Miracle-dz/UniFAR-FTUs huggingface dataset:
The Associations between Asymmetric Handgrip Strength and Chronic Disease Status in American Adults: Results from the National Health and Nutrition Examination Survey

This study examined the associations between asymmetric handgrip strength (HGS) and multimorbidity in American adults. Secondary analyses of data from persons aged at least 40 years from the 2011–2012 and 2013–2014 waves of the National Health and Nutrition Examination Survey were conducted. A handheld dynamometer collected HGS on each hand and persons with a strength imbalance >10% between hands were classified as having asymmetric HGS. Adults with the presence of ≥2 of the following conditions had multimorbidity: cardiovascular disease, chronic obstructive pulmonary disease, chronic kidney disease, asthma, arthritis, cancer, obesity, stroke, hypertension, high cholesterol, and diabetes. Of the n = 3483 participants included, n = 2700 (77.5%) had multimorbidity. A greater proportion of adults with multimorbidity had HGS asymmetry (n = 1234 (45.7%)), compared to persons living without multimorbidity (n = 314 (40.1%); p < 0.05). Relative to individuals without asymmetry, adults with asymmetric HGS had 1.31 (95% confidence interval (CI): 1.03–1.67) greater odds for multimorbidity. Moreover, persons with HGS asymmetry had 1.22 (CI: 1.04–1.44) greater odds for accumulating morbidities. Asymmetric strength, as another indicator of diminished muscle function, is linked to chronic morbidity status. Healthcare providers should recommend healthy behaviors for reducing asymmetries to improve muscle function and mitigate morbidity risk after completing asymmetry screenings.
Elevated serum FGF21 predicts the major adverse cardiovascular events in STEMI patients after emergency percutaneous coronary intervention

Background Although there have been several studies related to serum fibroblast growth factor 21 (FGF21) levels and acute myocardial infarction, the value of serum FGF21 levels in ST-segment elevation myocardial infarction (STEMI) patients after emergency percutaneous coronary intervention (PCI) has not been previously investigated. Methods A total of 348 STEMI patients who underwent emergency PCI were enrolled from January 2016 to December 2018. The primary endpoint was the occurrence of major adverse cardiovascular events (MACEs), with a median follow-up of 24 months. Eighty patients with stable angina (SA) who underwent selective PCI served as the control group. Serum FGF21 levels were measured by ELISA. Results Serum FGF21 levels were significantly higher in the STEMI group than in the SA group (225.03 ± 37.98 vs. 135.51 ± 34.48, P < 0.001). Multiple linear regression analysis revealed that serum FGF21 levels were correlated with NT-proBNP (P < 0.001). According to receiver operating characteristic (ROC) analysis, the areas under the ROC curve (AUCs) of FGF21 and NT-proBNP were 0.812 and 0.865, respectively. The Kaplan-Meier curves showed that STEMI patients with lower FGF21 levels had an increased MACE-free survival rate. Cox analysis revealed that high FGF21 levels (HR: 2.011, 95% CI: [1.160–3.489]) proved to be a powerful tool in predicting the risk of MACEs among STEMI patients after emergency PCI. Conclusion Elevated FGF21 levels on admission have been shown to be a powerful predictor of MACEs for STEMI patients after emergency PCI.
Health workers Motivators to uptake of the Covid-19 vaccine at Iganga Hospital Eastern Uganda, and Mengo Hospital Kampala Uganda; A qualitative study

Uganda continues extensive mobilization and administration of the Covid 19 vaccine to its people albeit some vaccine hesitancy with in the population. Amongst the health workers however, approximately 70 percent had received their first dose while 40 percent had received their second dose of the Covid19 vaccine by September 2021 respectively. These figures represent a recognizable acceptance rate among health workers. Exploring motivators to vaccine uptake among health workers is vital for the governments general population vaccine roll out plan. We conducted 12 focus group discussions and 20 indepth interviews with health workers to understand motivators to vaccine acceptance in their own perspective in central and eastern Uganda. Reported motivators to vaccine acceptance included risk susceptibility and personal protection, fear of death and or cost of treatment and experiences of Covid related grief. Others were trust in the vaccine, call to government policy and vaccine success stories elsewhere, real or perceived benefits of vaccination and peer influence. We recommend intensified dissemination of health worker tailor made tools for information, education and communication about the Covid 19 vaccine. The tools need to emphasize the elicited themes or motivators. We also recommend use of peers who have taken up the vaccine and survived Covid 19 or got a mild form of the disease to elicit positive peer influence about the vaccine amongst health workers. The information dissemination and peer narratives could be done through the health workers social media platforms, union or association websites, personal statements, editorials or other media.
Plasticity of olfactory bulb inputs mediated by dendritic NMDA-spikes in rodent piriform cortex

