Miracle-dz/UniFAR-FTUs huggingface dataset:
“Atypical femoral fractures” during bisphosphonate exposure in adult hypophosphatasia

We report a 55‐year‐old woman who suffered atypical subtrochanteric femoral fractures (ASFFs) after 4 years of exposure to alendronate and then zolendronate given for “osteoporosis. ” Before alendronate treatment, she had low bone mineral density. After several months of therapy, metatarsal stress fractures began. Bisphosphonate (BP) administration was stopped following the ASFFs, and the adult form of hypophosphatasia (HPP) was diagnosed from low serum alkaline phosphatase (ALP) activity, high endogenous levels of two natural substrates for the “tissue‐nonspecific” isoenzyme of ALP (TNSALP), and a heterozygous mutation within the gene that encodes this enzyme. Experience with other HPP families showed that her mutation (Arg71His) with a second defective TNSALP allele can cause severe HPP in infancy, and when heterozygous can cause mild HPP featuring premature loss of deciduous teeth in children. Because the skeletal disease of HPP results from extracellular accumulation of the TNSALP substrate inorganic pyrophosphate (PPi) and its inhibitory effect on mineralization, perhaps HPP patients or carriers will have adverse effects from BPs. BPs are analogues of PPi and can suppress bone turnover but also deactivate TNSALP. Our report is the first of BP exposure preceding ASFFs in adult HPP. To explore a potential role for TNSALP deactivation in ASFFs, mutation analysis of TNSALP should be studied in a cohort of these patients. Meanwhile, clinicians must suspect HPP when clinical or laboratory clues include premature loss of primary dentition, pseudofractures or recurrent poorly healing metatarsal stress fractures, a family history suggestive of HPP, or low serum ALP activity. If HPP is documented, BP treatment might be avoided. To establish the diagnosis of HPP, assays for two natural substrates for TNSALP and TNSALP mutation analysis are available in commercial laboratories. With positive findings, radiological or bone biopsy evidence of acquired osteomalacia would indicate the adult form of this inborn‐error‐of‐metabolism. © 2012 American Society for Bone and Mineral Research.
Coagulation factor XIII variants with altered thrombin activation rates

Abstract Coagulation factor XIII (FXIII) is activated by thrombin and catalyses crosslinking between fibrin monomers thereby providing mechanical strength to the fibrin network. V34L is a common FXIII-A polymorphism found in the activation peptide. FXIII-A V34L is activated faster by thrombin and provides formation of a tighter clot at fibrinogen concentrations in the low end of the physiological range. FXIII-A variants with potentially increased activation rates were generated. Introduction of an optimal thrombin cleavage site, V34L+V35T, increased the activation rate 7.6-fold and facilitated the formation of a fibrin network more resistant to fibrinolysis than obtained with wt FXIII-A. In contrast, introduction of fragments of fibrinopeptide A into the activation peptide resulted in severely impaired activation rates.
Fixation of disparity: a steady state error of disparity-induced vergence.

: Fusional vergence eye movements are controlled by a fast-acting mechanism that aligns the eyes in response to retinal image disparity and a slow-acting mechanism that sustains binocular alignment. These two control mechanisms are distinguished by their decay time constants and stimuli. Fast fusional vergence responds to retinal image disparity, and slow fusional vergence responds to the effort or output of the fast control mechanism. Fixation disparity is modeled as a steady-state error of fast fusional vergence. Fixation disparity is shown to be inversely related to prism adaptation, a manifestation of slow fusional vergence, in normal but not abnormal binocular vision. Sensory factors such as interocular suppression influence the magnitude of fixation disparity in strabismus. Clinical implications concerning the relation between fixation disparity and heterophoria in normal and abnormal binocular vision are discussed.
Validation and Clinical Application of Time‐Frequency Analysis of Atrial Fibrillation Electrocardiograms

Introduction: Fibrillatory rates can reliably be obtained from surface ECGs during atrial fibrillation (AF) and correspond with right atrial (RA) and coronary sinus (CS) rates, while both the relation with pulmonary venous (PV) rates and determinants of fibrillatory waveform are unknown. Class III antiarrhythmic drugs prolong atrial refractoriness and decrease its dispersion, effects that may be reflected in ECG parameters. Consequently, this study sought (1) to investigate the relation between ECG fibrillatory rate and waveform characteristics with intraatrial/PV fibrillatory activity and (2) to noninvasively monitor class III antiarrhythmic drug effects in patients with AF.
Response to fludarabine in B-cell chronic lymphocytic leukemia patients previously treated with chlorambucil as up-front therapy and a CHOP-like regimen as second line therapy.

