Miracle-dz/UniFAR-FTUs huggingface dataset:
Living in Food Deserts and Adverse Cardiovascular Outcomes in Patients With Cardiovascular Disease

Background Food deserts (FDs), defined as low‐income communities with limited access to healthy food, are a growing public health concern. We evaluated the impact of living in FDs on incident cardiovascular events. Methods and Results We recruited 4944 subjects (age 64±12, 64% male) undergoing cardiac catheterization into the Emory Cardiovascular Biobank. Using the US Department of Agriculture definition of FD, we determined whether their residential addresses had (1) poor access to healthy food, (2) low income, or (3) both (=FD). Subjects were prospectively followed for a median of 3.2 years for myocardial infarction (MI) and death. Fine and Gray's subdistribution hazard models for MI and Cox proportional hazard models for death/MI were used to examine the association between area characteristics (FD, poor access, and low income) and the rates of adverse events after adjusting for traditional risk factors. A total of 981 (20%) lived in FDs and had a higher adjusted risk of MI (subdistribution hazard ratio, 1.44 [95% CI, 1.06–1.95]) than those living in non‐FDs. In a multivariate analysis including both food access and area income, only living in a low‐income area was associated with a higher adjusted risk of MI (subdistribution hazard ratio, 1.40 [1.06–1.85]) and death/MI (hazard ratio, 1.18 [1.02–1.35]) while living in a poor‐access area was not significantly associated with either (subdistribution hazard ratio, 1.05 [0.80–1.38] and hazard ratio, 0.99 [0.87–1.14], respectively). Conclusions Living in an FD is associated with a higher risk of adverse cardiovascular events in those with coronary artery disease. Specifically, low area income of FDs, not poor access to food, was significantly associated with worse outcomes.
"I am a lefty in a right-handed world": Qualitative analysis of clinical learning experience of left-handed undergraduate dental students.

BACKGROUND Left-handedness is the preferential use of the left hand in single-handed activities such as writing. There are many studies in the literature on left-handedness in relation to professional sports, medicine and surgery. Although dentistry largely depends on manual dexterity and hand skills, there has been little research to investigate the effect of left-handedness on clinical dentistry, particularly in Australasia. AIM To gain an insight into the clinical learning experience of left-handed undergraduate dental students at the Faculty of Dentistry, University of Otago, New Zealand. METHODS Purposive sampling of left-handed students was done within the final-year class of undergraduate dental students, and they were invited to participate in a semi-structured group interview to discuss their clinical learning experience at the Faculty. Six participants agreed to participate, and the interview was recorded and transcribed verbatim. Collected data were analysed using a thematic inductive/interpretive analysis approach according to the constructivist grounded theory. RESULTS All participants reported having clinical difficulties being left-handed students learning using right-handed equipment. There was a common theme of experiencing hand and wrist musculoskeletal problems as well as feeling of guilt causing patient discomfort during treatment. The majority of participants reported incidents where they were told by their supervisors to learn practising dentistry with their right hand and they felt that little guidance was given on how to operate as a left-handed clinician. All participants perceived that being a left-handed operator affected their efficiency and confidence level in their early clinical years. CONCLUSION Left-handed students have a strong sense of adaptability. However, in order to improve the learning experience regardless of the difference in the operator's preference of dominant hand, students should be provided with appropriate equipment such as ambidextrous dental chairs and professional guidance, especially during their early career.
Physiologically based pharmacokinetic modelling to predict exposure differences in healthy volunteers and subjects with renal impairment: Ceftazidime case study

Ceftazidime is a widely used β‐lactam antibiotic and almost entirely excreted via glomerular filtration in kidney. The objective of this analysis was to assess the ability of physiologically based pharmacokinetic (PBPK) model to predict ceftazidime exposure in healthy volunteers and subjects with renal impairment. A full PBPK model of ceftazidime was developed using physiochemical properties and clinical data. The total clearance of 115 mL/min and renal clearance of 100 mL/min were obtained from ceftazidime package insert. Healthy and chronic kidney disease (CKD) populations were applied for sampling of virtual subjects. The established PBPK model predicted mean plasma AUCinf were 138.5 ± 19.6, 230.7 ± 22.2, 369.3 ± 53.1 and 561.8 ± 92.4 h µg/mL in healthy, mild, moderate and severe renal impairment subjects, respectively, after administration of 1 g ceftazidime intravenous bolus dose. The predicted values were in close agreement with the weighted mean of the five reported clinical studies. The exposure was slightly under predicted in subjects with severely impaired renal function, but still within 1.5‐fold range. The concentration‐time profiles of ceftazidime were also well captured in healthy volunteers and subjects with renal impairment. The developed PBPK model along with systems pharmacokinetics (PK) (renal impaired populations) well predicted the ceftazidime exposure. PBPK models verified with clinical study in healthy volunteers could be potentially applied to predict PK and recommend dose adjustment for CKD patients.
Dental caries among childhood cancer survivors