The piriform cortex (PCx) is essential for learning of odor information. The current view postulates that odor learning in the PCx is mainly due to plasticity in intracortical (IC) synapses, while odor information from the olfactory bulb carried via the lateral olfactory tract (LOT) is ‘hardwired. ’ Here, we revisit this notion by studying location- and pathway-dependent plasticity rules. We find that in contrast to the prevailing view, synaptic and optogenetically activated LOT synapses undergo strong and robust long-term potentiation (LTP) mediated by only a few local NMDA-spikes delivered at theta frequency, while global spike timing-dependent plasticity (STDP) protocols failed to induce LTP in these distal synapses. In contrast, IC synapses in apical and basal dendrites undergo plasticity with both NMDA-spikes and STDP protocols but to a smaller extent compared with LOT synapses. These results are consistent with a self-potentiating mechanism of odor information via NMDA-spikes that can form branch-specific memory traces of odors that can further associate with contextual IC information via STDP mechanisms to provide cognitive and emotional value to odors.
Changes of lipoprotein(a) levels with endogenous steroid hormones

Lipoprotein(a) [Lp(a)] is an LDL‐like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a).
GAS1 is required for NOTCH-dependent facilitation of SHH signaling in the ventral forebrain neuroepithelium

ABSTRACT Growth arrest-specific 1 (GAS1) acts as a co-receptor to patched 1, promoting sonic hedgehog (SHH) signaling in the developing nervous system. GAS1 mutations in humans and animal models result in forebrain and craniofacial malformations, defects ascribed to a function for GAS1 in SHH signaling during early neurulation. Here, we confirm loss of SHH activity in the forebrain neuroepithelium in GAS1-deficient mice and in induced pluripotent stem cell-derived cell models of human neuroepithelial differentiation. However, our studies document that this defect can be attributed, at least in part, to a novel role for GAS1 in facilitating NOTCH signaling, which is essential to sustain a persistent SHH activity domain in the forebrain neuroepithelium. GAS1 directly binds NOTCH1, enhancing ligand-induced processing of the NOTCH1 intracellular domain, which drives NOTCH pathway activity in the developing forebrain. Our findings identify a unique role for GAS1 in integrating NOTCH and SHH signal reception in neuroepithelial cells, and they suggest that loss of GAS1-dependent NOTCH1 activation contributes to forebrain malformations in individuals carrying GAS1 mutations.
Effects of Sargassum virgatum extracts on the testicular measurements, genomic DNA and antioxidant enzymes in irradiated rats

Abstract Background Oxidative stress and reactive oxygen species (ROS) are primarily responsible for the development of male infertility after exposure to γ-irradiation. The present work aimed to assess the ameliorative and therapeutic roles of the aqueous and ethanolic extracts of the edible seaweed Sargassum virgatum (S. virgatum) on spermatogenesis and infertility in γ-irradiated Wistar rats. Materials and methods Induction of infertility was performed by exposing the rats to 137Cs-gamma rays, using a single dose of 3.5 Gy. γ-irradiated rats were given the S. virgatum ethanolic (S. virgatum-EtOH) and aqueous extracts intraperitoneally on a daily base for two consecutive weeks at doses of 100 and 400 mg/kg body weight (b.wt.) for each seaweed extract. Morphometric data of the testes, semen quality indices, antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (GPx), and deoxyribonucleic acid (DNA) fragmentation were assessed. The results obtained were taken during two-time intervals of 15 and 60 days from the commencement of the algal treatments. In vitro antioxidant assays and polyphenolic compounds of S. virgatum were characterized. Results Significant negative changes in the semen quality and morphometric data of the testes, as well as remarkable DNA fragmentation, were detected in the irradiated rats compared to the control. The levels of the endogenous antioxidant enzymes (SOD, CAT, GSH, and GPx) were also significantly diminished. Nonetheless, treatments of γ-irradiated rats with the S. virgatum-EtOH and aqueous extracts significantly improved the above-mentioned enzymes, in addition to noteworthy amendments in the dimensions of the testes, the semen quality, as well as the DNA structure. Conclusions The ameliorative potency of S. virgatum to cure γ-irradiation-induced male infertility, particularly 400 mg/kg ethanolic extract for 60 days, is the result of the consistent therapeutic interventions of its potent antioxidant and anti-apoptotic polyphenols, particularly protocatechuic, p-hydroxybenzoic, rosmarinic, chlorogenic, cinnamic and gentisic acids, as well as the flavonoids catechin, hesperidin, rutin and quercetin. Besides its high-value nutraceutical importance, S. virgatum could be a natural candidate for developing well-accepted radioprotectant products capable of treating γ-irradiation-induced male infertility.
Intestinal UDP-Glucuronosyltransferase 1A1 and Protection against Irinotecan-Induced Toxicity in a Novel UDP-Glucuronosyltransferase 1A1 Tissue-Specific Humanized Mouse Model