BACKGROUND AND OBJECTIVES Fludarabine (FAMP) is the most active single agent in relapsed and refractory patients with B-cell chronic lymphocytic leukemia (B-CLL). However, it is not clear whether it should be used immediatly after failure of chlorambucil (CLB). We addressed such an issue retrospectively analyzing a series of patients in whom FAMP was used as third-line therapy after a sequential use of CLB and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or CHOP-like regimen, respectively. DESIGN AND METHODS On a retrospective basis, 57 B-CLL patients fulfilling the above mentioned criteria and followed-up in seven different hematologic institutions, were evaluated. RESULTS Of 57 patients who were evaluated for response, 3 (5.2%) achieved a complete response (CR), 30 (52.6%) had a partial response (PR) and the remaining 24 (42.1%) failed to respond to FAMP. Overall median survival from the start of FAMP therapy was 30 months. Survival by tumor response did not show any difference between responders and non-responders (p = 0.536). The survival was significantly shorter in the group of patients with progressive disease than in all other patients included in our study (p = 0.05). Using each patient as his own control (McNemar test) we attempted to evaluate the value of FAMP in inducing a therapeutic response after failure of previous therapies. Among the 37 patients resistant to CLB the response rate was 40.3% with FAMP (p = 0.037) and only 17.5% with CHOP (p = 1.0). Among 35 patients resistant to a CHOP-like regimen, the response rate was 29.8% (p = 0.066) after FAMP therapy. INTERPRETATION AND CONCLUSIONS From our results, it seems that FAMP works better than a CHOP-like regimen in patients resistant to CLB although results do not translate into a survival advantage for responders.
Organization of the dopaminergic innervation of forebrain areas relevant to learning: A combined immunohistochemical/retrograde tracing study in the domestic chick

The mediorostral neostriatum/hyperstriatum ventrale (MNH) and neostriatum dorsocaudale (Ndc) of the domestic chick are crucially involved in auditory filial imprinting, whereas the lobus parolfactorius (LPO) seems to be involved in the emotional modulation of behavior. Because there is evidence that MNH and Ndc are akin to higher association areas in mammals, the present study evaluates the dopaminergic and thalamic input to these areas, as well as to the avian caudate/putamen homologue LPO, by using retrograde pathway tracing, together with dopamine (DA) and tyrosine hydroxylase (TH) immunohistochemistry. By combining DA immunohistochemistry with retrograde fluorescent tracing, we demonstrated that dopaminergic afferents to the MNH and Ndc arise mainly from the area ventralis, whereas the main dopaminergic input to the LPO arises from the substantia nigra. The main thalamic input to the MNH and LPO arises from the dorsal thalamic nuclei, n. dorsomedialis anterior and n. dorsolateralis anterior, whereas the thalamic input to the Ndc arises from the n. dorsolateralis posterior and n. subrotundus. Furthermore, there are reciprocal intratelencephalic connections between distinct parts of the neostriatum caudale and the mediorostral neostriatum. DA‐immunoreactive (ir) fibers are present at moderate densities in the MNH and Ndc and at high densities in the LPO. At the ultrastructural level, DA‐ and TH‐ir axon terminals in the MNH and Ndc form predominantly symmetric synaptic contacts with dendritic shafts, which are often situated in close vicinity to unstained terminals. These results indicate that the general organization of dopaminergic afferents to the chick telecephalon is similar to that of the mesotelencephalic dopaminergic subsystems in mammals such as the mesostriatal and mesolimbocortical DA system. © 1996 Wiley‐Liss, Inc.
Refining the postmenopausal breast cancer treatment paradigm: the FACE trial

