Miracle-dz/UniFAR-FTUs huggingface dataset:
Gene therapy of severe combined immunodeficiencies

Primary immunodeficiency diseases (PID) are attractive candi dates for a gene therapy approach because many of these disorders convey a poor prognosis while a number of the genes mutated in these conditions have been identified. Gene transfer into hematopoietic stem cells (HSC) should, in theory, lead to a cure of the disease. There are, however, a number of limitations mostly related to the failure of clinically available vectors to enable transgene integration into HSC. Nevertheless PID due to a gene defect leading to failure of cell development could be amenable to gene therapy given the selective advantage conferred to transgene expression in progenitor cells. Terminally differentiated cells are, however, long lived, as is the case for T lymphocytes. This concept led to the first gene therapy trials for adenosine deaminase (ADA) deficiency several years ago. Results were in part disappointing mostly because of the concomitant substitutive treatment by polyethylene glycol-ADA. However, recent application to X-linked severe combined immunodeficiency (gamma(c) deficiency) turned out to be efficient at least on a relatively short term basis (i.e. one year so far). These results demonstrate that this concept is valid and can be the basis for the treatment of other forms of severe T-cell immunodeficiencies. Obviously, development of vectors (lentiviruses) able to efficiently target HSC could in the future considerably enlarge the field of PID treatable by gene transfer.
Comparison of Biomechanical Properties of Alloderm and Enduragen as Static Facial Sling Biomaterials

Background: Static slings are one of the most commonly used surgical rehabilitation methods in the management of chronic facial paralysis. Acellular human cadaveric dermis (Alloderm; Life Cell Corp., Branchburg, NJ) is used for this purpose; however, it has variable stretching properties that may necessitate additional “tuning‐up” procedure(s). Acellular porcine dermis (Enduragen; Tissue Sciences Laboratories, plc., Aldershot, U.K.) was recently introduced as a biologic implant and it is compositionally similar to Alloderm. However, no data currently exist regarding its biomechanical properties and potential use as an alternative implant to Alloderm in static facial sling procedures.
Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period.

OBJECTIVE To determine time trends in the epidemiology of rheumatoid arthritis (RA) in a population-based cohort. METHODS An inception cohort of residents of Rochester, Minnesota > or = 18 years of age who first fulfilled the American College of Rheumatology 1987 criteria between January 1, 1955 and December 31, 1994 (applied retrospectively, as appropriate) was assembled and followed up until January 1, 2000. Incidence rates were estimated and were age- and sex-adjusted to the 1990 white population of the US. A birth cohort analysis was performed, and survival rates over time were examined. RESULTS The incidence cohort comprised 609 patients, 445 (73.1%) of whom were female and 164 (26.9%) were male, with a mean age at incidence of 58.0 years. The overall age- and sex-adjusted annual incidence of RA among Rochester, Minnesota, residents > or = 18 years of age was 44.6/100,000 population (95% confidence interval 41.0-48.2). While the incidence rate fell progressively over the 4 decades of study, from 61.2/100,000 in 1955-1964, to 32.7/100,000 in 1985-1994, there were indications of cyclical trends over time. Birth cohort analysis showed diminishing incidence rates through successive cohorts following a peak in the 1880-1890 cohorts. Incidence rates increased with age until age 85, but peaked earlier in women than in men. The survival rate in RA patients was significantly lower than the expected rate in the general population (P < 0.001), and no improvement was noted over time. CONCLUSION The secular trends demonstrated in this study population, including the progressive decline in the incidence of RA over the last 40 years, suggest that an environmental factor may play a role in the etiology of RA.
Remodeling of Vertebral Bone After Outer Anular Injury in Sheep

