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Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.
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Modelos Animales de Enfermedad , Miositis Osificante , Osificación Heterotópica , Animales , Miositis Osificante/tratamiento farmacológico , Miositis Osificante/metabolismo , Osificación Heterotópica/tratamiento farmacológico , Osificación Heterotópica/metabolismo , Osificación Heterotópica/prevención & control , Ratones , Humanos , Receptores de Activinas Tipo II/metabolismo , Receptores de Activinas Tipo I/metabolismo , Receptores de Activinas Tipo I/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
IMPORTANCE: Tuberculosis (TB) remains one of the world's leading infectious disease killers, despite available treatments. Although highly sensitive molecular diagnostics are available, expensive equipment and poor infrastructure have hindered their implementation in low-resource settings. Furthermore, the collection of sputum poses challenges as it is difficult for patients to produce and creates dangerous aerosols. This manuscript explores tongue swabs as a promising alternative to sputum collection. While previous studies have explored the sensitivity of tongue swabs as compared to sputum, existing literature has not addressed the need to standardize and simplify laboratory processing for easy implementation in high TB burden areas. This manuscript provides the first evidence that detection of TB from a tongue swab is possible without the use of DNA extraction or purification steps. The data provided in this manuscript will improve the collection and testing of tongue swabs for the diagnosis of TB disease.
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Mycobacterium tuberculosis , Tuberculosis , Humanos , Mycobacterium tuberculosis/genética , Esputo , Tuberculosis/diagnóstico , Lengua , Reacción en Cadena de la PolimerasaAsunto(s)
Infecciones por VIH , Mycobacterium tuberculosis , Tuberculosis Pulmonar , Tuberculosis , Humanos , Esputo , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiología , Infecciones por VIH/diagnóstico , Infecciones por VIH/epidemiología , Sensibilidad y Especificidad , LipopolisacáridosRESUMEN
To cope with the global climate crisis and assist in achieving the carbon neutrality, the use of biomass materials to fully or partially replace petroleum-based products and unrenewable resources is expected to become a widespread solution. Based on the analysis of the existing literature, this paper firstly classified biomass materials with potential application prospects in pavement engineering according to their application and summarized their respective preparation methods and characteristics. The pavement performance of asphalt mixtures with biomass materials was analyzed and summarized, and the economic and environmental benefits of bio-asphalt binder were evaluated. The analysis shows that pavement biomass materials with potential for practical application can be divided into three categories: bio-oil, bio-fiber, and bio-filler. Adding bio-oil to modify or extend the virgin asphalt binder can mostly improve the low temperature performance of asphalt binder. Adding styrene-butadienestyrene (SBS) or other preferable bio-components for composite modification will have a further improved effect. Most of the asphalt mixtures prepared by using bio-oil modified asphalt binders have improved the low temperature crack resistance and fatigue resistance of asphalt mixtures, but the high temperature stability and moisture resistance may decrease. As a rejuvenator, most bio-oils can restore the high and low temperature performance of aged asphalt and recycled asphalt mixture, and improve fatigue resistance. Adding bio-fiber could significantly improve the high temperature stability, low temperature crack resistance and moisture resistance of asphalt mixtures. Biochar as a bio-filler can slow down the asphalt aging process and some other bio-fillers can improve the high temperature stability and fatigue resistance of asphalt binders. Through calculation, it is found that the cost performance of bio-asphalt has the ability to surpass conventional asphalt and has economic benefits. The use of biomass materials for pavements not only reduces pollutants, but also reduces the dependence on petroleum-based products. It has significant environmental benefits and development potential.