Abstract One of many possible complications of cancer therapy in children is enamel demineralization and such changes in the ion content of dental hard tissues may increase susceptibility to caries. The study aims to assess the prevalence of dental caries among childhood cancer survivors. A cross-sectional study was conducted on 225 children aged between 4 and 18 years, including 75 cancer patients and 150 sex- and age-matched controls. The cancer survivors were recruited from single pediatric oncology center. The control group was formed from students of randomly selected kindergartens and schools. Dental investigation was held between July 2013 and January 2016, approximately 5 years after the cessation of anticancer treatment (range: 6–155 months). The occurrence of dental caries was assessed with DMF/dmf index (showing the mean number of decayed, missing and filled permanent/deciduous teeth). Univariate statistical approach was performed and P-values < . 05 were considered as statistically significant. The frequency of dental caries was comparable in both groups (85.4% vs 84%). However, the DMF index was higher in cancer patients than in controls: the median and interquartile ranges were 2 (0–4) vs 0 (0–2); P < . 01. This correlates with duration of anticancer therapy (r = 0.26; P < .05). Moreover, children who had radiotherapy of the head and neck regions had significantly higher DMF scores than the ones who did not: 4.5 (1–6) vs 2 (0–4); P < . 05. Socioeconomic and education status within family also has a significant impact on DMF scores in the cancer group. In conclusion, cancer patients, particularly those with a poor social background, should receive professional dental care as their caries process is more active than that of healthy peers.
Endogenous Neoantigen-Specific CD8 T Cells Identified in Two Glioblastoma Models Using a Cancer Immunogenomics Approach

Immunogenomics were used to identify tumor-specific neoantigens in two well characterized models of glioblastoma. Endogenous immune responses harbored neoantigen-specific T cells within the brain and lymph nodes, providing a tractable system for additional preclinical immunotherapeutic studies in these systems. The “cancer immunogenomics” paradigm has facilitated the search for tumor-specific antigens over the last 4 years by applying comprehensive cancer genomics to tumor antigen discovery. We applied this methodology to identify tumor-specific “neoantigens” in the C57BL/6-derived GL261 and VM/Dk-derived SMA-560 tumor models. Following DNA whole-exome and RNA sequencing, high-affinity candidate neoepitopes were predicted and screened for immunogenicity by ELISPOT and tetramer analyses. GL261 and SMA-560 harbored 4,932 and 2,171 nonsynonymous exome mutations, respectively, of which less than half were expressed. To establish the immunogenicities of H-2Kb and H-2Db candidate neoantigens, we assessed the ability of the epitopes predicted in silico to be the highest affinity binders to activate tumor-infiltrating T cells harvested from GL261 and SMA-560 tumors. Using IFNγ ELISPOT, we confirmed H-2Db–restricted Imp3D81N (GL261) and Odc1Q129L (SMA-560) along with H-2Kb–restricted E2f8K272R (SMA-560) as endogenous tumor-specific neoantigens that are functionally immunogenic. Furthermore, neoantigen-specific T cells to Imp3D81N and Odc1Q129L were detected within intracranial tumors as well as cervical draining lymph nodes by tetramer analysis. By establishing the immunogenicities of predicted high-affinity neoepitopes in these models, we extend the immunogenomics-based neoantigen discovery pipeline to glioblastoma models and provide a tractable system to further study the mechanism of action of T cell–activating immunotherapeutic approaches in preclinical models of glioblastoma. Cancer Immunol Res; 4(12); 1007–15. ©2016 AACR.
Heterogeneity of Activity-Induced Sodium Transients between Astrocytes of the Mouse Hippocampus and Neocortex: Mechanisms and Consequences