Study Design This study uses semiautomated histoquantitative techniques to analyze subchondral bone architecture in adult merino sheep up to 2 years after outer anular cuts were created in lumbar discs. Objectives To describe morphometric changes to the adjacent vertebral bone structure in the lumbar spine, and to discuss these in relation to the pathology of other spinal components. Summary of Background Data Disc degeneration has been observed in the sheep lumbar spine 4–6 months after surgery to the outer anulus, whereas biomechanical testing has shown earlier changes. Methods Lumbar discs with adjacent subchondral trabecular bone were sectioned using standard histologic methods. An image‐analyzing computer was used to measure morphometric indices of bone structure. Results Trabecular bone volume was elevated significantly by 2 months because of consolidation of existing trabeculae and formation of new elements. The changes were evident 2 years after surgery. Conclusion Subchondral trabecular bone appears to be sensitive to changes in the disc after outer anular injury. There is evidence that these structural changes are influenced by changes in the biomechanical behavior of the incised disc.
Novel treatment concepts in Hodgkin lymphoma

Treatment of classical Hodgkin's lymphoma (HL) has been a success story, with cure of localized disease with radiotherapy in the 1930s, cure of advanced stages with combination chemotherapy with/without radiotherapy in the mid‐1960s and continuous improvements since then. Nonetheless, at present approximately 2% of patients with classical HL are primarily refractory to conventional therapy with only 50% becoming long‐term survivors. Another 13% of patients relapse, with only 60% being alive 10 years postrecurrence (as exemplified in this review in a Swedish cohort of 18‐ to 65‐year‐old patients diagnosed during the period 1992–2009). Recently, novel targeted drugs were approved for refractory/relapsed HL and here we review results of trials that form the basis for these approvals as well as new trials. In summary, brentuximab vedotin can be used in refractory patients (i) as a complement to high‐dose chemotherapy with autologous stem cell transplantation (SCT) improving the chances of being able to proceed to an allogenic SCT and cure, (ii) as consolidation after autologous SCT and (iii) as palliative life‐prolonging treatment. However, we have yet to determine whether this drug provides the greatest benefit in first‐ or second‐line treatment, as consolidation or in refractory disease or relapse. Trials of immune checkpoint inhibitors, such as those targeting programmed death 1 (nivolumab and pembrolizumab), and thus not primarily the tumour cells, have shown overall response rates of >65%. Long‐term results and data from Phase III trials are still lacking, but nivolumab recently gained approval in refractory patients already treated with brentuximab vedotin and autologous SCT. Other novel treatments of interest include T cells with a chimeric antigen receptor and combination therapies with histone deacetylase inhibitors.
Frequency- and amplitude-transitioned waveforms mitigate the onset response in high-frequency nerve block

High-frequency alternating currents (HFAC) have proven to be a reversible and rapid method of blocking peripheral nerve conduction, holding promise for treatment of disorders associated with undesirable neuronal activity. The delivery of HFAC is characterized by a transient period of neural firing at its inception, termed the ‘onset response’. The onset response is minimized for higher frequencies and higher amplitudes, but requires larger currents. However, the complete block can be maintained at lower frequencies and amplitudes, using lower currents. In this in vivo study on whole mammalian peripheral nerves, we demonstrate a method to minimize the onset response by initiating the block using a stimulation paradigm with a high frequency and large amplitude, and then transitioning to a low-frequency and low-amplitude waveform, reducing the currents required to maintain the conduction block. In five of six animals, it was possible to transition from a 30 kHz to a 10 kHz waveform without inducing any transient neural firing. The minimum transition time was 0.03 s. Transition activity was minimized or eliminated with longer transition times. The results of this study show that this method is feasible for achieving a nerve block with minimal onset responses and current amplitude requirements.
The effect of CEO tenure and specialization on timely audit reports of Iranian listed companies

