Miracle-dz/UniFAR-FTUs huggingface dataset:
Type 2 Diabetes Partitioned Polygenic Scores Associate With Disease Outcomes in 454,193 Individuals Across 13 Cohorts

OBJECTIVE Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.
Erroneous assumption of ocular hypertension in patients with elevated intraocular pressure

Purpose: To determine the proportion of erroneously assumed ocular hypertension (OHT) among referred patients of elevated intraocular pressure (IOP) seen in glaucoma clinic of a teaching hospital in Northern India. Methods: Retrospective review of case records of referred, diagnosed patients of OHT or unspecified glaucoma seen between January 2019 and March 2020. Using an algorithmic clinical approach, including gonioscopy, Goldmann applanation tonometry (GAT), and pachymetry, underlying cause for elevated-IOP was amended and proportion of erroneously assumed OHT was calculated. Results: Of 276 patients diagnosed either as OHT or unspecified glaucoma before being seen at our glaucoma clinic, 44 (16%) had IOP within normal range (10–21 mmHg) on GAT. In 97 (35%) cases elevated-IOP was associated with angle closure. The central corneal thickness (CCT) was >550 μm in 39 (14%) patients with elevated-IOP. The proportion of erroneously assumed OHT was 70% in this study. Conclusion: The elevated-IOP does not imply with OHT unless evident through comprehensive clinical examination and appropriate investigations.
Functional Genomic Identification of Predictors of Sensitivity and Mechanisms of Resistance to Multivalent Second-Generation TRAIL-R2 Agonists

Abstract Multivalent second-generation TRAIL-R2 agonists are currently in late preclinical development and early clinical trials. Herein, we use a representative second-generation agent, MEDI3039, to address two major clinical challenges facing these agents: lack of predictive biomarkers to enable patient selection and emergence of resistance. Genome-wide CRISPR knockout screens were notable for the lack of resistance mechanisms beyond the canonical TRAIL-R2 pathway (caspase-8, FADD, BID) as well as p53 and BAX in TP53 wild-type models, whereas a CRISPR activatory screen identified cell death inhibitors MCL-1 and BCL-XL as mechanisms to suppress MEDI3039-induced cell death. High-throughput drug screening failed to identify genomic alterations associated with response to MEDI3039; however, transcriptomics analysis revealed striking association between MEDI3039 sensitivity and expression of core components of the extrinsic apoptotic pathway, most notably its main apoptotic effector caspase-8 in solid tumor cell lines. Further analyses of colorectal cell lines and patient-derived xenografts identified caspase-8 expression ratio to its endogenous regulator FLIP(L) as predictive of sensitivity to MEDI3039 in several major solid tumor types and a further subset indicated by caspase-8:MCL-1 ratio. Subsequent MEDI3039 combination screening of TRAIL-R2, caspase-8, FADD, and BID knockout models with 60 compounds with varying mechanisms of action identified two inhibitor of apoptosis proteins (IAP) that exhibited strong synergy with MEDI3039 that could reverse resistance only in BID-deleted models. In summary, we identify the ratios of caspase-8:FLIP(L) and caspase-8:MCL-1 as potential predictive biomarkers for second-generation TRAIL-R2 agonists and loss of key effectors such as FADD and caspase-8 as likely drivers of clinical resistance in solid tumors.
The Mediating Role of Autobiographical Memory in the Relationship Between Narcissism and Rejection Sensitivity

Both grandiose and vulnerable narcissistic individuals perceive a threat to the self when they face real or imaginary rejection. The sensitivity to rejection may affect them differently. Thus, this research examines the role of grandiose and vulnerable narcissism in the retrieval of self-threatening memories. The study aims to test the mediating role of autobiographical memory (AM) in the relationship between rejection sensitivity (RS) and two dimensions of narcissism. A total of 369 university students (ages between 18 and 32) participated in the study. The Rejection Sensitivity Questionnaire was applied to the participants, triggering the memory of positive and negative autobiographical rejection. Then, the Autobiographical Memory Characteristics Questionnaire and the Pathological Narcissism Inventory were applied. The results showed that the autobiographical memory characteristics differ depending on the dimension of narcissism when they face rejection. This changes depending on having positive or negative content as well as recalling the sensory details especially emotional characteristics of the AM. The use of AM as a mediator in the relationship between narcissism and rejection sensitivity has provided a viewpoint beyond experimental and relational studies. The results have shed light on the role of narcissism and RS in the processing of autobiographical memories.
Survival Outcomes in Men with Unfavorable Intermediate-Risk and High-Risk Prostate Cancer Treated with Prostate-Only versus Whole Pelvic Radiation Therapy

