Miracle-dz/UniFAR-FTUs huggingface dataset:
Blood and urine biomarkers in osteoarthritis – an update on cartilage associated type II collagen and aggrecan markers

Purpose of review Osteoarthritis (OA) is a painful disease for which drug development has proven difficult. One major reason for this is the heterogeneity of the disease and the current lack of operationalized means to distinguish various disease endotypes (molecular subtypes). Biomarkers measured in blood or urine, reflecting joint tissue turnover, have been developed and tested during the last decades. In this narrative review, we provide highlights on biomarkers derived from the two most studied and abundant cartilage proteins – type II collagen and aggrecan. Recent findings Multiple biomarkers assessing type II collagen degradation and formation, and aggrecan turnover have been developed. Several markers, such as uCTX-II, have been validated for their association with disease severity and prognosis, as well as pharmacodynamically used to describe the mode of action and efficacy of drugs in development. There is a great need for biomarkers for subdividing patients (i.e., endotyping) and recent scientific advances have not yet come closer to achieving this goal. Summary There is strong support for using biomarkers for understanding OA, reflecting degradation and formation of the joint tissues, focused on type II collagen and aggrecan. There is still a lack of in vitro diagnostics, in all contexts of use.
Sleep Apnea Specific Hypoxic Burden, Symptom Subtypes and Risk of Cardiovascular Events and All-Cause Mortality.

BACKGROUND Data from population-based cohorts suggest that symptom subtypes, and OSA-specific hypoxic burden (HB) could help to better identify patients with OSA at high cardiovascular (CV) risk. AIM We aimed to evaluate whether those new markers are associated with the risk of major adverse CV events (MACE) in clinical setting. METHODS Data from the Pays de la Loire cohort were linked to health administrative data to identify the occurrence of MACE (a composite outcome including all-cause mortality, acute myocardial infarction, stroke, and unplanned coronary revascularization) in patients with newly diagnosed OSA and no overt CV disease. Latent class analysis was used to identify subtypes based on 8 clinically relevant variables. HB was defined as the total area under the respiratory event-related desaturation curve. Cox proportional hazards models were used to evaluate the association of symptom subtypes and HB with MACE. RESULTS Four symptom subtypes were identified (minimally symptomatic [22.0%], disturbed sleep [17.5%], excessively sleepy [49.8%], and moderately sleepy [10.6%]). After a median [inter-quartile range] follow-up of 78 months [52-109], 592 (11.05%) of 5,358 patients experienced MACE. In a fully adjusted model, HB and overall nocturnal hypoxemia assessed by sleep time with oxygen saturation <90% were the only predictors of MACE (HR 1.21; 95%CI [1.07-1.38] and 1.34 [1.16-1.55] respectively). The association appeared stronger towards younger patients and women. CONCLUSION In clinical setting, patients with OSA who demonstrate elevated OSA specific HB are at higher risk of CV event and all-cause mortality. Symptom subtypes were not associated with MACE after adjustment for confounders.
Neutrophil to Lymphocyte Ratio after Treatment Completion as a Potential Predictor of Survival in Patients with Triple-Negative Breast Cancer

Purpose Triple-negative breast cancer (TNBC) has been associated with worse prognosis, and biomarkers are needed to identify high-risk patients who may benefit from clinical trials or escalated treatment after completion of standard treatment. We aimed to assess whether the post-treatment neutrophil-to-lymphocyte ratio (NLR) can reflect patient prognosis and determine the follow-up period that can provide the most feasible data. Methods In this retrospective analysis involving patients with TNBC, clinicopathological data, including those on peripheral complete blood cell count, were collected. The prognostic powers of serial NLRs obtained at baseline and after treatment completion were compared. Kaplan-Meier curves were generated to compare the overall survival (OS) and distant disease-free survival (DDFS). Results In total, 210 patients were enrolled. Forty-three (20.5%) events were detected. Two-thirds of the events (29/43) were related to breast cancer. Most recurrent breast cancer-related diseases (27/29) were detected within 5 years of the initial diagnosis. In contrast, half of the events due to secondary malignancies or non-breast-related diseases (7/14) occurred 5 years after the initial diagnosis. Comparison of the prognostic performance of NLRs at baseline and at 6, 12, and 24 months after treatment completion revealed the strongest prognostic performance at 6 months after treatment completion (area under the curve = 0.745). The high NLR group (NLR >2.47) showed worse OS (p = 0.006) and DDFS (p < 0.001) than low NLR group. Conclusion Elevated post-treatment NLR was significantly associated with worse survival in patients with TNBC. We believe that it can be a useful surrogate marker for identifying high-risk patients with TNBC.
Ranitidine and Risk of Bladder and Kidney Cancer: A Population-Based Cohort Study