Purpose The purpose of this paper is to examine whether the characteristics of a CEO, that is, tenure and financial expertise, could affect the timeliness of an audit report. Design/methodology/approach Research data gathered from listed companies on the Tehran Stock Exchange during the four-year period 2013-2016. Findings The results obtained from model fittings indicated that there is only a negative and significant relationship between CEO financial expertise and natural logarithm of audit report lag and no significant relationship observed between the former and two other indices of timely audit report. Moreover, no significant relationship was found between the CEO tenure and other three indices of timely audit report. Originality/value This paper is the first study, which developed the literature of timely audit report using CEO tenure effect and financial expertise tests for timely audit reports in Iran.
Exploring the Living Heritage of Galle Fort: Residents’ Views on Heritage Values and Cultural Significance

The Galle Fort of Sri Lanka was inscribed as a World Heritage Site in 1988 by UNESCO on the basis of criterion (iv) of the outstanding universal value (OUV), which places clear emphasis on the physical exceptionality of the site. Its living, intangible heritage is only given partial recognition in the definition of cultural and universal significance of the place. At present, the living heritage of Galle Fort is a forgotten and neglected entity. Emerging theories on heritage discourse recognize that the OUV of living heritage sites are in a state of evolution and transformation and is not a, fixed notion that remains unchanged in time and place. This aspect requires frequent exploration in order to determine necessary improvements to be made to conservation and management strategies. The article focuses on heritage values attached to Galle Fort by its living community. In-depth interviews with a cross section of the community disclosed that the residents of Galle Fort lay greater emphasis on the social value of the place. They have pronounced concerns on the risks posed to the social value by commercial and tourism gentrification taking place. The study raises awareness of the importance of the residents’ values in informing, guiding, managing and conserving the cultural significance and OUV of Galle Fort for posterity.
Effects of the administration of ketoprofen at parturition on the milk yield and fertility of Holstein-Friesian cattle

A total of 220 cows and heifers were treated with 3 mg/kg ketoprofen immediately after calving and 24 hours later, and 227 were left untreated as controls. The treated animals tended to have a lower incidence of retained fetal membranes and were 1˙7 times less likely to develop the condition than the untreated animals. The treatment did not affect the incidence of milk fever, the endometritis score or the presence of a corpus luteum by 20 to 25 days after calving, and did not affect the cows' early lactation milk yield. There was no particular level of dystocia or periparturient conditions other than retained fetal membranes for which there might be a reproductive or productive advantage following the use of ketoprofen. The intervals from calving to first insemination or to pregnancy, the numbers of inseminations per pregnancy and the pregnancy rate to first insemination were also unaffected by ketoprofen treatment.
The role of sensory organs and the forebrain for the development of the craniofacial shape as revealed by Foxg1‐cre‐mediated microRNA loss

Cranial development is critically influenced by the relative growth of distinct elements. Previous studies have shown that the transcription factor Foxg1 is essential the for development of the telencephalon, olfactory epithelium, parts of the eye and the ear. Here we investigate the effects of a Foxg1‐cre‐mediated conditional deletion of Dicer1 and microRNA (miRNA) depletion on mouse embryos. We report the rapid and complete loss of the telencephalon and cerebellum as well as the severe reduction in the ears and loss of the anterior half of the eyes. These losses result in unexpectedly limited malformations of anterodorsal aspects of the skull. We investigated the progressive disappearance of these initially developing structures and found a specific miRNA of nervous tissue, miR‐124, to disappear before reduction in growth of the specific neurosensory areas. Correlated with the absence of miR‐124, these areas showed numerous apoptotic cells that stained positive for anticleaved caspase 3 and the phosphatidylserine stain PSVue® before the near or complete loss of those brain and sensory areas (forebrain, cerebellum, anterior retina, and ear). We conclude that Foxg1‐cre‐mediated conditional deletion of Dicer1 leads to the absence of functional miRNA followed by complete or nearly complete loss of neurons. Embryonic neurosensory development therefore depends critically on miRNA. Our data further suggest that loss of a given neuronal compartment can be triggered using early deletion of Dicer1 and thus provides a novel means to genetically remove specific neurosensory areas to investigate loss of their function on morphology (this study) or signal processing within the brain. genesis 49:326–341, 2011. © 2011 Wiley‐Liss, Inc.
Prevention and treatment of traveler's diarrhea.

