Miracle-dz/UniFAR-FTUs huggingface dataset:
Predictors of Corneal Perforation or Need for Therapeutic Keratoplasty in Severe Fungal Keratitis: A Secondary Analysis of the Mycotic Ulcer Treatment Trial II

Importance Identifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings. Objective To determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK). Design, Setting, and Participants This is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added. Main Outcomes and Measures The primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK. Results The mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis. Conclusions and Relevance These results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK. Trial Registration clinicaltrials.gov Identifier: NCT00996736
The Associations of SEA-α Thalassemia 1, XmnI-Gγ Polymorphism and β-Globin Gene Mutations with the Clinical Severity of β-thalassemia Syndrome in Northern Thailand

Background : At least three genetic factors including β-thalassemia mutations, α-thalassemia, and XmnI-Gγ polymorphism were shown to modify clinical symptoms in β-thalassemia disease. Objective : To determine associations of β-thalassemia mutations, SEA-α thalassemia 1, and XmnI-Gγ polymorphism, and clinical severity of β-thalassemia in northern Thailand. Material and Method : Thirty-two β-thalassemia major and 28 β-thalassemia intermedia attending the Thalassemia Clinic at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand were recruited. The β-globin gene mutations and SEA-α thalassemia 1 were determined by MS-PCR and Gap-PCR, respectively. The XmnI-Gγ polymorphism was identified by RFLP analysis. Odds ratio was calculated to evaluate the associations of these three genetic factors and clinical symptoms. Results : Eight β-globin gene mutations (both βO and β+) were found. Twenty-nine point one percent of the patients had at least one XmnI-Gγ site (XmnI-Gγ: +) and 4.1% of the patients were heterozygote for the SEA-α thalassemia 1. The β-globin gene mutations showed maximal impact and the XmnI-Gγ polymorphism had minimal influence on clinical severity in this cohort. The SEA-α thalassemia 1 had the least effect on the clinical severity due to its low prevalence in these patients. Conclusion : Although these three genetic factors play roles in modifying clinical symptoms of β-thalassemia, the β-thalassemia mutations should be considered first, followed respectively by the XmnI-Gγ polymorphism and the SEA-α thalassemia 1, in management and prenatal diagnosis of β-thalassemia in northern Thailand. Keywords : β-thalassemia, HbE/β-thalassemia, β-thalassemia mutations, SEA-α thalassemia 1, XmnI-Gγ polymorphism, HbE
Dynamics of the antibody response to Plasmodium falciparum infection in African children.

BACKGROUND Acquired immune responses to malaria have widely been perceived to be short-lived, with previously immune individuals losing immunity when they move from malaria-endemic areas. However long-lived Plasmodium falciparum-specific antibody responses lasting for an individual's lifetime are frequently observed. METHODS We fit mathematical models of the dynamics of antibody titers to P. falciparum antigens from longitudinal cohort studies of African children to estimate the half-lives of circulating immunoglobulin G (IgG) antibodies and IgG antibody-secreting cells (ASCs). RESULTS Comparison of antibody responses in the younger Ghanaian cohort and the older Gambian cohort suggests that young children are less able to generate the long-lived ASCs necessary to maintain the circulating antibodies that may provide protection against reinfection. Antibody responses in African children can be described by a model 15 including both short-lived ASCs (half-life range, 2-10 days), which are responsible for boosting antibody titers following infection, and long-lived ASCs (half-life range, 3-9 years), which are responsible for maintaining sustained humoral responses. CONCLUSIONS The rapid decay of antibodies following exposure to malaria and the maintenance of sustained antibody responses can be explained in terms of populations of short-lived and long-lived ASCs.
Use of adjuvant intralesional bevacizumab for aggressive respiratory papillomatosis in children.

