Miracle-dz/UniFAR-FTUs huggingface dataset:
The Role of Real‐World Evidence in FDA‐Approved New Drug and Biologics License Applications

The US Food and Drug Administration (FDA) is open to accepting real‐world evidence (RWE) to support its assessment of medical products. However, RWE stakeholders lack a shared understanding of FDA’s evidentiary expectations for the use of RWE in applications for new drugs and biologics. We conducted a systematic review of publicly available FDA approval documents from January 2019 to June 2021. We sought to quantify, by year, how many approvals incorporated RWE in any form, and the intended use of RWE in those applications. Among approvals with RWE intended to support safety and/or effectiveness, we classified whether and how those studies impacted FDA’s benefit‐risk considerations, whether those studies were incorporated into the product label, and the therapeutic area of the medical product. Finally, we qualified FDA’s documented feedback where available. We found that 116 approvals incorporated RWE in any form, with the proportion of approvals incorporating RWE increasing each year. Of these approvals, 88 included an RWE study intended to provide evidence of safety or effectiveness. Among these 88 approvals, 65 of the studies influenced FDA’s final decision and 38 were included in product labels. The 88 approvals spanned 18 therapeutic areas. FDA’s feedback on RWE study quality included methodological issues, sample size concerns, omission of patient level data, and other limitations. Based on these findings, we would anticipate that future guidance on FDA’s evidentiary expectations of RWE use will incorporate fit‐for‐purpose real‐world data selection and careful attention to study design and analysis.
Thyroid Feedback Quantile-based Index correlates strongly to renal function in euthyroid individuals

Abstract Background Previous studies have reported a negative relationship between thyroid-stimulating hormone (TSH) and renal function in euthyroid individuals, but others have found that higher free thyroxine (FT4) was associated with an increased risk of chronic kidney disease. This study was designed to analyze the relationship between thyroid and renal function from a new perspective of sensitivity to thyroid hormone. Methods This retrospective study included 2831 euthyroid individuals who underwent a health examination at the First Hospital of China Medical University between January 2017 and December 2018. Parametric Thyroid Feedback Quantile-based Index (PTFQIFT4), TSH index (TSHI), thyrotroph T4 resistance index (TT4RI), free triiodothyronine to FT4 ratio (FT3/FT4), the secretory capacity of the thyroid gland (SPINA-GT) and the sum activity of peripheral deiodinases (SPINA-GD) were calculated. We also innovated the TT3RI and PTFQIFT3 indices based on FT3 and TSH. Renal function was assessed by estimated glomerular filtration rate (eGFR) CKD-EPI and creatinine-cystatin C-KDIGO equations. Results After adjustment of basic characteristics and comorbidities, linear regression showed that eGFR CKD-EPI was positively associated with FT3/FT4 (β = 23.31), and inversely correlated to PTFQI FT4 (β= −2.69) (both p < .001). When comparing the fourth versus the first quartile of PTFQI FT4, the odds ratio (OR) for a reduced renal function was 1.89 (95% CI 1.28–2.80), and the OR was 0.64 (95% CI 0.43–0.95) when comparing quartiles of FT3/FT4 (both p for trend< .05). In addition, for every 1SD increase in PTFQI FT4, the OR for a reduced renal function was 1.27 (95%CI 1.10–1.47). TSHI, TT4RI and TT3RI also showed a negative correlation to renal function. Similar results were obtained in SPINA-GD as in FT3/FT4. Conclusions In euthyroid individuals, decreased sensitivity to thyroid hormone is associated with reduced renal function. The composite PTFQIFT4 index correlates more strongly to renal function than TSH or T4 alone. KEY MESSAGES Decreased sensitivity to thyroid hormone is associated with reduced renal function in the euthyroid population. The recently developed composite index PTFQIFT4 seems to correlate more strongly to renal function than individual TSH or FT4 parameters. Innovative indices TT3RI and PTFQIFT3 based on the interaction between T3 and TSH may also reflect sensitivity to thyroid hormone.
Clinical significance of microRNA-1180-3p for colorectal cancer and effect of its alteration on cell function