It is clear that letrozole and anastrozole provide significant benefits for patients with breast cancer. However, possible differences in efficacy have been suggested by varying degrees of aromatase inhibition and effectiveness in the neoadjuvant and first-line settings. Analyses of aromatase inhibitor-treated patient subgroups within the Arimidex, Tamoxifen, Alone or in Combination trial and Breast International Group 1–98 trial, and the National Cancer Institute of Canada Clinical Trials Group’s MA.17 study, have also suggested some differences in efficacy. The question is how best to maximize these differences to benefit specific patient subgroups, such as postmenopausal women with node-positive disease. Nodal status is one of the strongest prognostic factors for breast cancer recurrence and several studies have shown that patients with node-positive disease are at higher risk for early relapse. It is thought that patients at increased risk for early relapse may be better treated with an aromatase inhibitor upfront, but the guidelines are unclear as to which aromatase inhibitor should be used. To answer this important question quickly, the Femara Anastrozole Clinical Evaluation (FACE) trial is recruiting node-positive patients and randomizing them to receive either early adjuvant letrozole or early adjuvant anastrozole. The trial has been designed to differentiate between the two drugs in the shortest possible time frame by using patients at increased risk of early recurrence of breast cancer, so that the required number of events to initiate analysis will be obtained more quickly. In total, 4000 patients who have recently undergone surgery for node-positive primary breast cancer (and who have no clinical or radiological evidence of recurrent disease or metastasis) are being enrolled around the world. The FACE trial will not only provide an efficacy evaluation between these two aromatase inhibitors but also provide a valuable head-to-head comparison of the safety profiles of adjuvant letrozole and anastrozole. The data will be transferred to an independent academic organization, the Istituto Nazionale Tumori (Michelangelo Foundation, Milan, Italy), which will verify and analyze the data, removing any perception of bias. An Independent Data Monitoring Committee will then decide when and how the trial data are to be released. The results are expected to further refine the treatment paradigm for breast cancer in postmenopausal patients with node-positive disease.
Environmental health practices, constraints and possible interventions in peri-urban settlements in developing countries – a review of Kampala, Uganda

Like most cities in developing countries, Uganda's capital city, Kampala, is experiencing urbanisation leading to an increase in population, and rapid development of peri-urban (informal) settlements. More than 60% of the city's population resides in these settlements which have the lowest basic service levels (sanitation, water supply, solid waste collection, stormwater and greywater disposal). A review of earlier studies on infrastructure development and sustainability within Kampala's peri-urban settlements, field surveys in a typical peri-urban settlement in the city (Bwaise III Parish), and structured interviews with key personnel from the National Water and Sewerage Corporation (NWSC), Kampala City Council (KCC), and the National Environment Management Authority (NEMA) were undertaken. Findings on current environmental health practices as well as perspectives of local communities and interviewed institutions on problems, constraints and possible solutions to basic service provision are presented. The implications of these viewpoints for possible environmental health interventions are presented.
Iron Status Biomarkers and C-Reactive Protein in Children Aged 19 to 72 Months in Chile

Background The Chilean Ministry of Health has combated iron deficiency through the delivery of fortified milk by the National Complementary Feeding Program (NCFP). Objective To assess iron status and associations between biomarkers of iron status and serum C-reactive protein (CRP) in 218 beneficiaries of the NCFP aged 19 to 72 months in Santiago and Valparaiso, Chile. Methods Blood was collected from a cross-sectional representative sample. Iron status (measured by hemoglobin, zinc protoporphyrin, and serum ferritin levels) and inflammation (according to CRP level) were determined. Results Serum CRP level was positively associated with serum ferritin and zinc protoporphyrin levels (r = 0.16 and r = 0.15; p = .0168 and p = .0290, respectively). Serum ferritin was higher among children with high CRP (> 10 mg/dL) than among those with low CRP (≤ 10 mg/dL) (p = .003). After adjustment for 10, 6, and 5 mg/L CRP, the prevalence of low serum ferritin changed from 56.4% without adjustment to 60.6%, 61.5%, and 42.7%, respectively, and the prevalence of high zinc protoporphyrin changed from 22.9% to 21.6%, 17.4%, and 17.9%, respectively. There were no differences between regions in biomarkers of iron status. There was no association between consumption of fortified milk and the prevalence of abnormal serum ferritin (< 15 μg/L) after adjustment for sex, age, and breastfeeding (OR, 1.00; 95% CI, 0.99 to 1.01; p = .288). After adjustment for 10 mg/L CRP, 5.5% were classified as having iron-deficiency anemia, 42.7% as having iron-deficiency erythropoiesis, 17.9% as having depleted iron stores, and 35.8% as having normal iron status. Conclusions CRP level was positively associated with serum ferritin and zinc protoporphyrin levels. Chilean children aged 19 to 72 months from Santiago and Valparaiso who were beneficiaries of the NCFP had a low prevalence of iron-deficiency anemia, a high prevalence of iron-deficiency erythropoiesis, and a moderate prevalence of depleted iron stores.
Post-9/11 cancer incidence in World Trade Center-exposed New York City firefighters as compared to a pooled cohort of firefighters from San Francisco, Chicago and Philadelphia (9/11/2001-2009).