Background: In 2019, ranitidine was withdrawn due to high levels of N-nitrosodimethylamine, a probable human carcinogen. The risk of bladder and kidney cancer in ranitidine users, however, remains unclear. Methods: In a Danish nationwide cohort study, we included adults (18 years or older) without previous cancer, who between 1996 and 2008 redeemed at least two prescriptions for ranitidine and, as two separate comparison cohorts, patients with at least two prescriptions for other H2-receptor antagonists (H2-blockers), or proton pump inhibitors (PPI). Follow-up for bladder or kidney cancer started at date of the second prescription and continued to date of cancer, death, emigration, or December 31, 2018, whichever occurred first. We used propensity scores for ranitidine use to compute stabilized inverse probability of treatment (sIPT) weights and used Cox regression to compute crude and weighted HRs. Results: We identified 31,393 initiators of ranitidine, 65,384 initiating other H2-blockers, and 509,849 initiating PPI. Compared with other H2-blockers, the crude HR for bladder cancer was 1.33 [95% confidence interval (CI): 1.15–1.55], but sIPT weighting attenuated this to 1.11 (95% CI: 0.95–1.29). Compared with PPI initiators, the weighted HR was 1.24 (95% CI: 1.04–1.48). For kidney cancer, the weighted HR was 0.89 (95% CI: 0.72–1.10) compared with users of H2-blockers and 0.87 (95% CI: 0.67–1.13) compared with users of PPI. Conclusions: Our findings did not suggest a substantial increase in bladder or kidney cancer occurrence in ranitidine users. Impact: These findings are reassuring for previous ranitidine users.
Nonalcoholic fatty liver disease and early prediction of gestational diabetes mellitus using machine learning methods

Background/Aims To develop an early prediction model for gestational diabetes mellitus (GDM) using machine learning and to evaluate whether the inclusion of nonalcoholic fatty liver disease (NAFLD)-associated variables increases the performance of model. Methods This prospective cohort study evaluated pregnant women for NAFLD using ultrasound at 10–14 weeks and screened them for GDM at 24–28 weeks of gestation. The clinical variables before 14 weeks were used to develop prediction models for GDM (setting 1, conventional risk factors; setting 2, addition of new risk factors in recent guidelines; setting 3, addition of routine clinical variables; setting 4, addition of NALFD-associated variables, including the presence of NAFLD and laboratory results; and setting 5, top 11 variables identified from a stepwise variable selection method). The predictive models were constructed using machine learning methods, including logistic regression, random forest, support vector machine, and deep neural networks. Results Among 1,443 women, 86 (6.0%) were diagnosed with GDM. The highest performing prediction model among settings 1–4 was setting 4, which included both clinical and NAFLD-associated variables (area under the receiver operating characteristic curve [AUC] 0.563–0.697 in settings 1–3 vs. 0.740–0.781 in setting 4). Setting 5, with top 11 variables (which included NAFLD and hepatic steatosis index), showed similar predictive power to setting 4 (AUC 0.719–0.819 in setting 5, P=not significant between settings 4 and 5). Conclusions We developed an early prediction model for GDM using machine learning. The inclusion of NAFLD-associated variables significantly improved the performance of GDM prediction. (ClinicalTrials.gov Identifier: NCT02276144)
The correlation between high-risk HPV infection and precancerous lesions and cervical cancer.