Purpose: Men with unfavorable intermediate-risk (UIR-PCa) or high-risk prostate cancer (HR-PCa) are often treated with definitive external beam radiotherapy (EBRT) plus androgen deprivation therapy. Treatment is frequently intensified by electively treating the pelvic lymph nodes (LNs) with whole pelvis radiotherapy (WPRT), but practice patterns and the benefits of WPRT are not well defined. We hypothesized that men treated with WPRT would have improved overall survival (OS) relative to men treated with prostate-only radiotherapy. Materials and Methods: National Cancer Database records of men diagnosed between 2008–2015 with UIR-PCa or HR-PCa and treated with prostate EBRT±androgen deprivation therapy (72–86.4 Gy) with (15,175) or without (13,549) WPRT were reviewed. Risk of LN involvement was calculated using the Memorial Sloan Kettering Cancer Center nomogram. Measured confounders were balanced with inverse probability of treatment weighting and OS hazard ratios (HRs) were generated using multivariable Cox regression. Results: Of the men, 53% received WPRT. Every 1% increase in risk of LN involvement correlated with a 1% increase in risk of death (p <0.001). WPRT trended toward improved OS in all men with UIR-PCa and HR-PCa (HR: 0.95 [95% CI: 0.90–1.006], p=0.055). WPRT correlated with improved OS in men with Gleason 9 and 10 disease (HR: 0.87 [0.78–0.98], p=0.02) or risk of LN involvement ≥10% (HR: 0.93 [0.87–0.99], p=0.03). Conclusions: Men with higher LN risk scores and Gleason grade benefited from WPRT. These results complement the recent POP-RT randomized trial in mostly positron emission tomography/computerized tomography-staged patients, demonstrating that a more heterogeneous population of men staged without functional imaging benefits from WPRT.
Deletion of SUMO1 attenuates behavioral and anatomical deficits by regulating autophagic activities in Huntington disease

Significance SUMO protein can decorate other proteins via a process called SUMOylation that can regulate toxicity of proteins linked to neurodegenerative diseases. The mutant huntingtin (mHTT) protein in Huntington disease (HD) degenerates nerve cells, and SUMOylation of mHTT makes it more soluble and more toxic to the nerve cells. Here, we show that SUMO deletion in a humanized mouse HD model depletes mHTT and prevents brain shrinkage and behavioral abnormalities. SUMO deletion blocked inflammation and enhanced autophagy, a beneficial cellular degradation pathway. Importantly, ginkgolic acid (GA), a widely used plant supplement that can inhibit SUMOylation, activates autophagy and promotes the degradation of mHTT in human HD cells. Thus, our study indicates GA and analogs might be therapeutically beneficial to HD patients. The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. However, the underlying mechanisms of neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification of mHtt promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions while increasing cytoplasmic mHtt inclusions in the striatum of HD mice. SUMO1 deletion promoted autophagic activity, characterized by augmented interactions between mHtt inclusions and a lysosomal marker (LAMP1), increased LC3B- and LAMP1 interaction, and decreased interaction of sequestosome-1 (p62) and LAMP1 in DARPP-32–positive medium spiny neurons in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by regulating autophagy activities.
Effects of Added Humic Substances and Nutrients on Photochemical Degradation of Dissolved Organic Matter in a Mesocosm Amendment Experiment in the Gulf of Finland, Baltic Sea