IMPORTANCE Juvenile recurrent respiratory papillomatosis (RRP) can be an aggressive disease process necessitating frequent trips to the operating room with multiple anesthetics for tumor debulking and airway preservation. Adjuvant therapy, such as that which is reported in this article, may help reduce the number of operative procedures affected children need each year and therefore may also affect their overall quality of life (QOL). OBJECTIVE To describe our experience with intralesional bevacizumab (Avastin) treatment for children with severe RRP by comparing median number of surgical procedures per year, median duration of time between procedures, Derkay staging, and voice QOL before and after bevacizumab treatment. DESIGN Prospective, consecutive case series. SETTING Tertiary care aerodigestive center. PARTICIPANTS Ten children, aged 18 months to 18 years, with severe RRP necessitating more than 4 operative interventions in 1 year whose parents (or legal guardians) consented to intralesional bevacizumab treatment. INTERVENTIONS Intralesional bevacizumab administered at concentration of 2.5 mg/mL for 3 consecutive injections (with 532-nm pulsed KTP [potassium titanyl phosphate] laser when necessary) at intervals of 2 to 3 weeks. MAIN OUTCOME MEASURES Time between surgical procedures, number of procedures per year, Derkay staging, total Pediatric Voice-Related Quality of Life (PVRQOL) score, Emotional PVRQOL score, and Physical PVRQOL score defined by comparing the year leading up to first of 3 bevacizumab injections with the year following the third bevacizumab injection. RESULTS The median duration of time between surgical procedures increased by 5.9 weeks after bevacizumab (P = .002). The median number of procedures per year decreased by 4 (P = .002). Derkay staging decreased by 6 (P = .03). The median total PVRQOL score increased by 25.5 (P = .02), the median Emotional PVRQOL score increased by 11.3 (P = .047), and the median Physical PVRQOL score increased by 14.3 (P = .047). CONCLUSIONS AND RELEVANCE Intralesional bevacizumab treatment may increase duration of time between surgical procedures and decrease number of procedures per year, while improving voice QOL.
Interleukin 10 (IL-10)-producing CD1dhi regulatory B cells from Schistosoma haematobium-infected individuals induce IL-10-positive T cells and suppress effector T-cell cytokines.

BACKGROUND Chronic schistosome infections are associated with T-cell hyporesponsiveness and a strong regulatory network. Murine studies have shown that schistosome infections can induce regulatory CD1d(hi) B cells, which inhibit inflammatory responses. Here, we evaluated the influence of regulatory B cells (Bregs) on T-cell cytokines in vitro in human schistosomiasis. METHODS Gabonese young adults were recruited from areas where Schistosoma haematobium (S.h) infections were high or low endemic. The study participants were categorized as infected or uninfected from an high endemic area or uninfected from a low endemic (nonendemic) area. Their B cells were studied for Breg subset markers and cocultured with allogenic anti-CD3-stimulated CD4(+) T cells, followed by T-cell cytokine analysis. RESULTS A greater percentage of B cells from S. haematobium-infected donors expressed cytoplasmic interleukin 10 (IL-10) and membrane-bound latency-associated peptide/transforming growth factor β1, compared with uninfected donors. T cells produced less interferon γ, interleukin 4, and interleukin 17 upon coculture with B cells from schistosome-infected individuals only, while the conversion to CD25(hi)FoxP3(+) and the percentage of IL-10(+) T cells was enhanced. Interestingly, depletion of the prominent IL-10-producing B-cell subset, CD1d(hi) cells, resulted in less IL-10(+) T cells in the S. haematobium-infected group, while levels of FoxP3(+) regulatory T cells remained unaffected. CONCLUSIONS Schistosomes can induce functional Bregs in humans that may be instrumental in general T-cell hyporesponsiveness and may contribute to the increased regulatory milieu found in schistosomiasis.
The effects of smoking and hypoxia on skeletal muscle structure and function