BACKGROUND We previously reported a modest excess of cancer in World Trade Center (WTC)-exposed firefighters versus the general population. This study aimed to separate the potential carcinogenic effects of firefighting and WTC exposure by comparing to a cohort of non-WTC-exposed firefighters. METHODS Relative rates (RRs) for all cancers combined and individual cancer subtypes from 9/11/2001 to 12/31/2009 were modeled using Poisson regression comparing 11,457 WTC-exposed firefighters to 8,220 urban non-WTC-exposed firefighters. RESULTS Compared with non-WTC-exposed firefighters, there was no difference in the RR of all cancers combined for WTC-exposed firefighters (RR = 0.96, 95%CI: 0.83-1.12). Thyroid cancer was significantly elevated (RR = 3.82, 95%CI: 1.07-20.81) from 2001 to 2009; this was attenuated (RR = 3.43, 95%CI: 0.94-18.94) and non-significant when controlling for possible surveillance bias. Prostate cancer was elevated during the latter half (2005-2009; RR = 1.38, 95%CI: 1.01-1.88). CONCLUSIONS Further follow-up is needed to assess the relationship between WTC exposure and cancers with longer latency periods. Am. J. Ind. Med. 59:722-730, 2016. © 2016 Wiley Periodicals, Inc.
A 116 fps/74 mW Heterogeneous 3D-Media Processor for 3-D Display Applications

In this paper, a heterogeneous 3D-media processor is presented, which supports all 3-D display applications by combining a 3-D display IP with a 3-D graphics IP and a stereo video decoder. For mobile environments, adaptive power management scheme is proposed, which saves power consumption up to 186 mW by turning off idle functional blocks based on a target application, a target performance, and the run-time ratio between different IPs. As a result, the minimum power consumption of the processor is only 15 mW, while the overall power consumption is 201 mW. As well as the reduction of power consumption, this work shows impressive performance improvement. The proposed fast modulo operators and adopted division-free algorithm reduces the critical latencies of 3-D display image processing. The proposed fast datapath with parallel architecture increase synthesis rate up to 116 fps which is 17 times faster than a previous work. In addition, reordered operation sequence fixes memory bandwidth regardless of the number of images to be produced. In the 3-D graphics IP and the decoding IP, redundant datapath are merged using an IEEE 754 compliant floating-point vector unit to save both chip area and power consumption, which even reduces the critical latency by 30%.
Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population

