non-diabetics to diabetics (p=0.0042). Conclusions Regardless of age, BMI, or diabetes status, eugonadal total T levels were achieved in men administered oral TU. Age did not influence the final dose. In contrast, BMI and diabetes status influenced the final dose. Patient characteristics (BMI and diabetic status) may guide dosing of testosterone replacement with oral testosterone undecanoate to optimize T levels. Disclosure Yes, this is sponsored by industry/sponsor: Clarus Therapeutics Clarification Industry initiated, executed and funded study Any of the authors act as a consultant, employee or shareholder of an industry for: Clarus Therapeutics.

Gene expression profiling after exposure to a chemical carcinogen, Pentabrominated Diphenyl Ether, at different life stages.

Exposure to environmental hazards occurs at different stages of our lifetime-infant, child, adult. This study integrates recently published toxicogenomics data to examine how exposure to a known rat chemical carcinogen (pentabrominated diphenyl ether (PBDE)) upregulated liver transcriptomic changes at different life cycle stages (PND 4, PND 22, adult). We found that at all three life cycle stages PBDE exposure induced hepatocellular transcriptomic changes in disease pathways including cancer, metabolic, membrane function, and Nrf2 antioxidant pathways, pathways all characteristics of chemical carcinogens. In addition, in the adult rat after a 5-day exposure to the chemical carcinogen, there was upregulation of members of the Ras oncogenic pathway, a specific pathway found to be activated in the PBDE-induced tumors in rats in a previous hazard identification cancer study. The findings of liver transcript changes characteristic of carcinogenic activity after early life exposures and after short-term adult exposures provides data to support the use of transcriptomic data to predict the apical cancer endpoints in model studies. Using data from gene expression profiling studies after neonatal, young, or adult short-term chemical exposure helps to meet the 21st century toxicology goal of developing study designs to reduce, refine, and replace the use of traditional 2-year rodent cancer studies to provide hazard identification information. The studies reported here find that key transcripts associated with carcinogenesis were elevated in neonate (PND 4), young (PND 22) and adult animals after short-term exposure to PBDE, a known experimental chemical carcinogen in model systems.

Effect of adiposity and physical fitness on cardiometabolic risk factors in adolescents: A 2-year longitudinal study.

Although risk factors for cardiometabolic diseases begin to present in young people, the association between physical fitness and adiposity with traditional and novel risk factors for cardiometabolic diseases across adolescence remains relatively unknown. Following ethical approval, fifty-two adolescents (age 11.6 ± 0.6 years; 32 girls) were recruited for a 2-years longitudinal study. Adiposity was assessed based on sum of skinfolds, waist circumference and body mass index, and physical fitness as distance run on the multi-stage fitness test (MSFT). Risk factors for cardiometabolic diseases (pro- and anti-inflammatory cytokines, plasma insulin, Homeostatic Model Assessment of Insulin Resistance - HOMA-IR, blood pressure) were measured following an overnight fast. Relationships between independent and response variables were analysed using multi-level modelling (final combined models were created using the stepwise backward elimination method). Plasma insulin concentration and HOMA-IR were positively associated with adiposity and inversely associated with distance run on the MSFT (all p < 0.05). The final combined models for plasma insulin concentration and HOMA-IR contained main effects for age, skinfolds and distance run on the MSFT. Levels of the anti-inflammatory cytokine IL-10 were inversely related to the sum of skinfolds (p = 0.046), whereas there was a trend for levels of the pro-inflammatory cytokine TNF-α to be positively related to the sum of skinfolds (p = 0.056). Adiposity and physical fitness are important, independent, determinants of metabolic health in adolescents. Furthermore, adiposity influences levels of pro- and anti-inflammatory cytokines in adolescence, with greater adiposity associated with a poorer inflammatory profile. The present study demonstrates an independent effect of physical fitness on metabolic health longitudinally across adolescence. It is therefore recommended that future work develops therapeutic interventions that reduce adiposity and enhance physical fitness in adolescents, to promote lifelong health.

COVID-19 Increases Risk of Psychiatric Disorders

COVID-19 Increases Risk of Psychiatric Disorders

COVID-19 Takes Cognitive Toll on Older Patients

COVID-19 Takes Cognitive Toll on Older Patients

The Changes in Size of Periapical Lesions after Root Canal Treatments Assessed by Digital Periapical Radiography and Cone-Beam Computed Tomography: A 2-Years Prospective Clinical Study.

Background and Objectives: There is limited information regarding comparison of long-term dynamics of periapical bone destruction estimated by digital periapical radiography (DPR) and by cone-beam computed tomography (CBCT). This study aimed to compare the radiographically assessed periapical changes of endodontically treated teeth over 2 years of follow-up and to analyse disagreements in periapical lesion size estimates around the same roots using DPR and CBCT. Materials and Methods: A total of 176 endodontically treated teeth, of 128 patients with apical periodontitis, were assessed by DPR and CBCT, at baseline and after 2 years. All periapical radiolucencies were categorised by severity (S0, S1, S2, S3) concerning their size. Descriptive statistics were used to report distribution of the radiolucencies at baseline and at follow-up, and their size transitions over 2 years. Site-specific comparison of the radiolucencies identified by two methods was performed using Z test and Pearson’s chi-square test. Results: majority of the detected radiolucencies were scored as S0: 65% and 68% at baseline; 89% and 83% at follow-up, by DPR and CBCT, respectively. Site-specific score comparison showed that disagreements comprised 18% and 20% of the total number of radiolucencies detected by DPR and CBCT, respectively. There were more disagreements between DPR and CBCT within categories S1 and S2 + S3 compared to S0: at baseline, they comprised 17–33% and after two years 62–95% of all detected radiolucencies within the category. 65% of non-matching score transitions over two years occurred between S0 and S1. The CBCT-based evaluation resulted in negative treatment outcomes for 10 more root canals than the DPR-based result. Conclusions: Most remarkable disagreement between DPR and CBCT recordings was observed within the radiolucency categories S2 and S3. However, the diagnostic accuracy of both radiographic methods was questionable as it resulted in a high proportion of non-matching S0-S1 lesion transitions over 2 years.

APACHE: A multicentric prospective comparative analysis of placentas in women with and without Congenital Heart Disease

Although perinatal complications during pregnancy in women with Congenital Heart Disease (ACHD) are well known, the pathophysiological mechanisms are still to be elucidated. As the placenta is the interface between mother and fetus, its analysis might help to better understand their interactions and identify risk factors for complications. We hypothesize that abnormal findings would be more frequent in placentas of women with CHD than in those without cardiac disease. The main objective of this study is to compare the incidence of placental abnormalities (PA) in ACHD versus controls women. The present proposal is to conduct a prospective, multicentric, national, 2-years (2023–2024) cohort study (research involving human type III), in order to analyze Doppler imaging and histological placentas, and compare findings in a group of women with ACHD versus a group without. The secondary objectives of the study are to assess the association between PA and the occurrence of maternal cardiovascular, fetal and/or perinatal complications, and to assess risk factors for PA or maternal/fetal events ( Fig. 1 ). Placentas of ACHD would have significantly ( P < 0.05) more abnormalities and these would correlate with the occurrence of complications. Description of PA could help to elucidate the pathophysiological mechanisms and eventually propose preventive therapeutic strategies of fetal and/or neonatal complications. Risk factors could be stratified according to the type of heart disease (as the mWHO score) and could allow to propose a novel risk-score of pregnancy in women with CHD.

Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients

Neurological and psychiatric risk trajectories after SARS-CoV-2 infection: an analysis of 2-year retrospective cohort studies including 1 284 437 patients