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Hidrocarburos , Petróleo , BiomasaRESUMEN
Dietary supplements (DS) and their purchase is often based on a consumer's personal choice and advertisements. The associated DS regulations, particularly in manufacturing and marketing, are far more flexible and permissive than that of the well-regulated prescription pharmaceuticals. However, the adverse health effects associated with the inadvertent use of mega-doses of DS are not well understood. The demand for DS, nutraceuticals, and herbal remedies has experienced an upswing during the past two to three decades, and global product sales have thrived. More so, the prevention of cardiometabolic syndrome (CMS) and related disorders like diabetes mellitus, obesity, hypertension, and serum lipid abnormalities, as well as of other noncommunicable diseases (NCDs), is of highest health care priority globally, since these disorders impose very high economic burdens on health care systems and society. In this review, we argue why DS could prevent cardiometabolic syndrome, by providing the potential benefits and risks associated with them, especially self-medication considering their intake by the public at large. Good manufacturing practices and quality control are absolutely necessary for the manufacture of DS products, and proper labeling is needed regarding the optimal dose schedules of various DS and bioactive ingredients. Specific examples are used to underscore the indications and dosage recommendations made for the marketing and promotion of fish oil, coenzyme Q10, and Mg-containing products for the prevention of cardiometabolic syndrome.
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Human tissue samples are often mixtures of heterogeneous cell types, which can confound the analyses of gene expression data derived from such tissues. The cell type composition of a tissue sample may itself be of interest and is needed for proper analysis of differential gene expression. A variety of computational methods have been developed to estimate cell type proportions using gene-level expression data. However, RNA isoforms can also be differentially expressed across cell types, and isoform-level expression could be equally or more informative for determining cell type origin than gene-level expression. We propose a new computational method, IsoDeconvMM, which estimates cell type fractions using isoform-level gene expression data. A novel and useful feature of IsoDeconvMM is that it can estimate cell type proportions using only a single gene, though in practice we recommend aggregating estimates of a few dozen genes to obtain more accurate results. We demonstrate the performance of IsoDeconvMM using a unique data set with cell type-specific RNA-seq data across more than 135 individuals. This data set allows us to evaluate different methods given the biological variation of cell type-specific gene expression data across individuals. We further complement this analysis with additional simulations.
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Perfilación de la Expresión Génica , Humanos , Isoformas de Proteínas/genética , Análisis de Secuencia de ARNRESUMEN
While epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the treatment landscape for EGFR mutant (L858R and ex19del)-driven non-small-cell lung cancer (NSCLC), most patients will eventually develop resistance to TKIs. In the case of first- and second-generation TKIs, up to 60% of patients will develop an EGFR T790M mutation, while third-generation irreversible TKIs, like osimertinib, lead to C797S as the primary on-target resistance mutation. The development of reversible inhibitors of these resistance mutants is often hampered by poor selectivity against wild-type EGFR, resulting in potentially dose-limiting toxicities and a sub-optimal profile for use in combinations. BLU-945 (compound 30) is a potent, reversible, wild-type-sparing inhibitor of EGFR+/T790M and EGFR+/T790M/C797S resistance mutants that maintains activity against the sensitizing mutations, especially L858R. Pre-clinical efficacy and safety studies supported progression of BLU-945 into clinical studies, and it is currently in phase 1/2 clinical trials for treatment-resistant EGFR-driven NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Resistencia a Antineoplásicos , Receptores ErbB , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
The Miocene Climatic Optimum (MCO) from ~17 to 14 million years ago (Ma) represents an enigmatic reversal in Cenozoic cooling. A synthesis of marine paleotemperature records shows that the MCO was a local maximum in global sea surface temperature superimposed on a period from at least 19 Ma to 10 Ma, during which global temperatures were on the order of 10°C warmer than at present. Our high-resolution global reconstruction of ocean crustal production, a proxy for tectonic degassing of carbon, suggests that crustal production rates were ~35% higher than modern rates until ~14 Ma, when production began to decline steeply along with global temperatures. The magnitude and timing of the inferred changes in tectonic degassing can account for the majority of long-term ice sheet and global temperature evolution since 20 Ma.