More than 300 million people cross international boundaries each year1. Diarrhea is by far the most common medical problem among people traveling to the tropical and semitropical areas of Latin America; parts of the Caribbean, such as Haiti and the Dominican Republic; southern Asia; and North, East, and West Africa2. It affects 20 to 50 percent of such travelers3. The threat of diarrhea and the illness itself represent great economic costs to the traveling public and the host country. The loss of income from tourism and the failure of business ventures caused by the threat of illness .
Respiratory Syncytial Virus Can Tolerate an Intergenic Sequence of at Least 160 Nucleotides with Little Effect on Transcription or Replication In Vitro and In Vivo

ABSTRACT The intergenic sequences (IGS) between the first nine genes of human respiratory syncytial virus (RSV) vary in length from 1 to 56 nucleotides and lack apparent conserved sequence motifs. To investigate their influence on sequential transcription and viral growth, recombinant RSV strain A2, from which the SH gene had been deleted to facilitate manipulation, was further modified to contain an M-G IGS of 16, 30, 44, 58, 65, 72, 86, 100, 120, 140, or 160 nucleotides. All of the viruses were viable. For viruses with an M-G IGS of 100 nucleotides or more, plaque size decreased with increasing IGS length. In this same length range, increasing IGS length was associated with modest attenuation during single-step, but not multistep, growth in HEp-2 cells. Surprisingly, Northern blot analysis of the accumulation of six different mRNAs indicated that there was little or no change in transcription with increasing IGS length. Thus, the RSV polymerase apparently can readily cross IGS of various lengths, including unnaturally long ones, with little or no effect on the efficiency of termination and reinitiation. This finding supports the view that the IGS do not have much effect on sequential transcription and provides evidence from infectious virus that IGS length is not an important regulatory feature. To evaluate replication in vivo, BALB/c mice were infected intranasally with RSV containing an M-G IGS of 65, 140, or 160 nucleotides. Replication of the latter two viruses was decreased up to 5- and 25-fold in the upper and lower respiratory tracts, respectively, on day 3 following infection. However, the level of replication at both sites on days 4 and 5 was very similar to that of the virus with an IGS of 65 nucleotides. Thus, the modest attenuation in vivo associated with the longer IGS was additive to that conferred by deletion of the SH gene and might be useful to incrementally increase the level of attenuation of a live-attenuated vaccine virus.
Health status and preventative behaviors of immigrants by gender and origin: a Portuguese cross-sectional study.

Migration has been associated with a greater vulnerability in health. Migrants, especially women, go through several experiences during the migration process and in the host countries that ultimately put their health at risk. This study examines self-reported health status and preventive behaviors among female and male immigrants in Portugal, and identifies sociodemographic and behavioral factors underlying gender differences. A sample of 1375 immigrants (51.1% women) was studied. Data were analyzed through logistic regression. Good health status was reported by 66.7% of men and by 56.6% of women (P < 0.001). Gender differences were also found across preventative behaviors. Among women and men, reported good health was associated with younger age, African and Brazilian origin (compared to Eastern European), secondary/higher education, no chronic disease, and concern about eating habits. Among women, good health was also associated with perceived sufficient income, no experience of mental illness, and regular physical exercise. When developing health programs to improve immigrants' health, special attention must be given to existing gender inequalities, and socioeconomic and cultural context, in accordance with their experience of living in the host country over time.
Trauma caused by falling objects at construction sites