ABSTRACT An early diagnosis and effective prognostic factors would greatly reduce the mortality rate of colorectal cancer (CRC). This research is intended to complete the evaluation of the prognostic value and potential role of miR-1180-3p in CRC. The miR-1180-3p levels were reduced in CRC patients’ tissues, blood, and human CRC cell lines. The ability of miR-1180-3p was explored in discrimination of CRC patients and healths and the value in overall survival estimate. The effect of miR-1180-3p dysregulation on the CRC cellular function was investigated. miR-1180-3p is downregulated in CRC tissues, blood and cells than normal ones. This lower expression was correlated with vascular invasion, lymph node metastasis, and TNM stage. With the use of ROC curve, miR-1180-3p showed discriminating ability in CRC patients and healthy subjects. With the result of Kaplan–Meier analysis and multi-multivariate Cox analysis, miR-1180-3p was an independent predictor for CRC patients’ overall survival. Utilizing CCK-8, Transwell and matrigel assays, overexpression of miR-1180-3p reduced cancer cell proliferation and mobility, but induced apoptosis, by targeting COL12A1. miR-1180-3p might function as a suppressor in CRC progression and allowed the discovery of a new biomarker for diagnosis, prognosis and therapy target for CRC.
Nepetin Acts as a Multi‐Targeting Inhibitor of Protein Tyrosine Phosphatases Relevant to Insulin Resistance

Protein tyrosine phosphatases (PTPs) are essential modulators of signal transduction pathways and has been implicated in many human diseases such as cancer, diabetes, obesity, autoimmune disorders, and neurological diseases, indicating that PTPs are next‐generation drug targets. Since PTPN1, PTPN2, and PTPN11 have been reported to be negative regulators of insulin action, the identification of PTP inhibitors may be an effective strategy to develop therapeutic agents for the treatment of type 2 diabetes. In this study, we observed for the first time that nepetin inhibits the catalytic activity of PTPN1, PTPN2, and PTPN11 in vitro, indicating that nepetin acts as a multi‐targeting inhibitor of PTPN1, PTPN2, and PTPN11. Furthermore, treatment of mature 3T3‐L1 adipocytes with 20 μM nepetin stimulates glucose uptake through AMPK activation. Taken together, our findings provide evidence that nepetin, a multi‐targeting inhibitor of PTPN1, PTPN2, and PTPN11, could be a promising therapeutic candidate for the treatment of type 2 diabetes.
Socioeconomic disparities in the prevalence of comorbid chronic conditions among Canadian adults with cancer

Abstract Objective To evaluate the prevalence of comorbid chronic conditions among Canadian adults with cancer and the impact of socioeconomic background on the distribution of these conditions. Methods Canadian Community Health Survey (CCHS) 2017–2018 dataset was accessed and individuals with complete information about cancer history were reviewed. The prevalence of the following 10 chronic conditions was reviewed: asthma, chronic obstructive pulmonary disease, arthritis, hypertension, hypercholesterolemia/hyperlipidemia, heart disease, stroke, diabetes, mood disorder, and anxiety disorder. Stratification of the prevalence was done according to age, sex, and racial subgroups. Multivariable logistic regression analysis was done to evaluate the association between sociodemographic characteristics and having multiple comorbid conditions. Results A total of 104,362 participants were included in the current study (including 10,782 participants with a history of cancer; and 93,580 participants without a history of cancer). Among all age, sex, and race strata, participants with a history of cancer were more likely to have multiple chronic conditions (p < 0.05 for all comparisons). The most common three individual comorbid conditions among participants with cancer were arthritis (40.2%), hypertension (36.1%), and hypercholesterolemia (25.2%); while the most common cancer-comorbidity triad among participants with cancer was cancer/arthritis/hypertension (17.7%). In a multivariable logistic regression analysis among participants with cancer, the following sociodemographic factors were associated with having multiple comorbid conditions: older age (OR for age 80+ versus age 18–20 years: 8.32; 95% CI: 5.17–13.39), indigenous racial group (OR: 1.94; 95% CI: 1.43–2.63) and lower income (OR for income ≥80,000 Canadian dollars (CAD) versus income: ≤20,000 CAD: 0.29; 95% CI: 0.23–0.37). Conclusion History of cancer is associated with a higher probability of many comorbid conditions. This excess comorbidity burden seems to be unequally shouldered by individuals in the lower socioeconomic stratum as well as minority populations.
Mathematical modelling of human P2X-mediated plasma membrane electrophysiology and calcium dynamics in microglia

