Miracle-dz/UniFAR-FTUs huggingface dataset:
Baseline visual field findings in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT).

PURPOSE To characterize visual field (VF) loss at the baseline visit and to evaluate VF quality control (QC) procedures in the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). METHODS The Visual Field Reading Center (VFRC) evaluated 660 baseline VFs (1320 hemifields) from 165 enrolled patients. Three readers independently classified each superior and inferior hemifield and identified any abnormalities. A subset (20%) of the hemifields was reread to evaluate within- and between-reader agreements. The QC system addressed test parameters, patient data, and shipment errors. RESULTS The majority (60%) of the baseline hemifields consisted of localized nerve fiber bundle-type VF loss. Approximately one-third (31.5%) of all the classifications consisted of partial arcuate defects combined with an enlarged blind spot, making this the most common type of hemifield classification. Inferior hemifield loss was greater than superior loss for both study and nonstudy eyes. Reader agreements were >90% for both inferior and superior hemifields for two out of three readers. Test-retest reliability agreement for individual readers was 95% for both hemifields. There were few QC errors with only 5.48 error points per 100-point VF. CONCLUSIONS The most common type of IIHTT baseline hemifield abnormality was a localized nerve fiber bundle-like defect. Localized inferior hemifield loss was more common than superior hemifield loss. Quality control and within- and between-reader agreement were excellent for the IIHTT (ClinicalTrials.gov number, NCT01003639).
An alternative pathway for gene regulation by Myc

The c‐Myc protein activates transcription as part of a heteromeric complex with Max. However, Myc‐transformed cells are characterized by loss of expression of several genes, suggesting that Myc may also repress gene expression. Two‐hybrid cloning identifies a novel POZ domain Zn finger protein (Miz‐1; Myc‐interacting Zn finger protein‐1) that specifically interacts with Myc, but not with Max or USF. Miz‐1 binds to start sites of the adenovirus major late and cyclin D1 promoters and activates transcription from both promoters. Miz‐1 has a potent growth arrest function. Binding of Myc to Miz‐1 requires the helix–loop–helix domain of Myc and a short amphipathic helix located in the carboxy‐terminus of Miz‐1. Expression of Myc inhibits transactivation, overcomes Miz‐1‐induced growth arrest and renders Miz‐1 insoluble in vivo. These processes depend on Myc and Miz‐1 association and on the integrity of the POZ domain of Miz‐1, suggesting that Myc binding activates a latent inhibitory function of this domain. Fusion of a nuclear localization signal induces efficient nuclear transport of Miz‐1 and impairs the ability of Myc to overcome transcriptional activation and growth arrest by Miz‐1. Our data suggest a model for how gene repression by Myc may occur in vivo.
The South African Surgical Outcomes Study: A 7-day prospective observational cohort study.

BACKGROUND Non-cardiac surgical morbidity and mortality is a major global public health burden. Sub-Saharan African perioperative outcome data are scarce. South Africa (SA) faces a unique public health challenge, engulfed as it is by four simultaneous epidemics: (i) poverty-related diseases; (ii) non-communicable diseases; (iii) HIV and related diseases; and (iv) injury and violence. Understanding the effects of these epidemics on perioperative outcomes may provide an important perspective on the surgical health of the country. OBJECTIVES To investigate the perioperative mortality and need for critical care admission in patients undergoing inpatient non-cardiac surgery in SA. METHODS A 7-day national, multicentre, prospective, observational cohort study of all patients ≥16 years of age undergoing inpatient non-cardiac surgery between 19 and 26 May 2014 at 50 public sector, government-funded hospitals in SA. RESULTS The study included 3 927/4 021 eligible patients (97.7%) recruited, with 45/50 hospitals (90.0%) submitting data that described all eligible patients. Crude in-hospital mortality was 123/3 927 (3.1%; 95% confidence interval (CI) 2.6 - 3.7). The rate of postoperative admission to critical care units was 255/3,927 (6.5%; 95% CI 5.7 - 7.3), with 43.5% of admissions being unplanned. Of the surgical procedures 2,120/3,915 (54.2%) were urgent or emergency ones, with a population-attributable risk for mortality of 25.5% (95% CI 5.1 - 55.8) and a risk of admission to critical care of 23.7% (95% CI 4.7 - 51.4). CONCLUSIONS Most patients in SA's public sector hospitals undergo urgent and emergency surgery, which is strongly associated with mortality and unplanned critical care admissions. Non-communicable diseases have a larger proportional contribution to mortality than infections and injuries. However, the most common comorbidity, HIV infection, was not associated with in-hospital mortality. The study was registered on ClinicalTrials.gov (NCT02141867).
One-Stage Posterior Hemivertebra Resection and Correction Using Segmental Posterior Instrumentation