Chronic obstructive pulmonary disease (COPD) is increasingly common and in 80% of the patients it is caused by cigarette smoking, often over several decades. Exercise intolerance is a major problem in COPD and there is accumulating evidence that this is not solely due to reduced lung function but that it also involves skeletal muscle. It is not known if changes in skeletal muscle tissue occur before clinical symptoms of COPD are apparent. Therefore the main aim of the work described in this thesis was to gain insight into the extent to which cigarette smoking and hypoxaemia affect the functional and morphological changes of skeletal muscle. Percutaneous electrical stimulation of the quadriceps muscle (2 minutes 30 Hz with duty cycle of 0.5; 1 s on, 1 s off) was used to assess fatigue characteristics to avoid possible problems of differences in voluntary activation. In non-smoking participants, women were generally more fatigue-resistant than men. Young men with a relatively short smoking history were more susceptible to fatigue than non-smoking, ageand physical activity-matched peers. In a larger cohort of smokers spanning a wide range of age and smoking history, it appeared that this lower fatigue resistance was not related to smoking history. The similar contractile speed in smokers and non-smokers suggests that factors other than differences in muscle fibre composition underlie the reduced fatigue resistance in smokers. The reduced fatigue resistance might be more related to a possible acute, and possibly reversible, impairment of smoking on the oxygen supply or the ability to use oxygen for aerobic energy generation by the muscle. Subsequently, the effects of chronic hypoxia on determinants of oxygen supply and oxidative capacity were studied. Adaptations within the rat plantaris muscle to chronic hypoxia were regionrather than fibre type-specific. Hypoxia resulted in atrophy in all regions of the muscle. However, capillary proliferation only occurred in the deep, oxidative region, and mitochondrial biogenesis was restricted to the superficial, glycolytic region. Model calculations indicate that these adaptations to hypoxia prevent the occurrence of anoxic areas in the deep region, but that in superficial regions tissue oxygenation becomes more problematical during hypoxia. These results are discussed in relation to their possible relevance in understanding muscle function in COPD patients.
Regulatory variation in HIV-1 dependency factor ZNRD1 associates with host resistance to HIV-1 acquisition.

BACKGROUND ZNRD1 was identified as a host protein required for the completion of the human immunodeficiency virus (HIV) lifecycle in a genome-wide screen using small interfering RNA gene silencing. Subsequently, a genome-wide association study (GWAS) of host determinants for HIV-1 disease identified an association of single nucleotide polymorphisms (SNPs) in the ZNRD1 region with CD4(+) T-cell depletion. METHODS We investigated the effects of SNPs in the ZNRD1 region on human immunodeficiency virus type 1 (HIV-1) infection and progression to clinical outcomes in 5 US-based HIV-1 longitudinal cohorts consisting of men who have sex with men, males with hemophilia, and injection drug users (IDUs) (n = 1865). SNP function was evaluated by electrophoretic mobility shift assay and promoter luciferase assay. RESULTS A haplotype in the ZNRD1 gene showed significant association with a 35% decreased risk of HIV-1 acquisition (OR = 0.65, 95% CI, .47-.89), independent of HLA-C rs9264942, in European Americans. The SNP rs3132130 tagging this haplotype, located in the ZNRD1 5' upstream region, caused a loss of nuclear factor binding and decrease in ZNRD1 promoter activity. ZNRD1 variants also affected HIV-1 disease progression in European- and African-American cohorts. CONCLUSIONS This study provides novel evidence that ZNRD1 polymorphism may confer host resistance to HIV-1 acquisition.
An ahemolytic pneumolysin of Streptococcus pneumoniae manipulates human innate and CD4⁺ T-cell responses and reduces resistance to colonization in mice in a serotype-independent manner.

BACKGROUND Some Streptococcus pneumoniae serotypes express an ahemolytic pneumolysin (PLYa). Serotypes that commonly express PLYa, including serotype 8 (ST8) and ST1, are often associated with a low prevalence during colonization but a higher propensity to cause invasive disease. We sought to study the host response to ST8 PLYa in a homologous and heterologous capsular background. METHODS We genetically exchanged the PLYa of ST8 strain 6308 with the hemolytic PLY (PLYh) of ST3 A66.1 and vice versa and determined the impact of the exchange on nasopharyngeal colonization in mice. Then, to compare the response of human cells to PLYa-expressing and PLYh-expressing strains, we infected human peripheral blood mononuclear cells (PBMCs) with PLY-switched strains and assessed dendritic cell and CD4(+) T-cell responses by intracellular cytokine staining. RESULT Mice colonized with PLYa-expressing strains had significantly higher colonization densities than those colonized with PLYh-expressing strains, irrespective of capsular background. Compared with infection of PBMCs with PLYh-expressing strains, infection with PLYa-expressing strains induced diminished innate (dendritic cell cytokines, costimulatory receptor, and apoptotic) and adaptive (CD4(+) T-cell proliferative and memory interleukin 17A) responses. CONCLUSION Our findings demonstrate that PLYa has the potential to manipulate host immunity irrespective of capsule type. PLY exchange between STs expressing PLYa and PLYh could lead to unexpected colonization or invasion phenotypes.
Glutaryl‐coenzyme A dehydrogenase from Geobacter metallireducens – interaction with electron transferring flavoprotein and kinetic basis of unidirectional catalysis