Humic substances, a component of terrestrial dissolved organic matter (tDOM), contribute to dissolved organic matter (DOM) and chromophoric DOM (CDOM) in coastal waters, and have significant impacts on biogeochemistry. There are concerns in recent years over browning effects in surface waters due to increasing tDOM inputs, and their negative impacts on aquatic ecosystems, but relatively little work has been published on estuaries and coastal waters. Photodegradation could be a significant sink for tDOM in coastal environments, but the rates and efficiencies are poorly constrained. We conducted large‐scale DOM photodegradation experiments in mesocosms amended with humic substances and nutrients in the Gulf of Finland to investigate the potential of photochemistry to remove added tDOM and the interactions of DOM photochemistry with eutrophication. The added tDOM was photodegraded rapidly, as CDOM absorption decreased and spectral slopes increased with increasing photons absorbed in laboratory experiments. The in situ DOM optical properties became similar among the control, humic‐ and humic+nutrients‐amended mesocosm samples toward the end of the amendment experiment, indicating degradation of the excess CDOM/DOM through processes including photodegradation. Nutrient additions did not significantly influence the effects of added humic substances on CDOM optical property changes, but induced changes in DOM removal.
Potential nonpharmacological interventions to prevent frailty among elderly in low- and middle-income countries

Abstract Background: Frailty syndrome is a medical condition defined by a progressive loss of function that usually begins beyond 65 and necessitates assistance with daily activities. There are both pharmacological and nonpharmacological approaches to prevent frailty. The purpose of this systematic review is to investigate viable nonpharmacological therapies for reducing frailty among the elderly in low- and middle-income countries, to develop an appropriate guideline to determine the applicability of these nonpharmacological interventions in various feasible settings. Methods: Two independent researchers will explore 5 electronic databases for relevant and promising studies. The selected articles will be subjected to a full-text examination following the initial screening. Two independent authors will analyze the risk of bias using the Cochrane risk of bias assessment tool. The review findings on various nonpharmacological approaches to prevent frailty will be presented as a narrative synthesis. There will be a sensitivity analysis and an assessment of study heterogeneity if possible. Results and conclusion: The systematic review protocol has been evaluated and approved by the institutional review board of North South University. The preferred reporting items for systematic review and meta-analysis protocol recommendations for precisely reporting health care interventions and the Cochrane group standards will be strictly followed in this systematic review protocol. PROSPERO Registration number: CRD42021290417
Magnetic resonance elastography with guided pressure waves

Magnetic resonance elastography aims to non‐invasively and remotely characterize the mechanical properties of living tissues. To quantitatively and regionally map the shear viscoelastic moduli in vivo, the technique must achieve proper mechanical excitation throughout the targeted tissues. Although it is straightforward, ante manibus, in close organs such as the liver or the breast, which practitioners clinically palpate already, it is somewhat fortunately highly challenging to trick the natural protective barriers of remote organs such as the brain. So far, mechanical waves have been induced in the latter by shaking the surrounding cranial bones. Here, the skull was circumvented by guiding pressure waves inside the subject's buccal cavity so mechanical waves could propagate from within through the brainstem up to the brain. Repeatable, reproducible and robust displacement fields were recorded in phantoms and in vivo by magnetic resonance elastography with guided pressure waves such that quantitative mechanical outcomes were extracted in the human brain.
Enduring effect of abuse: Childhood maltreatment links to altered theory of mind network among adults

Childhood maltreatment (CM) confers a great risk of maladaptive development outcomes later in life, however, the neurobiological mechanism underlying this vulnerability is still unclear. The present study aimed to investigate the long‐term consequences of CM on neural connectivity while controlling for psychiatric conditions, medication, and, substance abuse. A sample including adults with (n = 40) and without CM (n = 50) completed Childhood Trauma Questionnaire (CTQ), personality questionnaires, and resting‐state functional magnetic resonance imaging scan were recruited for the current study. The whole‐brain functional connectivity (FC) was evaluated using an unbiased, data‐driven, multivariate pattern analysis method. Relative to controls, adults with CM suffered a higher level of temperament and impulsivity and showed decreased FC between the insula and superior temporal gyrus (STG) and between inferior parietal lobule (IPL) and middle frontal gyrus, STG, and dorsal anterior cingulate cortex (dACC), while increased FC between IPL and cuneus and superior frontal gyrus (SFG) regions. The FCs of IPL with dACC and SFG were correlated with the anxious and cyclothymic temperament and attentional impulsivity. Moreover, these FCs partially mediated the relationship between CM and attentional impulsivity. Our results suggest that CM has a significant effect on the modulation of FC within theory of mind (ToM) network even decades later in adulthood, and inform a new framework to account for how CM results in the development of impulsivity. The novel findings reveal the neurobiological consequences of CM and provide new clues to the prevention and intervention strategy to reduce the risk of the development of psychopathology.
An Integrated mHealth Campaign to Reduce the Risk of Falling for Older Adults