Activity-related sodium transients induced by glutamate uptake represent a special form of astrocyte excitability. Astrocytes of the neocortex, as opposed to the hippocampus proper, also express ionotropic glutamate receptors, which might provide additional sodium influx. We compared glutamate-related sodium transients in astrocytes and neurons in slices of the neocortex and hippocampus of juvenile mice of both sexes, using widefield and multiphoton imaging. Stimulation of glutamatergic afferents or glutamate application induced sodium transients that were twice as large in neocortical as in hippocampal astrocytes, despite similar neuronal responses. Astrocyte sodium transients were reduced by ∼50% upon blocking NMDA receptors in the neocortex, but not hippocampus. Neocortical, but not hippocampal, astrocytes exhibited marked sodium increases in response to NMDA. These key differences in sodium signaling were also observed in neonates and in adults. NMDA application evoked local calcium transients in processes of neocortical astrocytes, which were dampened upon blocking sodium/calcium exchange (NCX) with KB-R7943 or SEA0400. Mathematical computation based on our data predict that NMDA-induced sodium increases drive the NCX into reverse mode, resulting in calcium influx. Together, our study reveals a considerable regional heterogeneity in astrocyte sodium transients, which persists throughout postnatal development. Neocortical astrocytes respond with much larger sodium elevations to glutamatergic activity than hippocampal astrocytes. Moreover, neocortical astrocytes experience NMDA-receptor-mediated sodium influx, which hippocampal astrocytes lack, and which drives calcium import through reverse NCX. This pathway thereby links sodium to calcium signaling and represents a new mechanism for the generation of local calcium influx in neocortical astrocytes. SIGNIFICANCE STATEMENT Astrocyte calcium signals play a central role in neuron–glia interaction. Moreover, activity-related sodium transients may represent a new form of astrocyte excitability. Here we show that activation of NMDA receptors results in prominent sodium transients in neocortical, but not hippocampal, astrocytes in the mouse brain. NMDA receptor activation is accompanied by local calcium signaling in processes of neocortical astrocytes, which is augmented by sodium-driven reversal of the sodium/calcium exchanger. Our data demonstrate a significant regional heterogeneity in the magnitude and mechanisms of astrocyte sodium transients. They also suggest a close interrelation between NMDA-receptor-mediated sodium influx and calcium signaling through the reversal of sodium/calcium exchanger, thereby establishing a new pathway for the generation of local calcium signaling in astrocyte processes.
The novel CD19-targeting antibody-drug conjugate huB4-DGN462 shows improved anti-tumor activity compared to SAR3419 in CD19-positive lymphoma and leukemia models

Antibody-drug conjugates (ADC) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADC targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines. In vivo experiments using lymphoma xenografts models confirmed the in vitro data. The response of B-cell lymphoma lines to huB4-DGN462 was not correlated with CD19 expression, the presence of BCL2 or MYC translocations, TP53 inactivation or lymphoma histology. In conclusion, huB4-DGN462 is an attractive candidate for clinical investigation in patients with B-cell malignancies.
PUMILIO hyperactivity drives premature aging of Norad-deficient mice

Although numerous long noncoding RNAs (lncRNAs) have been identified, our understanding of their roles in mammalian physiology remains limited. Here we investigated the physiologic function of the conserved lncRNA Norad in vivo. Deletion of Norad in mice results in genomic instability and mitochondrial dysfunction, leading to a dramatic multi-system degenerative phenotype resembling premature aging. Loss of tissue homeostasis in Norad-deficient animals is attributable to augmented activity of PUMILIO proteins, which act as post-transcriptional repressors of target mRNAs to which they bind. Norad is the preferred RNA target of PUMILIO2 (PUM2) in mouse tissues and, upon loss of Norad, PUM2 hyperactively represses key genes required for mitosis and mitochondrial function. Remarkably, enforced Pum2 expression fully phenocopies Norad deletion, resulting in rapid-onset aging-associated phenotypes. These findings provide new insights and open new lines of investigation into the roles of noncoding RNAs and RNA binding proteins in normal physiology and aging.
Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism.
Cell–cell and virus–cell fusion assay–based analyses of alanine insertion mutants in the distal α9 portion of the JRFL gp41 subunit from HIV-1