Glutaryl‐CoA dehydrogenases (GDHs) are FAD containing acyl‐CoA dehydrogenases that usually catalyze the dehydrogenation and decarboxylation of glutaryl‐CoA to crotonyl‐CoA with an electron transferring flavoprotein (ETF) acting as natural electron acceptor. In anaerobic bacteria, GDHs play an important role in the benzoyl‐CoA degradation pathway of monocyclic aromatic compounds. In the present study, we identified, purified and characterized the benzoate‐induced BamOP as the electron accepting ETF of GDH (BamM) from the Fe(III)‐respiring Geobacter metallireducens. The BamOP heterodimer contained FAD and AMP as cofactors. In the absence of an artificial electron acceptor, at pH values above 8, the BamMOP‐components catalyzed the expected glutaryl‐CoA oxidation to crotonyl‐CoA and CO2; however, at pH values below 7, the redox‐neutral glutaryl‐CoA conversion to butyryl‐CoA and CO2 became the dominant reaction. This previously unknown, strictly ETF‐dependent coupled glutaryl‐CoA oxidation/crotonyl‐CoA reduction activity was facilitated by an unexpected two‐electron transfer between FAD(BamM) and FAD(BamOP), as well as by the similar redox potentials of the two FAD cofactors in the substrate‐bound state. The strict order of electron/proton transfer and C‐C‐cleavage events including transient charge‐transfer complexes did not allow an energetic coupling of electron transfer and decarboxylation. This explains why it was difficult to release the glutaconyl‐CoA intermediate from reduced GDH. Moreover, it provides a kinetic rational for the apparent inability of BamM to catalyze the reverse reductive crotonyl‐CoA carboxylation, even under thermodynamically favourable conditions. For this reason reductive crotonyl‐CoA carboxylation, a key reaction in C2‐assimilation via the ethylmalonyl‐CoA pathway, is accomplished by a different crotonyl‐CoA carboxylase/reductase via a covalent NADPH/ene‐adduct.
Sirtuin‐dependent epigenetic regulation in the maintenance of genome integrity

Sirtuins are a family of deacetylases that target histone and non‐histone proteins and require NAD+ as an enzymatic cofactor for their enzymatic activity. This requirement confers sirtuins with the ability to detect changes in metabolism and energy homeostasis and to coordinate cellular responses to maintain genome integrity. Thus, sirtuins are crucial in the crosstalk between environment and genome, and therefore in responses to stress at the cell and organism levels. Sirtuins play a major role in maintaining genome integrity, largely through regulation of epigenetic mechanisms. They target different histone marks, including H4K16Ac, H3K9Ac, H3K56Ac and H3K18Ac, and non‐histone components of the chromatin machinery, such as enzymes and structural proteins. Here we summarize our current view on the link between sirtuins and epigenetics, one that reflects the continual adaptation of the genome to stress.
Prevalence and impact of bilateral vestibular hypofunction: results from the 2008 US National Health Interview Survey.

