Miracle-dz/UniFAR-FTUs huggingface dataset:
Correlation of Lesional Uptake Parameters and Ratios with miPSMA Score and Estimating Normal Physiologic Concentration: An Exploratory Analysis in Metastatic Castration-Resistant Prostatic Carcinoma Patients with 68Ga-PSMA-11 PET/CT

Visual Abstract The use of prostate-specific membrane antigen (PSMA)–based PET/CT has grown rapidly in recent years. This study estimated lesional uptake, normal physiologic concentrations, and temporal variation on delayed PET/CT of 68Ga-PSMA-11 across different molecular imaging PSMA (miPSMA) expression scores in patients with metastatic castration-resistant prostatic carcinoma. Methods: We retrospectively studied 50 patients who were evaluated for 177Lu-PSMA–targeted radioligand therapy and underwent 68Ga-PSMA-11 PET/CT to determine disease status. Their mean age was 67.5 ± 8 y (52–84 y), and their average serum prostate-specific antigen level was 401 ± 1,353 ng/mL (0.098–9,235.13 ng/mL) at the time of scanning. They underwent standard 68Ga-PSMA-11 PET/CT an average of 65 min after injection (60–90 min). Tumors (n = 50) were correlated with miPSMA expression score and uptake. Physiologic tracer distribution was estimated by placing a volume of interest 1 cm in diameter for smaller organs (submandibular, parotid, lacrimal, and tubarial glands; renal cortices; blood pool; and bowel) and 3 cm for larger organs (liver and spleen). SUVmax and SUVmean were estimated for each region. Tumor-to-spleen (T/S), tumor-to-liver (T/L), and tumor-to-parotid (T/P) ratios were calculated for each lesion. For 16 patients who underwent a delayed scan an average of 135 min after injection (120–150 min), additional analysis evaluated the effect of the delay. Results: Uptake was maximal in renal cortices, followed by salivary glands, bowel, spleen, liver, lacrimal glands, and blood pool. SUVmax averaged 37.7 ± 22.1 for renal cortices, 15.4 ± 7.3 for submandibular glands, 14.4 ± 7.1 for parotid glands, 9.4 ± 4.9 for spleen, 6.2 ± 3.7 for lacrimal glands, 5.9 ± 2.3 for liver, 5.3 ± 1.41 for tubarial glands, 13.8 ± 7.6 for bowel, and 2.4 ± 1.9 for blood pool. SUVmax averaged 10.33 ± 3.27 (6.46–17) for miPSMA expression score 2 and 38.21 ± 25.9 (7.68–119.08) for score 3. T/S and T/P ratios averaged 1.21 ± 0.44 (0.48–2.04) and 0.6 ± 0.18 (0.39–0.87), respectively, for score 2 and 5.05 ± 4.46 (1.25–20.89) and 3.15 ± 2.09 (1.06–9.45), respectively, for score 3. SUVmax for score 3 lesions averaged 18.85, which increased significantly to 26.24 on delayed imaging (P = 0.0001). However, T/L, T/S, and T/P ratios did not significantly change. Temporal variation in normal organs showed SUVmax to increase significantly on delayed scans for salivary (submandibular and parotid) and lacrimal glands and renal cortices, whereas SUVmean increased significantly for spleen; liver; and parotid, tubarial, and lacrimal glands and insignificantly for other organs. Conclusion: These data form a basis for a proposed consensus on standard reference ranges for quantitative 68Ga-PSMA-11 PET/CT. The temporal variations should be kept in mind for delayed acquisitions; T/S, T/L, and T/P ratios might serve as better markers for such scenarios.
Global REACH 2018: the adaptive phenotype to life with chronic mountain sickness and polycythaemia

Humans suffering from polycythaemia undergo multiple circulatory adaptations including changes in blood rheology and structural and functional vascular adaptations to maintain normal blood pressure and vascular shear stresses, despite high blood viscosity. During exercise, several circulatory adaptations are observed, especially involving adrenergic and non‐adrenergic mechanisms within non‐active and active skeletal muscle to maintain exercise capacity, which is not observed in animal models. Despite profound circulatory stress, i.e. polycythaemia, several adaptations can occur to maintain exercise capacity, therefore making early identification of the disease difficult without overt symptomology. Pharmacological treatment of the background heightened sympathetic activity may impair the adaptive sympathetic response needed to match local oxygen delivery to active skeletal muscle oxygen demand and therefore inadvertently impair exercise capacity.
Distribution of virulence factors and its relatedness towards the antimicrobial response of enterotoxigenic Escherichia coli strains isolated from patients in Kolkata, India