Regulation of cytosolic calcium (Ca2+) dynamics is fundamental to microglial function. Temporal and spatial Ca2+ fluxes are induced from a complicated signal transduction pathway linked to brain ionic homeostasis. In this paper, we develop a novel biophysical model of Ca2+ and sodium (Na+) dynamics in human microglia and evaluate the contribution of purinergic receptors (P2XRs) to both intracellular Ca2+ and Na+ levels in response to agonist/ATP binding. This is the first comprehensive model that integrates P2XRs to predict intricate Ca2+ and Na+ transient responses in microglia. Specifically, a novel compact biophysical model is proposed for the capture of whole-cell patch-clamp currents associated with P2X4 and P2X7 receptors, which is composed of only four state variables. The entire model shows that intricate intracellular ion dynamics arise from the coupled interaction between P2X4 and P2X7 receptors, the Na+/Ca2+ exchanger (NCX), Ca2+ extrusion by the plasma membrane Ca2+ ATPase (PMCA), and Ca2+ and Na+ leak channels. Both P2XRs are modelled as two separate adenosine triphosphate (ATP) gated Ca2+ and Na+ conductance channels, where the stoichiometry is the removal of one Ca2+ for the hydrolysis of one ATP molecule. Two unique sets of model parameters were determined using an evolutionary algorithm to optimise fitting to experimental data for each of the receptors. This allows the proposed model to capture both human P2X7 and P2X4 data (hP2X7 and hP2X4). The model architecture enables a high degree of simplicity, accuracy and predictability of Ca2+ and Na+ dynamics thus providing quantitative insights into different behaviours of intracellular Na+ and Ca2+ which will guide future experimental research. Understanding the interactions between these receptors and other membrane-bound transporters provides a step forward in resolving the qualitative link between purinergic receptors and microglial physiology and their contribution to brain pathology.
Oral bisphosphonates: Adverse effects on the oral mucosa not related to the jaw bones. A scoping review

Abstract Background Oral bisphosphonates are widely used in the treatment of bone resorptive diseases. There is an evidence that oral bisphosphonates can exert adverse effects on the oral mucosa independently of their effects on the jaw bones. Objective To systematically map the literature on adverse effects of oral bisphosphonates on the oral mucosa of adults with bone resorptive diseases. Design Scoping review of the literature, including different study designs. Methods Systematic searches of the PubMed, LILACS, Google Scholar and EMBASE databases were conducted. Two independent reviewers screened titles and abstracts according to predetermined criteria. Results The search retrieved 26 unique articles, comprising 22 case reports, one case series and three reviews describing a total of 56 cases of oral adverse events related to oral bisphosphonates. 88% of the reported cases were female suffering from comorbidities other than metabolic bone diseases. The improper use of the oral bisphosphonate was the most suspected cause of the adverse effect on the oral mucosa. Its management mainly involved withdrawal of the medication. Conclusion Adverse effects on the oral mucosa can develop from using oral bisphosphonates. Standardised registration of these adverse effects in university clinics and private practises could provide additional information about their occurrence and severity.
Dendritic cell paucity in mismatch repair–proficient colorectal cancer liver metastases limits immune checkpoint blockade efficacy