Study Design. A retrospective study of 12 patients with congenital kyphoscoliosis caused by a single hemivertebra who underwent one-stage posterior hemivertebra resection and correction by posterior segmental instrumentation. Objectives. To evaluate the surgical outcomes of 12 patients with hemivertebra treated by hemivertebra resection by single posterior approach and correction with segmental posterior instrumentation. Summary of Background Data. Congenital scoliosis caused by hemivertebra causes extremely severe curves in some patients. Posterior fusion or posterior and anterior hemi-epiphysiodesis is performed to prevent progression of the deformity. The results of these procedures have been variable and not promising, especially in an adolescent patient with fixed kyphoscoliotic deformity. Hemivertebra resection offers more certain results and better correction of the deformity. To date, hemivertebra resection is performed by anterior and posterior approaches either by one-stage or two-stage operation. Few reports have been published describing a procedure consisting of one-stage posterior hemivertebra resection and correction of the deformity by segmental posterior instrumentation. Methods. A total of 12 patients with a single hemivertebra between the ages 8–24 years who underwent operative treatment were evaluated for a minimum of 2 years. All patients had a single nonincarcerated hemivertebra [T9 (1 patient), T10 (2), T11 (2), T12 (4), and L1 (3)]. After posterior hemivertebra resection, segmental posterior instrumentation was used for correction of the kyphoscoliotic deformity [CD (4 patients), Kaneda SR (2), and ISOLA (6)]. Radiographic evaluations were conducted on the preoperative, postoperative, and follow-up standing posteroanterior and lateral radiographs. Results. All 12 patients had kyphoscoliotic deformity. Preoperative scoliosis averaging 49° was corrected to 18° (correction rate, 64%). Preoperative kyphosis of 40° was corrected to 17° of kyphosis. Trunk shift of 23 mm was improved to 3 mm. Correction loss was 2° in the frontal plane and 3 ° in the sagittal plane, and no patients showed more than 5° of correction loss. No intraoperative complications were noted. Solid fusion was obtained in all patients, and no implant failure was verified at the final radiographic evaluations. Conclusions. This study indicated that correction of kyphoscoliosis caused by a single hemivertebra can be effectively conducted by one-stage posterior hemivertebra resection and correction using segmental posterior instrumentation. The operation was safe, and no associated adverse complications were noted. This procedure is best indicated for adolescent patients with a structural kyphoscoliotic deformity caused by a thoracic or thoracolumbar single hemivertebra.
Protein-disulfide Isomerase-associated 3 (Pdia3) Mediates the Membrane Response to 1,25-Dihydroxyvitamin D3 in Osteoblasts*