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BACKGROUND: Since 2011, WHO has recommended that HIV-positive inpatients be routinely screened for tuberculosis with the WHO four-symptom screen (W4SS) and, if screened positive, receive a molecular WHO-recommended rapid diagnostic test (eg, Xpert MTB/RIF [Xpert] assay). To inform updated WHO tuberculosis screening guidelines, we conducted a systematic review and individual participant data meta-analysis to assess the performance of W4SS and alternative screening tests to guide Xpert testing and compare the diagnostic accuracy of the WHO Xpert algorithm (ie, W4SS followed by Xpert) with Xpert for all HIV-positive inpatients. METHODS: We searched MEDLINE, Embase, and Cochrane Library from Jan 1, 2011, to March 1, 2020, for studies of adult and adolescent HIV-positive inpatients enrolled regardless of tuberculosis signs and symptoms. The separate reference standards were culture and Xpert. Xpert was selected since it is most likely to be the confirmatory test used in practice. We assessed the proportion of inpatients eligible for Xpert testing using the WHO algorithm; assessed the accuracy of W4SS and alternative screening tests or strategies to guide diagnostic testing; and compared the accuracy of the WHO Xpert algorithm (W4SS followed by Xpert) with Xpert for all. We obtained pooled proportion estimates with a random-effects model, assessed diagnostic accuracy by fitting random-effects bivariate models, and assessed diagnostic yield descriptively. This systematic review has been registered on PROSPERO (CRD42020155895). FINDINGS: Of 6162 potentially eligible publications, six were eligible and we obtained data for all of the six publications (n=3660 participants). The pooled proportion of inpatients eligible for an Xpert was 90% (95% CI 89-91; n=3658). Among screening tests to guide diagnostic testing, W4SS and C-reactive protein (≥5 mg/L) had highest sensitivities (≥96%) but low specificities (≤12%); cough (≥2 weeks), haemoglobin concentration (<8 g/dL), body-mass index (<18·5 kg/m2), and lymphadenopathy had higher specificities (61-90%) but suboptimal sensitivities (12-57%). The WHO Xpert algorithm (W4SS followed by Xpert) had a sensitivity of 76% (95% CI 67-84) and specificity of 93% (88-96; n=637). Xpert for all had similar accuracy to the WHO Xpert algorithm: sensitivity was 78% (95% CI 69-85) and specificity was 93% (87-96; n=639). In two cohorts that had sputum and non-sputum samples collected for culture or Xpert, diagnostic yield of sputum Xpert was 41-70% and 61-64% for urine Xpert. INTERPRETATION: The W4SS and other potential screening tests to guide Xpert testing have suboptimal accuracy in HIV-positive inpatients. On the basis of these findings, WHO now strongly recommends molecular rapid diagnostic testing in all medical HIV-positive inpatients in settings where tuberculosis prevalence is higher than 10%. FUNDING: World Health Organization.
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Infecciones por VIH , Tuberculosis Pulmonar , Tuberculosis , Adolescente , Adulto , Infecciones por VIH/complicaciones , Infecciones por VIH/diagnóstico , Humanos , Pacientes Internos , Prevalencia , Sensibilidad y Especificidad , Tuberculosis/complicaciones , Tuberculosis/diagnóstico , Tuberculosis/epidemiología , Tuberculosis Pulmonar/complicaciones , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/epidemiologíaRESUMEN
Targeting the programmed death 1/programmed death ligand 1 (PD-1/PD-L1) pathway with immunotherapy has revolutionized the treatment of many cancers. Somatic tumor mutational burden (TMB) and T-cell-inflamed gene expression profile (GEP) are clinically validated pan-tumor genomic biomarkers that can predict responsiveness to anti-PD-1/PD-L1 monotherapy in many tumor types. We analyzed the association between these biomarkers and the efficacy of PD-1 inhibitor in 11 commonly used preclinical syngeneic tumor mouse models using murinized rat anti-mouse PD-1 DX400 antibody muDX400, a surrogate for pembrolizumab. Response to muDX400 treatment was broadly classified into three categories: highly responsive, partially responsive, and intrinsically resistant to therapy. Molecular and cellular profiling validated differences in immune cell infiltration and activation in the tumor microenvironment of muDX400-responsive tumors. Baseline and on-treatment genomic analysis showed an association between TMB, murine T-cell-inflamed gene expression profile (murine-GEP), and response to muDX400 treatment. We extended our analysis to investigate a canonical set of cancer and immune biology-related gene signatures, including signatures of angiogenesis, myeloid-derived suppressor cells, and stromal/epithelial-to-mesenchymal transition/TGFß biology previously shown to be inversely associated with the clinical efficacy of immune checkpoint blockade. Finally, we evaluated the association between murine-GEP and preclinical efficacy with standard-of-care chemotherapy or antiangiogenic agents that previously demonstrated promising clinical activity, in combination with muDX400. Our profiling studies begin to elucidate the underlying biological mechanisms of response and resistance to PD-1/PD-L1 blockade represented by these models, thereby providing insight into which models are most appropriate for the evaluation of orthogonal combination strategies.