The human UDP-glucuronosyltransferases (UGTs) represent an important family of drug-metabolizing enzymes, with UGT1A1 targeting the conjugation and detoxification of many exogenous substances, including pharmaceutical drugs. In this study we generated humanized UGT1A1 mice expressing the human UGT1A1 gene in either liver (hUGT1A1HEP) or intestine (hUGT1A1GI), enabling experiments to examine tissue-specific properties of UGT1A1-specific glucuronidation. Hepatic and intestinal tissue-specific expression and function of UGT1A1 were demonstrated. Although the liver is considered a major organ for detoxification, intestinal UGT1A1 is an important contributor for drug clearance. Mice were challenged with irinotecan (CPT-11), a prodrug hydrolyzed by carboxylesterases to form the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) and detoxified by UGT1A1. Humanized UGT1A1HEP mice that have no intestinal UGT1A1 displayed a greater lethality rate when exposed to CPT-11 than hUGT1A1GI mice. When exposed to a low dose of CPT-11 (10 mg/kg), hUGT1A1HEP mice displayed greater intestinal inflammatory (IL-1β and IL-6) insult in addition to p53-triggered apoptotic responses. In vitro studies with intestinal crypt organoids exposed to CPT-11 confirmed the results observed in vivo and indicated that CPT-11 impacts stemness, apoptosis, and endoplasmic reticulum (ER) stress in organoids deficient in UGT1A1. When we examined the induction of ER stress in organoids with thapsigargin, an inhibitor of sarco/endoplasmic reticulum Ca2+ ATPase, apoptosis and the caspase surge that occurred in hUGT1A1HEP mice were blocked in hUGT1A1GI organoids. This study reveals the importance of intestinal UGT1A1 in preventing inflammation, apoptosis, and loss of stemness capacity upon systemic challenge with an important chemotherapeutic agent. SIGNIFICANCE STATEMENT Hepatic and intestinal UGT1A1 play a key role in the metabolism and detoxification of endogenous and exogenous compounds. The use of tissue-specific humanized models expressing UGT1A1 in liver or intestine has confirmed the relevance of the intestinal tract in the detoxification of irinotecan. Mechanistic studies using intestinal organoids highlighted the importance of UGT1A1 in reducing inflammation, apoptosis, and loss of stemness. These new models provide valuable tools for studying tissue-specific glucuronidation of substances that are metabolized by human UGT1A1.
Renadirsen, a Novel 2′OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients’ DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2′-O,4′-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2′-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2′OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.
Comparison of Novel Sandfly Control Interventions: A Pilot Study in Bangladesh

ABSTRACT. In this pilot comparative study, we investigated and compared the effects of existing vector control tools on sandfly densities and mortality to inform and support the National Kala-azar Elimination Program (NKEP). The interventions included insecticidal wall painting (IWP), reduced-coverage insecticidal durable wall lining (DWL), insecticide-impregnated bednets (ITN), and indoor residual spraying with deltamethrin (IRS). Sakhua union with seven villages was the study area, which was the most highly endemic visceral leishmaniasis union in Trishal upazila, Bangladesh. Each cluster containing the different interventions included approximately 50 households. Study methods included random selection of clusters, collection of sandfly by CDC light trap and manual aspirator to determine sandfly density, and sandfly mortality determined by WHO cone bioassay test. Trained field research assistants interviewed household heads using structured questionnaires for sociodemographic information, as well as safety and acceptability of the interventions. Descriptive and analytical statistical methods measured interventions’ effect and its duration on sandfly density reduction and mortality. We measured the relative efficacy of IWP on sandfly control against DWL, ITN, and IRS by the difference-in-difference regression model. We found that existing interventions were effective and safe for sandfly control with different duration of effect and acceptability. The relative efficacy of IWP for sandfly reduction varied by –59% to –91%, –75% to –81%, and –30% to –104% compared with DWL, ITN, and IRS, respectively, at different time points during the 12-month follow-up. These study results will guide the NKEP for selection of sandfly control tool(s) in its subsequent consolidation and maintenance phases.
Brainstem Mechanisms of Pain Modulation: A within-Subjects 7T fMRI Study of Placebo Analgesic and Nocebo Hyperalgesic Responses