Significance Immune checkpoint blockade (ICB) has been efficacious in several cancer types. However, mismatch repair–proficient (pMMR) metastatic colorectal cancer (CRC), ∼95% of total metastatic CRC cases, typically does not respond to ICB. Here, we show that orthotopic liver metastasis mouse models of pMMR CRC cell lines are unresponsive to ICB and recapitulate the resistance of human disease, unlike subcutaneous tumors of the same cell lines. We also show that just like the human disease, orthotopic pMMR CRC liver metastases have a paucity of T cells and dendritic cells, and that treatment with Flt3L sensitizes the liver metastases to ICB. Our findings highlight that orthotopic tumor models, and not subcutaneous models, should be used for preclinical studies of cancer immunotherapy. Liver metastasis is a major cause of mortality for patients with colorectal cancer (CRC). Mismatch repair–proficient (pMMR) CRCs make up about 95% of metastatic CRCs, and are unresponsive to immune checkpoint blockade (ICB) therapy. Here we show that mouse models of orthotopic pMMR CRC liver metastasis accurately recapitulate the inefficacy of ICB therapy in patients, whereas the same pMMR CRC tumors are sensitive to ICB therapy when grown subcutaneously. To reveal local, nonmalignant components that determine CRC sensitivity to treatment, we compared the microenvironments of pMMR CRC cells grown as liver metastases and subcutaneous tumors. We found a paucity of both activated T cells and dendritic cells in ICB-treated orthotopic liver metastases, when compared with their subcutaneous tumor counterparts. Furthermore, treatment with Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 ligand (Flt3L) plus ICB therapy increased dendritic cell infiltration into pMMR CRC liver metastases and improved mouse survival. Lastly, we show that human CRC liver metastases and microsatellite stable (MSS) primary CRC have a similar paucity of T cells and dendritic cells. These studies indicate that orthotopic tumor models, but not subcutaneous models, should be used to guide human clinical trials. Our findings also posit dendritic cells as antitumor components that can increase the efficacy of immunotherapies against pMMR CRC.
Safety, tolerability, and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, administered concomitantly with influenza vaccine in healthy adults aged ≥50 years: a randomized phase 3 trial (PNEU-FLU)

ABSTRACT Streptococcus pneumoniae and influenza viruses are associated with significant morbidity and mortality in older adults. Concomitant vaccination against these agents reduces hospitalization and mortality rates. This phase 3 trial evaluated safety, tolerability, and immunogenicity of concomitant and non-concomitant administration of V114, a 15-valent pneumococcal conjugate vaccine containing serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F, 19A, 22F, 23F, 33F, and quadrivalent inactivated influenza vaccine (QIV), in healthy adults aged ≥50 years. Participants (N = 1,200) were randomized 1:1 to receive either V114 administered concomitantly with QIV (concomitant group) or QIV plus placebo (non-concomitant group) on Day 1, followed by placebo (concomitant group) or V114 (non-concomitant group) 30 days later. Randomization was stratified by age and history of pneumococcal polysaccharide vaccine receipt. Overall, 426 (71.0%) and 438 (73.5%) participants in the concomitant and non-concomitant groups experienced solicited injection-site adverse events (AEs); 278 (46.3%) and 300 (50.3%) reported solicited systemic AEs. Most solicited AEs were mild or moderate in severity and of short duration. Non-inferiority for pneumococcal- and influenza-specific antibody responses (lower bound 95% confidence interval of opsonophagocytic activity [OPA] and hemagglutination inhibition geometric mean titers [GMTs] ratios ≥0.5) was demonstrated for concomitant versus non-concomitant administration for all 15 pneumococcal serotypes and all four influenza strains. Consistent with previous studies, a trend was observed toward lower pneumococcal OPA GMTs in the concomitant versus the non-concomitant group. V114 administered concomitantly with QIV is generally well tolerated and immunologically non-inferior to non-concomitant administration, supporting coadministration of both vaccines.
Optimization in the Absorption and Desorption of CO2 Using Sodium Glycinate Solution

This study used sodium glycinate as an absorbent to absorb CO2 in the bubble column scrubber under constant pH and temperature environments to obtain the operating range, CO2 loading, and mass transfer coefficient. For efficient experimentation, the Taguchi method is used for the experimental design. The process parameters are the pH, gas flow rate (Qg), liquid temperature (T), and absorbent concentration (CL). The effects of the parameters on the absorption efficiency, absorption rate, overall mass transfer coefficient, gas–liquid molar flow rate ratio, CO2 loading, and absorption factor are to be explored. The optimum operating conditions and the order of parameter importance are obtained using the signal/noise (S/N) ratio analysis, and the optimum operating conditions are further verified. The verification of the optimum values was also carried out. The order of parameter importance is pH > CL > Qg > T. Evidence in the 13CNMR (Carbon 13 Nuclear Magnetic Resonance) spectra shows that the pH value has an effect on the solution composition, which affects both the absorption efficiency and mass transfer coefficient. There are 18 experiments for regeneration, where the operating temperature is 100–120 °C. The heat of regeneration was measured according to the thermodynamic data. The CO2 loading, the overall mass transfer, and the heats of regeneration correlation are also discussed in this work. Finally, an operating policy for the CO2 absorption process was confirmed.
Compatibility of two types of gummy jelly tests for detecting decreased masticatory function.