OBJECTIVE To analyze the correlation between high-risk human papillomavirus (HPV) infection and precancerous lesions and cervical cancer. METHODS Patients with cervicitis (N=100), cervical intraepithelial neoplasia grade I (CIN I) (N=100), cervical intraepithelial neoplasia grades II-III (CIN II-III) (N=100) and cervical cancer (N=100) were enrolled. The exfoliated cervical cells were collected with the same method, and the detection of the HPV types was carried out by PCR-reverse dot blot (RDB) assay. RESULTS The top 5 HPV types in stage I-II cervical cancer were 16, 18, 52, 58, and 53, with a HPV positivity rate of 83.61%, while top 5 HPV types in stage III-IV cervical cancer were 16, 18, 58, 52, and 33, with a HPV positivity rate of 82.05%. The rate of high-risk HPV positivity for cervicitis was 5%, with HPV types of 16, 18, 52, and 33, 12% for CIN I, with HPV types of 16, 58, 52, 33, 56, 66, and 68, and 42% for CIN II-III, with HPV types of 16, 18, 58, 52, 33, 66, and 68. The prevalence of single, dual, and multiple HPV infection was 8.00%, 1.00%, and 0.00% for CIN I, 24.00%, 7.00%, and 1.00% for CIN II-III, and 57.00%, 25.00%, and 3.00% for cervical cancer, respectively. The age of patients with CIN I was mainly ≤24 and 25-34 years while CIN II-III in 25-34 and 35-44 years, and cervical cancer in 35-44 and 45-54 years. CONCLUSION The distribution of HPV subtypes in cervical cancer is closely related to the pathological types, lesion grades, and stages of cervical cancer. The incidence of cervical lesions varies with age, suggesting that high-risk groups should be well monitored and receive regular screening and timely HPV vaccination to effectively prevent cervical cancer.
HNSC exosome-derived MIAT improves cognitive disorders in rats with vascular dementia via the miR-34b-5p/CALB1 axis.

OBJECTIVE To explore the molecular mechanism by which hippocampal neural stem cell (HNSC) exosome (exo)-derived MIAT improves cognitive disorders in rats with vascular dementia (VD). METHODS Rat hippocampal tissues were collected, and HNSCs and hippocampal neuronal cells (HNCs) were isolated, purified, and identified. Then the exosomes (exo) of the HNSCs were extracted and identified. A VD rat model was constructed. HE staining was used to evaluate the hippocampal pathology in each group. The expressions of the RNAs in the HNSCs were intervened, and the cells were then grouped. ELISA was used to measure the of TNF-α, IL-1, and Aβ1-42 expression levels. The kits were used to determine the oxidative stress factor levels. The targeting relationships among MIAT, miR-34b-5p, and CALB1 were measured using dual-luciferase assays. The MIAT expressions in exo were measured using qRT-PCR. The proliferation and apoptosis of the HNCs were determined using CCK-8 and Annexin V-FITC/PI staining, respectively. The CALB1, TH, and Bcl-2 protein expressions were determined using Western blot. The Morris water maze test was used for the spatial learning and memory testing. RESULTS The hippocampal tissues in the model group were clearly damaged, but the pathological characteristics were significantly improved in the exo group. The exo group also showed an increased SOD level, decreased MDA and ROS levels, and down-regulated TNF-α, IL-1, and Aβ1-42 expressions (all P<0.05). MiR-34b-5p had a targeting relationship with both MIAT and CALB1, and MIAT was found to be expressed in exo. The oe-MIAT-exo group and the miR-34b-5p inhibitor group showed significantly up-regulated CALB1, TH, and Bcl-2 protein expressions in the HNCs, increased cell viability, as well as reduced apoptosis, but the si-MIAT-exo group showed the opposite results (all P<0.05). The MiR-34b-5p inhibitor partially reversed the effect on the si-MIAT-exo group. The miR-34b-5p mimic group showed significantly down-regulated CALB1, TH, and Bcl-2 protein expressions in the HNCs, inhibited cell viability, as well as increased apoptosis, but the oe-CALB1 group showed the opposite results (all P<0.05). Oe-CALB1 partially reversed the effect on the miR-34b-5p mimic group. The memory and learning abilities of the rats in the oe-MIAT-exo group and the model + exo group were significantly improved but not as much as they were in the normal rats. CONCLUSION MIAT-containing exo from HNSCs can improve cognitive disorders in VD rats via the miR-34b-5p/CALB1 axis.
ASSOCIATION BETWEEN PRE-STROKE PHYSICAL ACTIVITY AND MOBILITY AND WALKING ABILITY IN THE EARLY SUBACUTE PHASE: A REGISTRY-BASED STUDY