Protein-disulfide isomerase-associated 3 (Pdia3) is a multifunctional protein hypothesized to be a membrane receptor for 1,25(OH)2D3. In intestinal epithelium and chondrocytes, 1,25(OH)2D3 stimulates rapid membrane responses that are different from genomic effects via the vitamin D receptor (VDR). In this study, we show that 1,25(OH)2D3 stimulates phospholipase A2 (PLA2)-dependent rapid release of prostaglandin E2 (PGE2), activation of protein kinase C (PKC), and regulation of bone-related gene transcription and mineralization in osteoblast-like MC3T3-E1 cells (WT) via a mechanism involving Pdia3. Pdia3 was present in caveolae based on co-localization with lipid rafts and caveolin-1. In Pdia3-silenced (Sh-Pdia3) cells, 1,25(OH)2D3 failed to stimulate PKC and PGE2 responses; in Pdia3-overexpressing cells (Ov-Pdia3), responses to 1,25(OH)2D3 were augmented. Downstream mediators of Pdia3, PLA2-activating protein (PLAA) and arachidonic acid, stimulated similar PKC activation in wild-type, Sh-Pdia3, and Ov-Pdia3 cells supporting the hypothesis that Pdia3 mediates the membrane action of 1,25(OH)2D3. Treatment of MC3T3-E1 cells with 1,25(OH)2D3 for 9 min stimulated rapid phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and increased expression of alkaline phosphatase, MMP-13, and osteopontin but decreased expression of osteocalcin, osteoprotegerin (mRNA and protein), and smad2. These effects were attenuated in Sh-Pdia3 cells. Sh-Pdia3 cells produced higher numbers of von Kossa-positive nodules and alizarin red-positive nodules compared with WT cells with or without 1,25(OH)2D3 treatment whereas Ov-Pdia3 did not show any mineralization. Our data suggest Pdia3 is an important initiator of 1,25(OH)2D3-stimulated membrane signaling pathways, which have both genomic and non genomic effects during osteoblast maturation.
Pharmacokinetics of Tacrolimus During Pregnancy

Background: Information on the pharmacokinetics of tacrolimus during pregnancy is limited to case reports despite the increasing number of pregnant women being prescribed tacrolimus for immunosuppression. Methods: Blood, plasma, and urine samples were collected over 1 steady-state dosing interval from women treated with oral tacrolimus during early to late pregnancy (n = 10) and postpartum (n = 5). Total and unbound tacrolimus as well as metabolite concentrations in blood and plasma were assayed by a validated liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) method. A mixed-effect linear model was used for comparison across gestational age and using postpartum as the reference group. Results: The mean oral clearance (CL/F) based on whole-blood tacrolimus concentration was 39% higher during mid-pregnancy and late pregnancy compared with postpartum (47.4 ± 12.6 vs. 34.2 ± 14.8 L/h, P < 0.03). Tacrolimus-free fraction increased by 91% in plasma (fP) and by 100% in blood (fB) during pregnancy (P = 0.0007 and 0.002, respectively). Increased fP was inversely associated with serum albumin concentration (r = −0.7, P = 0.003), which decreased by 27% during pregnancy. Pregnancy-related changes in fP and fB contributed significantly to the observed gestational increase in tacrolimus whole-blood CL/F (r2 = 0.36 and 0.47, respectively, P < 0.01). In addition, tacrolimus whole-blood CL/F was inversely correlated with both hematocrit and red blood cell counts, suggesting that binding of tacrolimus to erythrocytes restricts its availability for metabolism. Treating physicians increased tacrolimus dosages in study participants during pregnancy by an average of 45% to maintain tacrolimus whole-blood trough concentrations in the therapeutic range. This led to striking increases in unbound tacrolimus trough concentrations and unbound area under the concentration–time curve, by 112% and 173%, respectively, during pregnancy (P = 0.02 and 0.03, respectively). Conclusions: Tacrolimus pharmacokinetics are altered during pregnancy. Dose adjustment to maintain whole-blood tacrolimus concentration in the usual therapeutic range during pregnancy increases circulating free drug concentrations, which may impact clinical outcomes.
Prevalence and Clinical Significance of Potential Drug-Drug Interactions at Ayder Referral Hospital, Northern Ethiopia

Introduction: Clinically significant drug-drug interactions reduce effectiveness of drugs or cause fatal adverse events. Although harmful drug interactions are preventable, clinicians’ recognition and detection of drug interactions is not optimal. Objective: To assess prevalence, clinical significance and factors associated with potential drug-drug interactions at medical ward of Ayder Referral Hospital, Ethiopia. Methods: A cross-sectional study was conducted to determine potential drug-drug interactions. A total of 204 patients’ medical records were analyzed for drug-drug interaction using Micromedex drug interaction software. Data were analyzed using SPSS version 16. Results: We identified 135 interacting-combinations in a total of 266 potential drug-drug interactions (pDDIs) with a mean of 1.3 pDDIs per patient. Of these, 30.1% and 53.7% of patients had at least one major and one moderate pDDIs respectively. The most common pDDIs involved were concurrent use of clarithromycin with simvastatin, aspirin with heparin and dexamethasone with rifampin which have contraindication, major and moderate severity respectively. There was significant association of occurrence of pDDIs with polypharmacy (p<0.01). Conclusion: Potential drug-drug interactions were common at the medical ward of our hospital.
Osteoporosis in Diffuse Parenchymal Lung Disease.