OBJECTIVE This study aimed to verify the compatibility of masticatory performance tests using different two types of gummy jellies. BACKGROUND DATA DISCUSSING THE PRESENT STATUS OF THE FIELD Compatibility between the glucose concentration measuring method (GC) and 10-steps visual scoring method (VS), which are masticatory performance tests for diagnosing decreased masticatory function (DMF) in oral hypofunction and the use of different types of gummy jelly, has yet to be confirmed. MATERIALS AND METHODS The participants consisted of 134 Japanese older people (51 men and 83 women). GC, VS and the increased surface area measuring method (ISA), as an alternative analysis method for VS, were conducted to evaluate masticatory performance. Cohen's Kappa coefficient was used to verify the consistency for detecting DMF between GC and VS. Pearson's correlation coefficient was used to analyse the relationship between GC and ISA. Each masticatory performance was compared among three different groups for the number of residual teeth. Cut-off values of VS and ISA for DMF that were consistent with GC were identified. RESULTS Glucose concentration measuring method and VS showed an excellent consistency (Kappa coefficient = 0.86). There was a high positive correlation between GC and ISA (r = .70). However, the change in masticatory performance according to the number of teeth was different between GC and VS/ISA. The cut-off values of VS and ISA were a Score of 2 and 1687 mm2 , respectively. CONCLUSION Glucose concentration measuring method and VS/ISA remained fairly consistent for detecting DMF, which might be useful information to interconnect the various studies on masticatory performance.
Conflicted or close: Which relationships to the deceased are associated with loss-related psychopathology?

OBJECTIVES Prior studies have shown that pre-loss closeness and conflict with a deceased person are associated with the severity of symptoms of prolonged grief and/or depression. Nevertheless, mechanisms underlying these relationships are not well understood. We propose a theoretical model in which past closeness and conflict are related to prolonged grief and depression via concrete and symbolic continuing bonds (CB). The aim of our study was to test this model in a sample of bereaved family members. METHODS Individuals (N = 244) who had lost a family member from 0.5 to 8.0 years before the survey completed the Quality of Relationships Inventory-Bereavement Version, the Continuing Bonds Scale, the Prolonged Grief Disorder-13 scale, and the Patient Health Questionnaire-9. RESULTS The findings partially confirmed our model. Closeness was positively and moderately associated with symptoms of prolonged grief but not with symptoms of depression. Conflict was positively and weakly associated with symptoms of depression and prolonged grief. All of these relationships were only partially mediated by concrete/maladaptive and symbolic/adaptive CB. CONCLUSIONS The differences in the relationship of past closeness and conflict to prolonged grief and depression symptoms suggest that inter- and intrapersonal mechanisms of prolonged grief and depressive symptoms may be distinct. If future, especially longitudinal studies, confirm our model, CB would be a possible target for interventions for bereaved persons who had a close and/or conflicted relationship with a deceased family member and experience loss-related psychopathology. PRACTITIONER POINTS Continuing bonds (CB) are a potential target of interventions for bereaved persons who had a close and/or conflicted relationship with a deceased family member and experience symptoms of prolonged grief and/or depression. Internalization of the capacity to care for yourself and feel autonomous in a safe and stable therapeutic relationship may lead to increased self-confidence, promote working through past experiences in the relationship with the deceased, and gradual reduction of concrete forms of CB. Increasing awareness and acceptance of emotional experiences may contribute to the appreciation of past relationship with a deceased person and the growth of symbolic forms of CB. Future research should focus on verifying the effectiveness of the attachment-informed therapeutic approach to working with CB.