Pain perception can be powerfully influenced by an individual's expectations and beliefs. Although the cortical circuitry responsible for pain modulation has been thoroughly investigated, the brainstem pathways involved in the modulatory phenomena of placebo analgesia and nocebo hyperalgesia remain to be directly addressed. This study used ultra-high-field 7 tesla functional MRI (fMRI) to accurately resolve differences in brainstem circuitry present during the generation of placebo analgesia and nocebo hyperalgesia in healthy human participants (N = 25, 12 male). Over 2 successive days, through blinded application of altered thermal stimuli, participants were deceptively conditioned to believe that two inert creams labeled lidocaine (placebo) and capsaicin (nocebo) were acting to modulate their pain relative to a third Vaseline (control) cream. In a subsequent test phase, fMRI image sets were collected while participants were given identical noxious stimuli to all three cream sites. Pain intensity ratings were collected and placebo and nocebo responses determined. Brainstem-specific fMRI analysis revealed altered activity in key pain modulatory nuclei, including a disparate recruitment of the periaqueductal gray (PAG)–rostral ventromedial medulla (RVM) pathway when both greater placebo and nocebo effects were observed. Additionally, we found that placebo and nocebo responses differentially activated the parabrachial nucleus but overlapped in engagement of the substantia nigra and locus coeruleus. These data reveal that placebo and nocebo effects are generated through differential engagement of the PAG–RVM pathway, which in concert with other brainstem sites likely influences the experience of pain by modulating activity at the level of the dorsal horn. SIGNIFICANCE STATEMENT Understanding endogenous pain modulatory mechanisms would support development of effective clinical treatment strategies for both acute and chronic pain. Specific brainstem nuclei have long been known to play a central role in nociceptive modulation; however, because of the small size and complex organization of the nuclei, previous neuroimaging efforts have been limited in directly identifying how these subcortical networks interact during the development of antinociceptive and pro-nociceptive effects. We used ultra-high-field fMRI to resolve brainstem structures and measure signal change during placebo analgesia and nocebo hyperalgesia. We define overlapping and disparate brainstem circuitry responsible for altering pain perception. These findings extend our understanding of the detailed organization and function of discrete brainstem nuclei involved in pain processing and modulation.
Potentiality of α-fetoprotein (AFP) and soluble intercellular adhesion molecule-1 (sICAM-1) in prognosis prediction and immunotherapy response for patients with hepatocellular carcinoma

ABSTRCT The α-fetoprotein (AFP) and soluble intercellular adhesion molecule-1 (sICAM-1) have certain diagnostic value, but their potential value in prognosis prediction, especially immunotherapy response prediction, remains unclear in liver cancer. Through the tumor-free survival (TFS) and overall survival (OS) rates analyses of serum AFP and sICAM-1 levels in 87 patients with primary hepatocellular carcinoma (HCC), the patients whose AFP and sICAM-1 levels were normal (AFP < 20 μg/L or sICAM-1 < 1000 μg/L) before surgery or recovered to normal after surgery exhibited a lower tumor recurrence rate and better OS than patients with elevated serum levels of the two markers. Combined analysis showed that patients with synchronously elevated levels of AFP and sICAM-1 showed the lowest TFS and OS. In addition, the RNA-seq data and clinical information of The Cancer Genome Atlas Liver Hepatocellular Carcinoma were collected to analyze the predictive values of AFP and ICAM-1 in the diagnosis, prognosis and immunotherapy of HCC. The results indicated that the combined application of the two indicators had higher accuracy in both the diagnosis and prognostic prediction of HCC by receiver operating characteristic curves. AFP and ICAM-1 were significantly correlated with multiple immune cells in HCC samples but not in normal samples. The patients with low expression of the two indicators were most likely to benefit from the immune checkpoint blockade therapy. In conclusion, AFP and ICAM-1 play vital roles in the diagnosis, prognostic prediction, and immunotherapy of HCC, suggesting that they are considered as prognostic predictors in clinical practice.
Primary HBB gene mutation severity and long‐term outcomes in a global cohort of β‐thalassaemia

In β‐thalassaemia, the severity of inherited β‐globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long‐term outcomes remain limited. We analysed data from 2109 β‐thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β0/β0, β0/β+, β+/β+, β0/β++, β+/β++, and β++/β++. Patients were followed from birth until death or loss to follow‐up. The median follow‐up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β0 and β+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β0/β0, β0/β+, or β+/β+ had a 2·104‐increased risk of death [95% confidence interval (CI): 1·176–3·763, P = 0·011] and 2·956‐increased odds of multiple morbidity (95% CI: 2·310–3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β‐thalassaemia and suggests inclusion of both β+ and β0 mutations in strata of greatest severity.