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Antígeno B7-H1 , Inmunoterapia , Neoplasias , Receptor de Muerte Celular Programada 1 , Animales , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Humanos , Inhibidores de Puntos de Control Inmunológico , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microambiente TumoralRESUMEN
PURPOSE: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab. PATIENTS AND METHODS: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated. RESULTS: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation. CONCLUSIONS: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.
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Neoplasias , Receptor de Muerte Celular Programada 1 , Anticuerpos Monoclonales , Humanos , Dosis Máxima Tolerada , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Criterios de Evaluación de Respuesta en Tumores Sólidos , Microambiente TumoralRESUMEN
BACKGROUND: Urine cell-free DNA (cfDNA) is an attractive target for diagnosing pulmonary Mycobacterium tuberculosis (MTB) infection, but has not been thoroughly characterized as a biomarker. METHODS: This study was performed to investigate the size and composition of urine cfDNA from tuberculosis (TB) patients with minimal bias using next-generation sequencing (NGS). A combination of DNA extraction and single-stranded sequence library preparation methods demonstrated to recover short, highly degraded cfDNA fragments was employed. Urine cfDNA from 10 HIV-positive patients with pulmonary TB and two MTB-negative controls was examined. RESULTS: MTB-derived cfDNA was identifiable by NGS from all MTB-positive patients and was absent from negative controls. MTB cfDNA was significantly shorter than human cfDNA, with median fragment lengths of ≤19-52 bp and 42-92 bp, respectively. MTB cfDNA abundance increased exponentially with decreased fragment length, having a peak fragment length of ≤19 bp in most samples. In addition, we identified a larger fraction of short human genomic cfDNA, ranging from 29 to 53 bp, than previously reported. Urine cfDNA fragments spanned the MTB genome with relative uniformity, but nucleic acids derived from multicopy elements were proportionately over-represented. CONCLUSIONS: TB urine cfDNA is a potentially powerful biomarker but is highly fragmented, necessitating special procedures to maximize its recovery and detection.
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Ácidos Nucleicos Libres de Células , Mycobacterium tuberculosis , Tuberculosis Pulmonar/diagnóstico , Biomarcadores/orina , Ácidos Nucleicos Libres de Células/orina , ADN Bacteriano/orina , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mycobacterium tuberculosis/genéticaRESUMEN
BACKGROUND: Empirical tuberculosis (TB) treatment in human immunodeficiency virus (HIV)-positive inpatients is common and may undermine the impact of new diagnostics. We sought to describe empirical TB treatment and compare characteristics and outcomes with patients treated for TB after screening. METHODS: This was a retrospective observational cohort study of HIV-positive inpatients treated empirically for TB prior to TB screening. Data on clinical characteristics, investigations, and outcomes were collected from medical records. Comparison cohorts with microbiologically confirmed or empirical TB treatment after TB screening with Xpert MTB/RIF and urine lipoarabinomannan assays were taken from South African Screening for Tuberculosis to Reduce AIDS-Related Mortality in Hospitalized Patients in Africa (STAMP) trial site. In-hospital mortality was compared using a competing-risks analysis adjusted for age, sex, and CD4 cell count. RESULTS: Between January 2016 and September 2017, 100 patients excluded from STAMP were treated for TB empirically prior to TB screening. After enrollment in STAMP and TB screening, 240 of 1177 (20.4%) patients received TB treatment, of whom 123 had positive TB tests and 117 were treated empirically. Characteristics were similar among early empirically treated patients and those treated after TB screening. 50% of early empirical TB treatment was based on radiological investigations, 22% on cerebrospinal or pleural fluid testing, and 28% on clinical features alone. Only 11 of 100 empirically treated patients had subsequent microbiological confirmation. In-hospital mortality was lower in patients with microbiologically confirmed TB compared to those treated empirically (adjusted subdistribution hazard ratio, 0.5 [95% confidence interval, .3-.9). CONCLUSIONS: Empirical TB treatment remains common in severely ill HIV-positive inpatients. These patients may benefit from TB screening using existing rapid diagnostics, both to improve confirmation of TB disease and reduce overtreatment for TB.