STUDY OBJECTIVES There are no studies focused on skeletal status in patients with diffuse parenchymal lung disease (DPLD). We hypothesized that patients with DPLD referred for lung transplantation would have a high prevalence of osteoporosis related to corticosteroid use or reduced pulmonary function and exercise capacity. DESIGN Retrospective cohort study. SETTING Tertiary care center. PATIENTS Eighty-six patients with DPLD referred to our center for lung transplantation evaluation between March 1999 and April 2004. MEASUREMENTS AND RESULTS Dual-energy X-ray absorptiometry was used to measure bone mineral density (BMD) at the lumbar spine, femoral neck, total hip, and radius at the time of referral. Criteria developed by the World Health Organization were used to define osteopenia and osteoporosis. Fifty-five patients (64%) had usual interstitial pneumonia-pattern lung disease, 14 patients (16%) had nonspecific interstitial pneumonia-pattern lung disease, and 17 patients (20%) had other forms of DPLD. Sixty-four patients (74%) were receiving corticosteroids, and 43 patients (50%) were receiving preventive therapy for osteoporosis. Eleven patients (13%; 95% confidence interval [CI], 7 to 22%) met criteria for osteoporosis at any site, and 49 patients (57%; 95% CI, 46 to 68%) had osteopenia. Lower body mass index (BMI) [adjusted odds ratio (OR), 1.3; 95% CI, 1.1 to 1.6; p = 0.007] and Hispanic ethnicity (adjusted OR, 9.7; 95% CI, 1.8 to 52; p = 0.008) were independently associated with an increased risk of osteoporosis. Linear regression analysis confirmed that BMD at the femoral neck and hip was directly associated with BMI (p < 0.002). These findings were not affected by adjustment for the use of corticosteroids or osteoporosis prophylaxis, pulmonary function, or exercise performance. CONCLUSIONS Reduced BMD was common in patients with DPLD who were referred for lung transplantation. Lower BMD was associated with lower BMI, whereas there was no association with other clinical factors in our cohort. Hispanic patients with DPLD had a higher risk of osteoporosis than non-Hispanic patients, independent of other variables. Given their increased risk of bone loss, patients with DPLD should undergo screening for osteoporosis and receive prophylaxis and treatment according to published guidelines.
Structural Basis for Toughness and Flexibility in the C-terminal Passenger Domain of an Acinetobacter Trimeric Autotransporter Adhesin*

Trimeric autotransporter adhesins (TAAs) on the cell surface of Gram-negative pathogens mediate bacterial adhesion to host cells and extracellular matrix proteins. However, AtaA, a TAA in the nonpathogenic Acinetobacter sp. strain Tol 5, shows nonspecific high adhesiveness to abiotic material surfaces as well as to biotic surfaces. It consists of a passenger domain secreted by the C-terminal transmembrane anchor domain (TM), and the passenger domain contains an N-terminal head, N-terminal stalk, C-terminal head (Chead), and C-terminal stalk (Cstalk). The Chead-Cstalk-TM fragment, which is conserved in many Acinetobacter TAAs, has by itself the head-stalk-anchor architecture of a complete TAA. Here, we show the crystal structure of the Chead-Cstalk fragment, AtaA_C-terminal passenger domain (CPSD), providing the first view of several conserved TAA domains. The YadA-like head (Ylhead) of the fragment is capped by a unique structure (headCap), composed of three β-hairpins and a connector motif; it also contains a head insert motif (HIM1) before its last inner β-strand. The headCap, Ylhead, and HIM1 integrally form a stable Chead structure. Some of the major domains of the CPSD fragment are inherently flexible and provide bending sites for the fiber between segments whose toughness is ensured by topological chain exchange and hydrophobic core formation inside the trimer. Thus, although adherence assays using in-frame deletion mutants revealed that the characteristic adhesive sites of AtaA reside in its N-terminal part, the flexibility and toughness of the CPSD part provide the resilience that enables the adhesive properties of the full-length fiber across a wide range of conditions.
A2A Adenosine Receptors on Bone Marrow-Derived Cells Protect Liver from Ischemia-Reperfusion Injury1