Enterotoxigenic Escherichia coli (ETEC) is one of the most widely recognized diarrhoeal pathogens in developing countries. The advancement of ETEC vaccine development depends on the antigenic determinants of the ETEC isolates from a particular geographical region. So, the aim here was to comprehend the distribution of virulence determinants of the clinical ETEC strains of this region. Additionally, an attempt was made to find any correlation with the antimicrobial response pattern.
Neoantigen vaccination induces clinical and immunologic responses in non-small cell lung cancer patients harboring EGFR mutations

Background Neoantigen (NeoAg) peptides displayed at the tumor cell surface by human leukocyte antigen molecules show exquisite tumor specificity and can elicit T cell mediated tumor rejection. However, few NeoAgs are predicted to be shared between patients, and none to date have demonstrated therapeutic value in the context of vaccination. Methods We report here a phase I trial of personalized NeoAg peptide vaccination (PPV) of 24 stage III/IV non-small cell lung cancer (NSCLC) patients who had previously progressed following multiple conventional therapies, including surgery, radiation, chemotherapy, and tyrosine kinase inhibitors (TKIs). Primary endpoints of the trial evaluated feasibility, tolerability, and safety of the personalized vaccination approach, and secondary trial endpoints assessed tumor-specific immune reactivity and clinical responses. Of the 16 patients with epidermal growth factor receptor (EGFR) mutations, nine continued TKI therapy concurrent with PPV and seven patients received PPV alone. Results Out of 29 patients enrolled in the trial, 24 were immunized with personalized NeoAg peptides. Aside from transient rash, fatigue and/or fever observed in three patients, no other treatment-related adverse events were observed. Median progression-free survival and overall survival of the 24 vaccinated patients were 6.0 and 8.9 months, respectively. Within 3–4 months following initiation of PPV, seven RECIST-based objective clinical responses including one complete response were observed. Notably, all seven clinical responders had EGFR-mutated tumors, including four patients that had continued TKI therapy concurrently with PPV. Immune monitoring showed that five of the seven responding patients demonstrated vaccine-induced T cell responses against EGFR NeoAg peptides. Furthermore, two highly shared EGFR mutations (L858R and T790M) were shown to be immunogenic in four of the responding patients, all of whom demonstrated increases in peripheral blood neoantigen-specific CD8+ T cell frequencies during the course of PPV. Conclusions These results show that personalized NeoAg vaccination is feasible and safe for advanced-stage NSCLC patients. The clinical and immune responses observed following PPV suggest that EGFR mutations constitute shared, immunogenic neoantigens with promising immunotherapeutic potential for large subsets of NSCLC patients. Furthermore, PPV with concurrent EGFR inhibitor therapy was well tolerated and may have contributed to the induction of PPV-induced T cell responses.
Structure and driving factors of the soil microbial community associated with Alhagi sparsifolia in an arid desert

Environmental properties are important factors in structuring soil microbial communities. The primary driving factors vary in different ecosystems. In the present work, we analyzed the microbial communities of rhizosphere and bulk soils associated with the halophyte Alhagi sparsifolia across three salt/water gradients in the desert area around Ebinur Lake Basin, China, using high-throughput sequencing technology. We found that there were significant differences in soil water content (SWC), soil salinity (SAL), total nitrogen (TN), and total phosphorus (TP) contents between the three water/salt gradients. In the L (low water and salt) plot, Actinobacteria was the most abundant bacterial phylum while Ascomycota was the dominant fungal phylum. The relative abundance of Actinobacteria was negatively correlated with soil pH, soil organic carbon (SOC), TP, and available phosphorus (AP). The abundance of Bacteroidetes was significantly positively correlated with soil SOC, SWC, SAL, pH, TN, and TP (P < 0.05). The abundance of fungal phylum Chytridiomycota was significantly positively correlated with pH (P < 0.01), SWC, AP, and sulfate ion (P < 0.05). SOC and nitrate nitrogen were the main factors impacting the bacterial community, while ammonium nitrogen (NH4+) and TP were the main driving forces for the fungal community. Soil nutrients were the main contributors to the dissimilarities in the bacterial and fungal communities, explaining 48.06% and 44.45% of the variation. SWC, SAL, and pH explained only a small percentage of the microbial community dissimilarity. In conclusion, soil microbial community structure was affected by SWC, SAL, pH, and soil nutrients, with soil nutrients as the main driving factors. Nitrogen has a differential effect on the different microbial communities: bacterial communities of Alhagi sparsifolia were mainly affected by nitrate nitrogen, while fungal communities were mainly driven by ammonium nitrogen.
Cardiovascular risks associated with calcium supplementation in patients with osteoporosis: a nationwide cohort study.