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Transrenal urine cell-free DNA (cfDNA) is a promising tuberculosis (TB) biomarker, but is challenging to detect because of the short length (<100 bp) and low concentration of TB-specific fragments. We aimed to improve the diagnostic sensitivity of TB urine cfDNA by increasing recovery of short fragments during sample preparation. We developed a highly sensitive sequence-specific purification method that uses hybridization probes immobilized on magnetic beads to capture short TB cfDNA (50 bp) with 91.8% average efficiency. Combined with short-target PCR, the assay limit of detection was ≤5 copies of cfDNA in 10 ml urine. In a clinical cohort study in South Africa, our urine cfDNA assay had 83.7% sensitivity (95% CI: 71.0 to 91.5%) and 100% specificity (95% CI: 86.2 to 100%) for diagnosis of active pulmonary TB when using sputum Xpert MTB/RIF as the reference standard. The detected cfDNA concentration was 0.14 to 2,804 copies/ml (median 14.6 copies/ml) and was inversely correlated with CD4 count and days to culture positivity. Sensitivity was nonsignificantly higher in HIV-positive (88.2%) compared to HIV-negative patients (73.3%), and was not dependent on CD4 count. Sensitivity remained high in sputum smear-negative (76.0%) and urine lipoarabinomannan (LAM)-negative (76.5%) patients. With improved sample preparation, urine cfDNA is a viable biomarker for TB diagnosis. Our assay has the highest reported accuracy of any TB urine cfDNA test to date and has the potential to enable rapid non-sputum-based TB diagnosis across key underserved patient populations.
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Ácidos Nucleicos Libres de Células , Tuberculosis Pulmonar , Estudios de Cohortes , Infecciones por VIH , Humanos , Mycobacterium tuberculosis/genética , Sensibilidad y Especificidad , Sudáfrica , Esputo , Tuberculosis Pulmonar/diagnósticoRESUMEN
OBJECTIVE: To assess the safety and efficacy of RSLV-132, an RNase Fc fusion protein, in a phase II randomized, double-blind, placebo-controlled clinical trial in patients with primary Sjögren's syndrome (SS). METHODS: Thirty patients with primary SS were randomized to receive treatment with RSLV-132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks. Eight patients received placebo and 20 patients received RSLV-132 at a dose of 10 mg/kg. Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST). RESULTS: Patients randomized to receive RSLV-132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT-F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures. This improvement was significantly correlated with increased expression of selected interferon-inducible genes (Pearson's correlations, each P < 0.05). CONCLUSION: Administration of RSLV-132 improved severe fatigue, as determined by 4 independent patient-reported measures of fatigue, in patients with primary SS.