Objective To investigate associations between prestroke physical activity and mobility, walking ability, and self-perceived upper extremity function during stroke unit care. Design A longitudinal, registry-based study with a consecutively collected cohort. Subjects/patients A total of 1,092 adults with stroke admitted to 3 Swedish stroke units between 2017 and 2018. Methods Logistic mixed effects regression models were performed to investigate associations (adjusted for age and sex). Pre-stroke physical activity was assessed with Saltin-Grimby Physical Activity Level Scale on admission. Mobility, walking ability, and self-perceived upper extremity function were assessed at admission and discharge from the stroke units and compared between pre-stroke physically active (45%) and inactive (55%) groups. Results All groups of patients showed improvements in mobility (p < 0.001), walking ability (p < 0.001), and upper extremity function (p < 0.001). The changes over time tended to differ between the physically inactive and active groups for mobility (p < 0.062) and walking ability (p < 0.056), but the differences were not significant. Conclusion Pre-stroke physically active people showed a tendency to be more independent in physical functioning early after stroke. Regardless of prestroke physical activity, all patients showed improvements in mobility, walking ability, and self-perceived upper extremity function during inpatient care. LAY ABSTRACT To be physically active prior to a stroke may improve the post-stroke recovery process. Therefore, we hypothesized that pre-stroke physical activity might reduce the consequences of a stroke. This study investigated associations between pre-stroke physical activity and post-stroke recovery of mobility, walking ability, and arm and hand function. A total of 1,092 patients were examined; 44% were women, 89% had ischaemic stroke, and 55% were physically inactive before the stroke. All patients showed improvements during care at the stroke units, regardless of their previous physical activity level. At hospital discharge, 71% of patients showed independent mobility, 68% could walk independently, and 55% reported self-perceived arm and hand impairments. Patients with higher pre-stroke physical activity levels had a tendency of being more independent in mobility and walking compared with inactive patients. However, the frequencies of self-perceived arm and hand impairments were similar between the physically active and physically inactive groups. To be physically active prior to a stroke may improve the post-stroke recovery process.
Kinematics of bicruciate stabilized and cruciate retaining total knee arthroplasty

Few studies have been reported about kinematic comparison between bicruciate stabilized and cruciate retaining total knee arthroplasty with the same anatomical surface geometry. The aim of this study was to demonstrate the in vivo kinematics and postoperative patient‐reported outcomes of these two surgeries with the same anatomical surface geometry. We analyzed 17 bicruciate stabilized and 18 cruciate retaining total knee arthroplasties using single‐plane fluoroscopic surveillance with two‐ to three‐dimensional registration techniques during squatting from minimum to maximum flexion. Flexion angle, femoral external rotation, anteroposterior position of the medial and lateral sides, and postoperative 2011 Knee Society Scores were analyzed. Maximum flexion angles were larger for bicruciate stabilized than for cruciate retaining total knee arthroplasties. There was no significant difference in femoral external rotation between the two types. The medial and lateral femoral condyles in bicruciate stabilized type translated more posteriorly during deeper flexion and at maximum flexion angle, respectively, than those in cruciate retaining total knee arthroplasty. Both groups revealed medial pivots in early flexion, but during deep flexion, bicruciate stabilized total knee arthroplasty revealed bicondylar roll‐back and cruciate retaining total knee arthroplasty revealed paradoxical anterior motion. Both groups exhibited similar results in postoperative 2011 Knee Society Scores. Bicruciate stabilized and cruciate retaining total knee arthroplasties with the same anatomical articular surfaces demonstrated different kinematics patterns during squatting. However, there were no significant differences in postoperative 2011 Knee Society Scores between the two types of surgery.
Phospholipase C‐zeta levels are not correlated with fertilisation rates in infertile couples