Membrane fusion is the first essential step in HIV-1 replication. The gp41 subunit of HIV-1 envelope protein (Env), a class I fusion protein, achieves membrane fusion by forming a structure called a six-helix bundle composed of N- and C-terminal heptad repeats. We have recently shown that the distal portion of the α9 helix in the C-terminal heptad repeat of X4-tropic HXB2 Env plays a critical role in the late-stage membrane fusion and viral infection. Here, we used R5-tropic JRFL Env and constructed six alanine insertion mutants, 641+A to 646+A, in the further distal portion of α9 where several glutamine residues are conserved (the number corresponds to the position of the inserted alanine in JRFL Env). 644+A showed the most severe defect in syncytia formation. Decreased fusion pore formation activity, revealed by a dual split protein assay, was observed in all mutants except 641+A. Sequence analysis and substitution of inserted 644A with Gln revealed that the glutamine residue at position 644 that forms complex hydrogen-bond networks with other polar residues on the surface of the six-helix bundle is critical for cell–cell fusion. We also developed a split NanoLuc® (Nluc) reporter-based assay specific to the virus–cell membrane fusion step to analyze several of the mutants. Interestingly syncytia-competent mutants failed to display Nluc activities. In addition to defective fusion activity, a reduction of Env incorporation into virions may further contribute to differences in cell–cell and virus–cell fusions.
Conference on ‘ Multi-stakeholder nutrition actions in Africa: Translating evidence into policies, and programmes for impact ’ Is iodine de ﬁ ciency still a problem in sub-Saharan Africa?: a review

Iodine is an essential trace mineral, vital for its functions in many physiological processes in the human body. Both iodine de ﬁ ciency (ID) and excess are associated with adverse health effects; ID and excess iodine intake have both been identi ﬁ ed in sub-Saharan Africa (SSA). The review aims to (1) review the iodine status among populations in SSA until October 2018, and (2) identify populations at risk of excess or inadequate iodine intakes. A systematic search of relevant articles was carried out by a seven-member research team using PubMed, Science Direct and Scopus. A total of twenty-two articles was included for data extraction. Of the articles reviewed, the majority sought to determine the prevalence of iodine status of the study populations; others measured the impact of uncontrolled and unmonitored salt iodisation on iodine excess and tested the effectiveness of water iodisation. Although iodine status varied largely in study populations, ID and excessive iodine intake often coexisted within populations. The implementation of nutrition interventions and other strategies across SSA has resulted in the reduction of goitre prevalence. Even so, goitre prevalence remains high in many populations. Improvements in access to iodised salt and awareness of its importance are needed. The emerging problem of excess iodine intakes, however, should be taken into consideration by policy makers and programme implementers. As excessive iodine intakes may have adverse health effects greater than those induced by iodine de ﬁ cient diets, more population-based studies are needed to investigate iodine intakes of the different population groups.
A systematic review and meta‐analysis of locoregional treatments for in‐transit melanoma

In‐transit melanoma (ITM) metastases present a therapeutic challenge and management decisions can be difficult. There are multiple treatments available, with differing efficacy, and supported by different levels of evidence. The primary objective was to perform a systematic review and where suitable, a meta‐analysis of the literature reporting on the use of locoregional treatments for the management of ITM.
Incidence, etiology, and patterns of maxillofacial traumas in Syrian patients in Hatay, Turkey: A 3 year retrospective study.

BACKGROUND This study aimed to assess the demographics, clinical features, and treatment costs of maxillofacial trauma cases referred to our hospital during the Syrian civil war. METHODS The study included 80 cases of maxillofacial trauma. Patients with additional pathologies were excluded from the study. The patients were examined with respect to their demographics and clinical characteristics, Injury Severity Score (ISS), Glasgow Coma Score (GCS), treatments applied, costs, and outcomes. RESULTS A total of 80 patients included 76 (95%) males and 4 (5%) females, with the mean age of 29.05±9.97 years (range, 13-56 years), and 72 (90%) of them were Syrians injured in the war. The most common mechanism of trauma was the firearms injury in 72 (90%) cases, and the most frequently seen lesion was the mandible fracture (n=48, 60%). The ISS of all the patients was <16, as a severe trauma score. The GCS value was 8-12 in 4 (5%) patients, and 15 in 76 (95%). The most common treatment applied were the reduction and fixation, and graft-flap following fracture (n=12, 15%). The mean duration of hospitalization was 15.27±13.0 days (range, 2-60 days). All patients were discharged from hospital. The mean cost per case was calculated as 5,581.55±56.3 Turkish Lira (range, 772-18,697 TL) or 1,251.24±14.2 US Dollars (US$173-4,192). There was a significant correlation between the costs and the length of hospitalization (p<0.001, r=+0.729) and trauma scores (p=0.004, r=-0.616). CONCLUSION Firearms-injured young males with mandible fractures were the most common group of maxillofacial trauma cases seen during the Syrian war. The intensity of patients and the cost of the hospital stay have significantly increased because of the ongoing conflict in the neighboring country of Syria.