AIMS This study aimed to evaluate the real effects of calcium supplementation on cardiovascular outcomes within a population-based cohort. METHODS AND RESULTS From a nationwide health screening database in Korea, a total of 11,297 patients with osteoporosis who had taken calcium supplementation with or without vitamin D for at least 90 days (total-calcium group; calcium supplementation only [CaO], n = 567; calcium supplementation in combination with vitamin D [CaD], n = 10,730) were matched at a 1:1 ratio to patients who had not taken calcium supplements (control group) by using propensity scores. The overall mean age was 59.9 ± 8.8 years and the percentage of women was 87.9% in our study population. Over a median follow-up of 54 months, the incidence rate of composite cardiovascular diseases (CVD) per 1000 person-years was not different between the groups: 9.73 in the total-calcium group and 8.97 in the control group (adjusted hazard ratio [HR]: 1.12; 95% confidence interval [CI]: 0.99 to 1.28; P = 0.08). However, calcium supplementation without vitamin D was associated with an increased risk of composite CVD (HR: 1.54; 95% CI: 1.17 to 2.04; P < 0.01), especially non-fatal myocardial infarction (HR:1.89; 95% CI: 1.23 to 2.91; P < 0.01), compared with no calcium supplementation. CONCLUSION Our population-based study supported that taking calcium supplementation with vitamin D together did not appear to be harmful to cardiovascular health, but reminding that calcium supplementation without vitamin D should be used carefully even in populations with low dietary calcium intake.
The GAS6-AXL signaling pathway triggers actin remodeling that drives membrane ruffling, macropinocytosis, and cancer-cell invasion

Significance Metastasis remains the major cause of cancer-related deaths. Overactivation of receptor tyrosine kinase AXL has been correlated with cancer invasion and metastasis, resistance to therapies, and poor patient prognosis. However, the cellular processes activated by AXL and its ligand, GAS6, are largely unknown. Here, we identified a proximity interactome of AXL and revealed actin-dependent processes activated by GAS6-AXL, including membrane ruffling and macropinocytosis, that provide insights into the role of AXL in cancer progression. The identified AXL interactors can be used in translational research toward development of effective therapies for metastatic and/or chemoresistant cancers with AXL overactivation. Moreover, our data provide a mechanistic explanation for previous studies reporting that AXL might contribute to macropinocytic uptake of viruses. AXL, a member of the TAM (TYRO3, AXL, MER) receptor tyrosine kinase family, and its ligand, GAS6, are implicated in oncogenesis and metastasis of many cancer types. However, the exact cellular processes activated by GAS6-AXL remain largely unexplored. Here, we identified an interactome of AXL and revealed its associations with proteins regulating actin dynamics. Consistently, GAS6-mediated AXL activation triggered actin remodeling manifested by peripheral membrane ruffling and circular dorsal ruffles (CDRs). This further promoted macropinocytosis that mediated the internalization of GAS6-AXL complexes and sustained survival of glioblastoma cells grown under glutamine-deprived conditions. GAS6-induced CDRs contributed to focal adhesion turnover, cell spreading, and elongation. Consequently, AXL activation by GAS6 drove invasion of cancer cells in a spheroid model. All these processes required the kinase activity of AXL, but not TYRO3, and downstream activation of PI3K and RAC1. We propose that GAS6-AXL signaling induces multiple actin-driven cytoskeletal rearrangements that contribute to cancer-cell invasion.
Association between COVID-19-related loneliness or worry and symptoms of anxiety and depression among first-year college students