In mammals, ‘oocyte activation’ is triggered by certain proteins, one of which is phospholipase C‐zeta. Recent evidence suggests that low expression of phospholipase C‐zeta might be associated with male infertility, while a limited number of studies claimed the opposite. This study was designed to test whether quantity of phospholipase C‐zeta and in vitro fertilisation rates are correlated or not, assessed by flow cytometry. Semen samples from 43 infertile couples were analysed for the percentage and mean fluorescent intensity (MFI) of phospholipase C‐zeta protein. Results were confirmed by immunofluorescent labelling. Patients with a fertilisation rate of 40% or lower were involved in the low fertilisation group, while the high fertilization group consisted of patients with a fertilisation rate of 60% and higher. Quantitative analyses by flow cytometry showed no significant difference among the low fertilisation and high fertilisation groups when phospholipase C‐zeta ratio or MFI was considered. No correlation was found between pregnancy rates and phospholipase C‐zeta quantity. None of the total fertilisation failure cases were lack of phospholipase C‐zeta. In fact, fertilisation was possible even when phospholipase C‐zeta levels were very low. Thus, we concluded that phospholipase C‐zeta quantity cannot be considered as a diagnostic tool for male infertility.
Physical disturbance by recovering sea otter populations increases eelgrass genetic diversity

Description The importance of disturbance Work in sea otters over the last few decades has transformed our understanding of the importance of specific species, or keystones, as drivers of community structure and stability. Foster et al. took the next step and tested whether otter foraging might influence genetic diversity in an eelgrass ecosystem (see the Perspective by Roman). The authors found that eelgrass genetic diversity was significantly higher where otters were present and that the impact was related to time: Longer otter presence was associated with higher genetic diversity. These results illustrate how the actions of a predator can affect the diversity of a producer in a tropic system. —SNV Digging by sea otters promotes increases in genetic diversity and ecological resilience in eelgrass meadows. Most knowledge regarding the role of predators is ecological in nature. Here, we report how disturbance generated by sea otters (Enhydra lutris) digging for infaunal prey in eelgrass (Zostera marina) meadows increases genetic diversity by promoting conditions for sexual reproduction of plants. Eelgrass allelic richness and genotypic diversity were, respectively, 30 and 6% higher in areas where recovering sea otter populations had been established for 20 to 30 years than in areas where they had been present <10 years or absent >100 years. The influence of sea otter occupancy on the aforementioned measures of genetic diversity was stronger than those of depth, temperature, latitude, or meadow size. Our findings reveal an underappreciated evolutionary process by which megafauna may promote genetic diversity and ecological resilience.
Associations Between Device-Measured Physical Activity and Glycemic Control and Variability Indices Under Free-Living Conditions

Background: Disturbances of glycemic control and large glycemic variability have been associated with increased risk of type 2 diabetes in the general population as well as complications in people with diabetes. Long-term health benefits of physical activity are well documented but less is known about the timing of potential short-term effects on glycemic control and variability in free-living conditions. Materials and Methods: We analyzed data from 85 participants without diabetes from the Food & You digital cohort. During a 2-week follow-up, device-based daily step count was studied in relationship to glycemic control and variability indices using generalized estimating equations. Glycemic indices, evaluated using flash glucose monitoring devices (FreeStyle Libre), included minimum, maximum, mean, standard deviation, and coefficient of variation of daily glucose values, the glucose management indicator, and the approximate area under the sensor glucose curve. Results: We observed that every 1000 steps/day increase in daily step count was associated with a 0.3588 mg/dL (95% confidence interval [CI]: −0.6931 to −0.0245), a 0.0917 mg/dL (95% CI: −0.1793 to −0.0042), and a 0.0022% (95% CI: −0.0043 to −0.0001) decrease in the maximum glucose values, mean glucose, and in the glucose management indicator of the following day, respectively. We did not find any association between daily step count and glycemic indices from the same day. Conclusions: Increasing physical activity level was linked to blunted glycemic excursions during the next day. Because health-related benefits of physical activity can be long to observe, such short-term physiological benefits could serve as personalized feedback to motivate individuals to engage in healthy behaviors.