Activation of the A2A adenosine receptor (A2AR) during reperfusion of various tissues has been found to markedly reduce ischemia-reperfusion injury. In this study, we used bone marrow transplantation (BMT) to create chimeric mice that either selectively lack or selectively express the A2AR on bone marrow-derived cells. Bolus i.p. injection of the selective A2A agonist, 4-{3-[6-amino-9-(5-cyclopropylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-piperidine-1-carboxylic acid methyl ester (ATL313; 3 μg/kg), at the time of reperfusion protects wild-type (wt) mice from liver ischemia-reperfusion injury. ATL313 also protects wt/wt (donor/recipient BMT mouse chimera) and wt/knockout chimera but produces modest protection of knockout/wt chimera as assessed by alanine aminotransferase activity, induction of cytokine transcripts (RANTES, IFN-γ-inducible protein-10, IL-1α, IL-1-β, IL-1Rα, IL-18, IL-6, and IFN-γ), or histological criteria. ATL313, which is highly selective for the A2AR, produces more liver protection of chimeric BMT mice than 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester, which is rapidly metabolized in mice to produce 4-{3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid, which has similar affinity for the A2AR and the proinflammatory A3 adenosine receptor. GFP chimera mice were created to show that vascular endothelial cells in the injured liver do not account for liver protection because they are not derived by transdifferentiation of bone marrow precursors. The data suggest that activation of the A2AR on bone marrow-derived cells is primarily responsible for protecting the liver from reperfusion injury.
Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 binding

The HIV-1 envelope glycoprotein (Env) undergoes conformational transitions consequent to CD4 binding and coreceptor engagement during viral entry. The physical steps in this process are becoming defined, but less is known about their significance as targets of antibodies potentially protective against HIV-1 infection. Here we probe the functional significance of transitional epitope exposure by characterizing 41 human mAbs specific for epitopes exposed on trimeric Env after CD4 engagement. These mAbs recognize three epitope clusters: cluster A, the gp120 face occluded by gp41 in trimeric Env; cluster B, a region proximal to the coreceptor-binding site (CoRBS) and involving the V1/V2 domain; and cluster C, the coreceptor-binding site. The mAbs were evaluated functionally by antibody-dependent, cell-mediated cytotoxicity (ADCC) and for neutralization of Tiers 1 and 2 pseudoviruses. All three clusters included mAbs mediating ADCC. However, there was a strong potency bias for cluster A, which harbors at least three potent ADCC epitopes whose cognate mAbs have electropositive paratopes. Cluster A epitopes are functional ADCC targets during viral entry in an assay format using virion-sensitized target cells. In contrast, only cluster C contained epitopes that were recognized by neutralizing mAbs. There was significant diversity in breadth and potency that correlated with epitope fine specificity. In contrast, ADCC potency had no relationship with neutralization potency or breadth for any epitope cluster. Thus, Fc-mediated effector function and neutralization coselect with specificity in anti-Env antibody responses, but the nature of selection is distinct for these two antiviral activities.
Mechanism of action of regulatory proteins encoded by complex retroviruses

Complex retroviruses are distinguished by their ability to control the expression of their gene products through the action of virally encoded regulatory proteins. These viral gene products modulate both the quantity and the quality of viral gene expression through regulation at both the transcriptional and posttranscriptional levels. The most intensely studied retroviral regulatory proteins, termed Tat and Rev, are encoded by the prototypic complex retrovirus human immunodeficiency virus type 1. However, considerable information also exists on regulatory proteins encoded by human T-cell leukemia virus type I, as well as several other human and animal complex retroviruses. In general, these data demonstrate that retrovirally encoded transcriptional trans-activators can exert a similar effect by several very different mechanisms. In contrast, posttranscriptional regulation of retroviral gene expression appears to occur via a single pathway that is probably dependent on the recruitment of a highly conserved cellular cofactor. These two shared regulatory pathways are proposed to be critical to the ability of complex retroviruses to establish chronic infections in the face of an ongoing host immune response.