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Fatiga/fisiopatología , Inmunoglobulina G/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Ribonucleasas/uso terapéutico , Síndrome de Sjögren/tratamiento farmacológico , Adulto , Anciano , Método Doble Ciego , Femenino , Expresión Génica , Humanos , Interferones/genética , Interferones/inmunología , Fatiga Mental/fisiopatología , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Síndrome de Sjögren/genética , Síndrome de Sjögren/inmunología , Síndrome de Sjögren/fisiopatología , Resultado del TratamientoRESUMEN
All around the world, intestinal helminths constitute one of the most prevalent life-long occurring infections and re-infections affecting all horse age groups. A range of parasite species among strongyles, ascarids, and tapeworms is known to have the potential to cause colic in horses. However, there is a lack of current scientific evidence on the actual relevance of helminth infection levels in the context of colic in horses kept during prevailing epidemiological conditions. Thus, a prospective case-control study on the occurrence of intestinal helminths in a total of 620 mainly adult equine clinic patients was conducted to investigate the association between colic and helminth infection. For each horse, a range of copromicroscopic, serological, and clinical data was obtained, in addition to a questionnaire on relevant anamnestic data, including previous anthelmintic treatment and husbandry. Using a FLOTAC-based copromicroscopic diagnosis, the highest infection rates were seen for strongyles (41.8%), followed by Anoplocephala perfoliata and Parascaris spp. (both 0.8%), with no significant difference between the two study groups. Employing a real-time PCR a 1.1% S. vulgaris DNA prevalence was found. Considerably higher seroprevalences were observed using S. vulgaris and A. perfoliata ELISAs, with 32.3% and 10.7%, respectively. It was noteworthy that no association concerning either serologic status was encountered with colic status. The shedding of strongyle eggs was associated with a 1.8-times increased risk of S. vulgaris seropositivity. Recent anthelmintic treatment was associated with the onset of colic, as animals who had received an anthelmintic during the previous week had a 2.4-times higher risk of signs of colic compared to those who had been treated at least eight weeks prior. Another noteworthy observation was that ponies were significantly less often affected by colic than warmbloods. The high S. vulgaris and considerable A. perfoliata seroprevalences encountered in this investigation should prompt veterinarians, farm managers, and horse owners to maintain consequent and effective worm control measures.
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BACKGROUND: People successfully completing treatment for tuberculosis remain at elevated risk for recurrent disease, either from relapse or reinfection. Identifying risk factors for recurrent tuberculosis may help target post-tuberculosis screening and care. METHODS: We enrolled 500 patients with smear-positive pulmonary tuberculosis in South Africa and collected baseline data on demographics, clinical presentation and sputum mycobacterial cultures for 24-loci mycobacterial interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) typing. We used routinely-collected administrative data to identify recurrent episodes of tuberculosis occurring over a median of six years after successful treatment completion. RESULTS: Of 500 patients initially enrolled, 333 (79%) successfully completed treatment for tuberculosis. During the follow-up period 35 patients with successful treatment (11%) experienced a bacteriologically confirmed tuberculosis recurrence. In our Cox proportional hazards model, a 3+ AFB sputum smear grade was significantly associated with recurrent tuberculosis with a hazard ratio of 3.33 (95% CI 1.44-7.7). The presence of polyclonal M. tuberculosis infection at baseline had a hazard ratio for recurrence of 1.96 (95% CI 0.86-4.48). CONCLUSION: Our results indicate that AFB smear grade is independently associated with tuberculosis recurrence after successful treatment for an initial episode while the association between polyclonal M. tuberculosis infection and increased risk of recurrence appears possible.
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Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/genética , Esputo/microbiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/epidemiología , Adulto , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Repeticiones de Minisatélite/genética , Recurrencia , Factores de Riesgo , Sudáfrica/epidemiología , Resultado del Tratamiento , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/microbiología , Adulto JovenRESUMEN
Immunotherapies have attracted lots of research interests recently. The need to understand the underlying mechanisms of immunotherapies and to develop precision immunotherapy regimens has spurred great interest in characterizing immune cell composition within the tumor microenvironment. Several methods have been developed to estimate immune cell composition using gene expression data from bulk tumor samples. However, these methods are not flexible enough to handle aberrant patterns of gene expression data, e.g., inconsistent cell type-specific gene expression between purified reference samples and tumor samples. We propose a novel statistical method for expression deconvolution called ICeD-T (Immune Cell Deconvolution in Tumor tissues). ICeD-T automatically identifies aberrant genes whose expression are inconsistent with the deconvolution model and down-weights their contributions to cell type abundance estimates. We evaluated the performance of ICeD-T versus existing methods in simulation studies and several real data analyses. ICeD-T displayed comparable or superior performance to these competing methods. Applying these methods to assess the relationship between immunotherapy response and immune cell composition, ICeD-T is able to identify significant associations that are missed by its competitors.