IMPORTANCE Profound bilateral vestibular hypofunction (BVH) causes disabling oscillopsia, chronic disequilibrium, and postural instability, but little is known about its epidemiology and impact. OBJECTIVE To assess prevalence and functional impact of BVH in the US adult population. DESIGN AND SETTING National cross-sectional survey using a national database and corollary validation study. PATIENTS Adult respondents to the 2008 Balance and Dizziness Supplement to the US National Health Interview Survey (N = 21 782). MAIN OUTCOMES AND MEASURES Prevalence of BVH, socioeconomic and quality-of-life impact of BVH, and fall risk. Criteria for the survey-based diagnosis of BVH included all of the following: presence of visual blurring with head movement; unsteadiness; difficulty walking in darkness or unsteady surfaces and in a straight path; and symptoms being at least "a big problem" and present for at least 1 year, in the absence of other neurologic conditions or eye pathologic conditions affecting vision. RESULTS Adjusted national estimates from this survey indicate the prevalence of BVH in 2008 was 28 per 100 000 US adults (64 046 Americans). Of the participants with BVH, 44% reported changing their driving habits because of their symptoms, 56% reported reduced participation in social activities, and 58% reported difficulties with activities of daily living. Respondents with BVH had a 31-fold increase in the odds of falling in multivariate analyses compared with all respondents, with 25% reporting a recent fall-related injury. CONCLUSIONS AND RELEVANCE As estimated by the presence of specific symptoms in a nationally representative survey, BVH has considerable socioeconomic and quality-of-life impacts and significantly increases fall risk. These data support the need for new therapeutic strategies for BVH, including vestibular rehabilitation and implantable vestibular prostheses.
Measles outbreak response among adolescent and adult Somali refugees displaced by famine in Kenya and Ethiopia, 2011.

BACKGROUND The refugee complexes of Dadaab, Kenya, and Dollo-Ado, Ethiopia, experienced measles outbreaks during June-November 2011, following a large influx of refugees from Somalia. METHODS Line-lists from health facilities were used to describe the outbreak in terms of age, sex, vaccination status, arrival date, attack rates (ARs), and case fatality ratios (CFRs) for each camp. Vaccination data and coverage surveys were reviewed. RESULTS In Dadaab, 1370 measles cases and 32 deaths (CFR, 2.3%) were reported. A total of 821 cases (60.1%) were aged ≥15 years, 906 (82.1%) arrived to the camps in 2011, and 1027 (79.6%) were unvaccinated. Camp-specific ARs ranged from 212 to 506 cases per 100 000 people. In Dollo-Ado, 407 cases and 23 deaths (CFR, 5.7%) were reported. Adults aged ≥15 years represented 178 cases (43.7%) and 6 deaths (26.0%). Camp-specific ARs ranged from 21 to 1100 cases per 100 000 people. Immunization activities that were part of the outbreak responses initially targeted children aged 6 months to 14 years and were later expanded to include individuals up to 30 years of age. CONCLUSIONS The target age group for outbreak response-associated immunization activities at the start of the outbreaks was inconsistent with the numbers of cases among unvaccinated adolescents and adults in the new population. In displacement of populations from areas affected by measles outbreaks, health authorities should consider vaccinating adults in routine and outbreak response activities.
Intracranial pressure monitoring

Abstract Brain specific monitoring enables detection and prevention of secondary cerebral insults, especially in the injured brain, thereby preventing permanent neurological damage. Intracranial pressure (ICP) monitoring is widely used in various neurological, neurosurgical and even medical conditions, both intraoperatively and in critical care, to improve patient outcome. It is especially useful in patients with traumatic brain injury, as a robust predictor of cerebral perfusion, and can help to guide therapy and assess long-term prognosis. Intraventricular catheters remain the gold standard for ICP monitoring, as they are the most reliable, accurate and cost-effective, and allow therapeutic cerebrospinal fluid drainage. Newer fibreoptic catheter tip and microchip transducer techniques have revolutionised ICP monitoring, with their ease of insertion in patients with narrow ventricles, and reduced risk of infection and haemorrhage. Furthermore, non-invasive methods of ICP monitoring, such as transcranial Doppler, optic nerve sheath diameter, etc., have emerged as promising techniques for screening patients with raised ICP in settings where invasive techniques are either not feasible (patients with severe coagulopathy) or not available (setups without access to a neurosurgeon). Therefore, ICP monitoring, as a part of multi-modality neuromonitoring, is a useful tool in the armamentarium of the neuro-intensivist in decreasing morbidity and mortality of critically ill neurological patients.