Background: Apolipoprotein E (APOE) polymorphisms are unequivocally associated with risk for Alzheimer’s disease (AD). It is crucial to understand how this genetic factor affects dementia risk in the general population, as well as in narrowly diagnosed, selected, patient groups. Methods: We assessed the cross sectional association between APOE genotype and dementia status in a community based sample, the MRC Cognitive Function and Ageing Study (MRC CFAS). In addition, we tested the effects of APOE genotypes on the differences in MMSE scores between the first and third assessment waves (about six years apart), an index of cognitive decline. Results: The APOE ε4 allele conferred increased risk for dementia (OR=1.5, 95% CI=1.1 to 2.2) compared to ε3 in the MRC CFAS sample. Compared with APOE ε3/ε3 subjects, those with the ε3/ε4 genotypes were not at significantly higher risk for dementia (OR=1.1, 95% CI=0.6 to 1.9), although ε4/ε4 subjects were (OR= 3.8, 95% CI=1.0 to 14.0). Risk estimates were not different between men and women. Notably, our risk estimates for dementia were significantly lower than those reported for a diagnosis of Alzheimer’s disease. MMSE scores at wave 3 and the difference in MMSE between baseline and at the third assessment wave were not different across APOE genotypes. Interpretation: The APOE ε4 allele is a weaker predictor for dementia in the general population than for AD. This may be because dementia can be caused by non-AD pathological processes and because most prevalent dementia occurs at an age when the APOE ε4 effect on AD risk (and therefore dementia) has started to decline.
The Key Role of Experiential Uncertainty when Dealing with Risks: Its Relationships with Demand for Regulation and Institutional Trust

The results of a survey and an experiment show that experiential uncertainty—people's experience of uncertainty in risk contexts—plays a moderating role in individuals’ risk‐related demand for government regulation and trust in risk‐managing government institutions. First, descriptions of risks were presented to respondents in a survey (N = 1,017) and their reactions to questions about experiential uncertainty, risk perception, and demand for government regulation were measured, as well as levels of risk‐specific knowledge. When experiential uncertainty was high, risk perceptions had a positive relationship with demand for government regulation of risk; no such relationship showed under low experiential uncertainty. Conversely, when people experience little experiential uncertainty, having more knowledge about the risk topic involved was associated with a weaker demand for government regulation of risk. For people experiencing uncertainty, this relationship between knowledge and demand for regulation did not emerge. Second, in an experiment (N = 120), experiential uncertainty and openness in risk communication were manipulated to investigate effects on trust. In the uncertainty condition, the results showed that open versus nonopen government communication about Q‐fever—a zoonosis—led to higher levels of trust in the government agency, but not in in the control condition. Altogether, this research suggests that only when people experience relatively little uncertainty about the risk, knowledge provision may preclude them from demanding government action. Also, only when persons experience uncertainty are stronger risk perceptions associated with a demand for government regulation, and they are affected by openness of risk communication in forming institutional trust.
Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions

A new langerin+ DC subset has recently been identified in murine dermis (langerin+ dDC), but the lineage and functional relationships between these cells and langerin+ epidermal Langerhans cells (LC) are incompletely characterized. Selective expression of the cell adhesion molecule EpCAM by LC allowed viable LC to be easily distinguished from langerin+ dDC in skin and lymphoid tissue and ex vivo as well. Differential expression of EpCAM and langerin revealed the presence of at least 3 distinct skin DC subsets. We determined that LC and langerin+ dDC exhibit different migratory capabilities in vitro and repopulate distinct anatomic compartments in skin at different rates after conditional depletion in vivo. Langerin+ dDC, in contrast to LC, did not require TGFβ1 for development. Carefully timed gene gun immunization studies designed to take advantage of the distinct repopulation kinetics of langerin+ dDC and LC revealed that langerin+ dDC were required for optimal production of β-galactosidase-specific IgG2a/c and IgG2b in the acute phase. In contrast, immunization via LC-deficient skin resulted in persistent and strikingly reduced IgG1 and enhanced IgG2a Ab production. Our data support the concepts that LC and langerin+ dDC represent distinct DC subsets that have specialized functions and that LC are important immunoregulatory cells. The presence of at least 3 functionally distinct skin DC subsets may have particular relevance for vaccines that are administered epicutaneously.
CEO Dismissal in Venture Capital-Backed Firms: Further Evidence from an Agency Perspective

This study uses agency theory to examine CEO dismissal in venture capital-backed firms. Prior applications of agency theory have focused on reducing managerial opportunism by aligning the interests of manager with owner. Unlike large, mature firms, venture capital-backed companies feature high levels of CEO stock ownership. In this environment, we find that the primary reason for CEO dismissal is lack of agent ability, followed by good faith disagreements between principal and agent, with managerial opportunism ranking last. Further, we find that CEOs dismissed for opportunism owned more stock than those dismissed for other reasons.