BACKGROUND Workplace-related injuries carry a significant health care challenge. The state of Qatar is developing rapidly, with much construction and an expanding industrial work force. This study aimed to assess the incidence and social impact of work-related injuries requiring hospitalization caused by falling objects at the construction sites. METHODS We performed a prospective study for all admissions, which resulted from falling objects between January 2008 and June 2010 at the only trauma center in the state of Qatar. Data were analyzed, and outcomes were described (mortality, length of hospital stay, and safety measures). RESULTS Of the total injured patients (N = 4,302) admitted between January 2008 and June 2010, 185 (4%) had injuries caused purely by falling objects. Patients’ mean age was 29 years, and 97% of the patients were men. All injuries occurred at construction sites. Most patients (86%) were brought by ambulance, and the reminder was brought by private vehicles. After initial evaluation and resuscitation, 120 patients (65%) were found to have a single-system injury, and 65 (35%) had multisystem injury. Operative interventions were required in 50% of the patients. Mean length of hospital stay varied from 6.5 days for single-system injuries to 19 days for multisystem injuries. Safety devices were used in 32 patients (17.3%). All of the 16 mortality cases (8.6%) were reported in multiple injuries. CONCLUSION Traumatic injury caused by falling object represents a significant problem in a rapidly developing country. Many of these injuries could be prevented by following established safety guidelines. LEVEL OF EVIDENCE Epidemiologic study, level III.
The Collusive Effect of Multimarket Contact on Prices: Evidence from Retail Lumber Markets

In this paper, we investigate whether multimarket contact leads to collusive pricing in the retail lumber market and assess the effect of potential regulation on consumer welfare. In particular, we focus on the competition between Home Depot and Lowe's since they are the main players in retail lumber market. For our analysis, we assemble an original data set of prices and sales in the pressure treated lumber category. We first provide reduced form evidence for the effect of multimarket contact on collusion in pricing strategies by showing a positive and significant correlation between price and multimarket contact. Guided by this evidence we estimate a model, using the Berry, Levinsohn and Pakes (1995) equilibrium framework, that includes both the demand and supply side with conduct parameters which capture the degree of collusion in setting prices. We specify the conduct parameters as a function of multimarket contact, following the framework developed by Sudhir (2001) and Ciliberto and Williams (2014). We find that the conduct parameter for capturing the effect of multimarket contact on collusion is significant and positive, implying that multimarket contact leads to higher prices than those from a competitive Bertrand-Nash equilibrium. Using the model estimates, we conduct a counterfactual analysis to measure the consumer welfare impact due to collusive pricing. We find that consumer surplus in January, 2016 increases by $57.7k and this amounts to $692.4k in a year. To the best of our knowledge, this is the first paper that shows state-level multimarket contact facilitates collusive pricing with implications for consumer welfare. The finding has important policy implications that might suggest the need for monitoring prices in states where retail firms have a greater degree of multimarket contact.
Embryogenesis of the phrenic nerve and diaphragm in the fetal rat

The embryogenesis of the mammalian phrenic nerve and diaphragm continues to be poorly understood. The purpose of this study was to reexamine this general issue and resolve some long‐standing controversies. Specifically, we examined 1) the migratory path and the initial target for phrenic axons; 2) the relationship between the phrenic nerve and the primordial diaphragm during descent from the cervical to the thoracic spinal cord levels; and 3) the nature of the interaction between the progression of phrenic nerve intramuscular branching, myoblast and/or myogenic cell migration, and diaphragmatic myotube formation. We demonstrate that a leading group of “pioneering” phrenic axons migrate along a well‐defined track of neural cell adhesion molecule (NCAM)‐expressing and low‐affinity nerve growth factor (p75) receptor‐expressing cells to reach the primordial diaphragm, the pleuroperitoneal fold, at embryonic day (E) 13. During the next day of development, the phrenic nerve and the primordial diaphragm descend together toward the level of the thoracic spinal cord. By E14.5, intramuscular branching has commenced. There is a tight spatiotemporal correlation between the outgrowth of intramuscular phrenic nerve branches, the distribution of myoblasts and/or myogenic cells, and the formation of myotubes within the developing diaphragm, implicating intimate mutual regulation. J. Comp. Neurol. 382:459‐468, 1997. © 1997 Wiley‐Liss Inc.