The number of falls among older adults is rising due to an aging population worldwide. An integrated communication campaign utilizing mHealth (mobile health) encouraged older adults to perform strength, balance, and flexibility exercises to reduce their risk of falling. Campaign development was guided by a mixed-method approach which incorporated expert interviews (N = 3), qualitative interviews (N = 22), and a quantitative baseline pre-campaign survey (N = 274) with older adults. We evaluated the campaign impact with a pre-post survey analysis (post n = 141). Impact was measured by knowledge, attitudes, self-efficacy, and behaviors as key Social Cognitive Theory factors to exercise adoption. Results showed that respondents with campaign exposure had a significant increase in all factor scores from pre- to post-campaign survey, which was significantly higher in the group with campaign exposure. The impact evaluation illustrated how digital mobile channels effectively provide means to reach older adults to reduce their risk of falling.
A review of electronic medical records and safe transfusion practice for guideline development

Electronic medical records (EMRs) are often composed of multiple interlinking systems, each serving a particular task, including transfusion ordering and administration. Transfusion may not be prioritized when developing or implementing electronic platforms. Uniform guidelines may assist information technology (IT) developers, institutions and healthcare workforces to progress with shared goals.
Risk of Guillain–Barré syndrome after vaccination against human papillomavirus: a systematic review and meta-analysis, 1 January 2000 to 4 April 2020

Background Guillain–Barré syndrome (GBS) is a rare autoimmune disease that can follow viral infections and has in a few cases been linked to vaccinations. Pre-licensure clinical trials did not observe an association between human papillomavirus (HPV) vaccination and GBS, a post-marketing study from 2017 reported an increased relative risk. Aim We assessed the risk of GBS after HPV vaccination through a systematic literature review and meta-analysis. Methods We searched Embase, MEDLINE and Cochrane for studies reporting on the risk of GBS after HPV vaccination in individuals aged ≥ 9 years, published between 1 January 2000 and 4 April 2020, excluding studies without a comparator group. Seven studies reporting relative effect sizes were pooled using random-effects meta-analysis. We assessed quality of evidence using the GRADE approach. Study protocol was registered (PROSPERO No. #CRD42019123533). Results Of 602 identified records, we included 25 studies. Based on over 10 million reports, cases of GBS were rare. In 22 studies no increased risk was observed, while in three studies a signal of increased risk of GBS after HPV vaccination was identified. Meta-analysis yielded a pooled random-effects ratio of 1.21 (95% CI: 0.60–2.43); I2 = 72% (95% CI: 36–88). This translates to a number needed to harm of one million to be vaccinated to generate one GBS case. Quality of evidence was very low. Conclusions The absolute and relative risk of GBS after HPV vaccination is very low and lacks statistical significance. This is reassuring for the already implemented vaccination programmes and should be used in respective communication activities.
Transmission of multidrug-resistant Mycobacterium tuberculosis in Wuhan, China

Abstract How multidrug-resistant tuberculosis (MDR-TB) spreads and expands in Wuhan population is not clear. The study aimed to determine the transmission patterns of MDR-TB in Wuhan city, China, including 149 patients with MDR-TB. Tuberculosis isolates were genotyped by deletion-targeted multiplex polymerase chain reaction, mycobacterial interspersed repetitive unit-variable number tandem repeat typing, and sequencing of drug resistance-associated genes. The risk factors of genomic-clustering were analyzed with logistic regression. The genomic-clustering patients were deeply investigated. The analysis identified 111 unique and 11 clustered genotypes (38 isolates). The clustering rate was 25.50% and the minimum estimate proportion of recent transmission was 18.12%. Two clusters (5 isolates) shared the same mutation, the remain 9 clusters (33 isolates) had different mutation. Logistic regression showed that older than 60 years (adjusted OR 2.360, 95% CI:1.052-5.292) was an independent factor associated with the genomic-clustering of MDR-TB. Among the 38 genomic-clustering cases, 14 cases had epidemiological transmission links. The most common type of transmission link was social contact. The local transmission of MDR-TB in Wuhan was really an issue. The elderly population might be the high-risk groups for transmission of MDR-TB, and the community or public transportation might be the main transmission places.