Abstract Objective To examine the relationship between COVID-19-related distress and mental health among first-year college students. Participants Data for this longitudinal study (n = 727) were collected before the school year (August 2019), end of fall semester (December 2019), and soon after the university suspended in-person instruction (April 2020). Methods We used multivariable log-linear and logistic regressions to examine continuous and dichotomous outcomes on the 9-item Patient Health Questionnaire and the 7-item Generalized Anxiety Disorder scale. Results The most consistent predictor of during-pandemic mental health was feeling extremely isolated (versus not at all), which was associated with increased symptom severity of depression (proportional change[95% CI] = 2.43[1.87, 3.15]) and anxiety (2.02[1.50, 2.73]) and greater odds of new moderate depression (OR[95% CI] = 14.83[3.00, 73.41]) and anxiety (24.74[2.91, 210.00]). Greater COVID-19-related concern was also related to increased mental health symptoms. Conclusions Results highlight the need for mental health services during crises that lead to social isolation.
Functional Reach Test, Single-Leg Stance Test, and Tinetti Performance-Oriented Mobility Assessment for the Prediction of Falls in Older Adults: A Systematic Review.

OBJECTIVE To systematically review the existing literature on the falls-related diagnostic test properties of the Functional Reach Test (FRT), single-leg stance test (SLST), and Tinetti Performance-Oriented Mobility Assessment (POMA) in older adults across settings and patient populations. METHODS Databases PubMed, EMBASE, and CINAHL were searched (inception-July 2020). Inclusion criteria were an age of 60 years or more for participants, prospectively recorded falls, and the reporting of falls-related predictive validity. Manuscripts not published in English were excluded. Methodological quality of reporting was assessed using the Tooth Scale. RESULTS Of 1071 studies reviewed, 21 met the inclusion criteria (12 POMA, 8 FRT, 6 SLST). Seven studies (58.3%) used a modified version of the POMA (POMA), while 3 (37.5%) used a modified FRT (FRT). For the outcome of any fall, the respective ranges of sensitivity and specificity were 0.076 to 0.615 and 0.695 to 0.97 for the POMA, 0.27 to 0.70 and 0.52 to 0.83 for the modified POMA, 0.73 and 0.88 for the FRT, 0.47 to 0.682 and 0.59 to 0.788 for the modified FRT, and 0.51 and 0.61 for the SLST in community-dwelling older adults. For the SLST, the sensitivity and specificity for recurrent falls in the community-dwelling setting were 0.33 and 0.712, respectively. CONCLUSIONS All the clinical tests of balance demonstrated an overall low diagnostic accuracy and a consistent inability to correctly identify fallers. None of these tests individually are able to predict future falls in older adults. Future research should develop a better understanding of the role that clinical tests of balance play in the comprehensive assessment of falls risk in older adults. IMPACT Neither the FRT, SLST, or POMA alone show consistent evidence of being able to correctly identify fallers across fall types, settings, or older adult subpopulations. These clinical tests of balance cannot substitute a comprehensive falls risk assessment, thus should be incorporated in practice solely to identify and track balance impairment in older adults.
Taking a critical stance towards mixed methods research: A cross-disciplinary qualitative secondary analysis of researchers’ views

Recent growth and institutionalization in the field of mixed methods research has provided fertile ground for a wide range of thoughtful criticism of how this research approach has been developed and conceptualized by some members of the mixed methods community. This criticism reflects the increasing maturity of the field as well as the different theoretical perspectives and methodological practices of researchers in different disciplines. While debates addressing these criticisms are likely to lead to valuable insights, no empirical studies have been carried out to date that have investigated researchers’ critical views on the development and conceptualization of mixed methods research. This study examines the criticisms of the mixed methods field raised by a cross-national sample of researchers in education, nursing, psychology, and sociology. We carried out a secondary analysis of semi-structured interviews with 42 researchers and identified 11 different criticisms, which we classified in four domains: essence of mixed methods, philosophy, procedures, and politics. The criticisms related to the procedures domain were equally distributed among the four disciplines, while those related to the essence, philosophy and politics domains were more common among sociologists. Based on our findings, we argue that the divergence of views on foundational issues in this field reflects researchers’ affiliation to different communities of practice, each having its own principles, values, and interests. We suggest that a greater awareness of this divergence of perspectives could help researchers establish effective collaboration and anticipate potential challenges when working with researchers having different methodological approaches.
Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats

Compounds with novel or fentanyl-like structures continue to appear on the illicit drug market and have been responsible for fatalities, yet there are limited preclinical pharmacological data available to evaluate the risk of these compounds to public health. The purpose of the present study was to examine acetyl fentanyl, butyryl fentanyl, 3,4-dichloro-N-[[1-(dimethylamino)cyclohexyl]methyl]benzamide (AH-7921), 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45), 4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide (W-15), and 4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide (W-18) for their relative potency to reference opioids and their susceptibility to naltrexone antagonism using the 55oC warm-water, tail-withdrawal assay of antinociception and a morphine drug discrimination assay in male, Sprague-Dawley rats. In the antinociception assay, groups of 8 rats per drug were placed into restraining tubes, their tails were immersed into 40o or 55oC water, and the latency for tail withdrawal was measured with a cutoff time of 15 seconds. In the drug discrimination assay, rats (n = 11) were trained to discriminate between 3.2 mg/kg morphine and saline, subcutaneously, in a two-choice, drug discrimination procedure under a fixed ratio-5 schedule of sucrose pellet delivery. Morphine, fentanyl, and four of the synthetic opioids dose dependently produced antinociception and fully substituted for morphine in the drug discrimination assay with the following rank order of potency: fentanyl > butyryl fentanyl > acetyl fentanyl > AH-7921 > MT45 > morphine. All drugs that produced antinociception or morphine-like discriminative stimulus effects were blocked by naltrexone. W-15 and W-18 did not show antinociceptive or morphine-like discriminative stimulus effects at the doses tested supporting a lack of opioid activity for these two compounds. These findings suggest that butyryl fentanyl, acetyl fentanyl, AH-7941, and MT-45 have abuse liability like other opioid agonists. SIGNIFICANCE STATEMENT As novel psychoactive substances appear on the illicit drug market, preclinical pharmacological testing is required to assist law enforcement, medical professionals, and legal regulators with decisions about potential public health risks. In this study, four synthetic opioids, acetyl fentanyl, butyryl fentanyl, AH-7921, and MT-45 produced effects similar to fentanyl and morphine and were blocked by naltrexone. These data suggest the four synthetic opioids possess similar abuse liability risks as typical opioid agonists.
Risk of major adverse cardiovascular events in patients initiating biologics/apremilast for psoriatic arthritis: a nationwide cohort study

Abstract Objective Several biological DMARDs (bDMARDs) have demonstrated anti-inflammatory effects in PsA. However, their comparative cardiovascular safety profiles remain unknown. We evaluated the risk of major adverse cardiovascular events (MACEs) in PsA patients on therapy with different classes of bDMARDs and apremilast. Methods This nationwide cohort study involved the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database. All adults with PsA who were new users of bDMARDs/apremilast (neither in the year before the index date) during 2015–19 were included. Patients with previous cardiovascular diseases were excluded. End of follow-up was 31 December 2019. The primary endpoint was an occurrence of MACEs in a time-to-event analysis with propensity score-weighted Cox and Fine–Gray models. Results Between 2015 and 2019, we included 9510 bDMARD new users [mean age 48.5 (s.d. 12.7) years; 42% men], including 7289 starting a TNF inhibitor, 1058 an IL-12/23 inhibitor and 1163 an IL-17 inhibitor, with 1885 apremilast new users [mean age 54.0 (s.d. 12.5) years; 44% men]. MACEs occurred in 51 (0.4%) patients. After propensity score weighting, the risk of MACEs was significantly greater with IL-12/23 (weighted hazard ratio 2.0, 95% CI 1.3, 3.0) and IL-17 (weighted hazard ratio 1.9, 95% CI 1.2, 3.0) inhibitors than TNF inhibitors, with no significant increased risk with apremilast (weighted hazard ratio 1.3, 95% CI 0.8, 2.2). Similar results were observed with the Fine–Gray competing risks survival model. Conclusion Analysis of a large database revealed a small overall number of MACEs, and the risk of MACEs was greater for PsA new users of IL-12/23 and IL-17 vs TNF inhibitors.