Rechallenge in idiosyncratic drug-induced liver injury: An analysis of cases in two large prospective registries according to existing definitions.

INTRODUCTION: Data on positive rechallenge in idiosyncratic drug-induced liver injury (DILI) are scarce. We aim to analyse the clinical presentation, outcome and drugs associated with positive rechallenge in two DILI registries. METHODS: Cases from the Spanish and Latin American DILI registries were included. Demographics, clinical characteristics and outcome of cases with positive rechallenge according to CIOMS/RUCAM and current definitions were analysed. RESULTS: Of 1418 patients with idiosyncratic DILI, 58 cases had positive rechallenge (4.1%). Patients with positive rechallenge had shorter duration of therapy (p=0.001) and latency (p=0.003). In patients with rechallenge, aspartate transaminase levels were increased (p=0.026) and showed a prolonged time to recovery (p=0.020), albeit no differences were seen in terms of fatal outcomes. The main drug implicated in rechallenge was amoxicillin-clavulanate (17%). The majority of re-exposure events were unintentional (71%). Using both existing definitions of positive rechallenge, there were four cases which exclusively fulfilled the current criteria and five which only meet the historical definition. All cases of positive rechallenge, irrespective of the pattern of damage, fulfilled the criteria of either alanine transaminase (ALT) ≥3 times the upper limit of normal (ULN) and/or alkaline phosphatase (ALP) ≥2 times ULN. CONCLUSIONS: Episodes of rechallenge were characterised by shorter duration of therapy and latency, and longer time to resolution, but did not show an increased incidence of fatal outcome. Based on our findings, ALT ≥3 times ULN and/or ALP ≥2 times ULN, regardless of the pattern of damage, is proposed as a new definition of rechallenge in DILI.

Roadmap to DILI research in Europe. A proposal from COST action ProEuroDILINet.

In the current article the aims for a constructive way forward in Drug-Induced Liver Injury (DILI) are to highlight the most important priorities in research and clinical science, therefore supporting a more informed, focused, and better funded future for European DILI research. This Roadmap aims to identify key challenges, define a shared vision across all stakeholders for the opportunities to overcome these challenges and propose a high-quality research program to achieve progress on the prediction, prevention, diagnosis and management of this condition and impact on healthcare practice in the field of DILI. This will involve 1. Creation of a database encompassing optimised case report form for prospectively identified DILI cases with well-characterised controls with competing diagnoses, biological samples, and imaging data; 2. Establishing of preclinical models to improve the assessment and prediction of hepatotoxicity in humans to guide future drug safety testing; 3. Emphasis on implementation science and 4. Enhanced collaboration between drug-developers, clinicians and regulatory scientists. This proposed operational framework will advance DILI research and may bring together basic, applied, translational and clinical research in DILI.

Effects and mechanotransduction pathways of therapeutic ultrasound on healthy and osteoarthritic chondrocytes: a systematic review of in vitro studies.

OBJECTIVE: To investigate the effects and mechanotransduction pathways of therapeutic ultrasound on chondrocytes. METHOD: PubMed, EMBASE and Web of Science databases were searched up to 19th September 2021 to identify in vitro studies exploring ultrasound to stimulate chondrocytes for osteoarthritis (OA) treatment. Study characteristics, ultrasound parameters, in vitro setup, and mechanotransduction pathways were collected. Risk of bias was judged using the Risk of Bias Assessment for Non-randomized Studies (RoBANS) tool. RESULTS: Thirty-one studies were included comprising healthy and OA chondrocytes and explants. Most studies had high risk of performance, detection and pseudoreplication bias due to lack of temperature control, setup calibration, inadequate semi-quantitatively analyzes and independent experiments. Ultrasound was applied to the culture plate via acoustic gel, water bath or culture media. Regardless of the setup used, ultrasound stimulated the cartilage production and suppressed its degradation, although the effect size was nonsignificant. Ultrasound inhibited p38, c-Jun N-terminal kinases (JNK) and factor nuclear kappa B (NFκB) pathways in OA chondrocytes to reduce apoptosis, inflammation and matrix degradation, while triggered phosphoinositide-3-kinase/akt (PI3K/Akt), extracellular signal-regulated kinase (ERK), p38 and JNK pathways in healthy chondrocytes to promote matrix synthesis. CONCLUSION: The included studies suggest that ultrasound application induces therapeutic effects on chondrocytes. However, these results should be interpreted with caution because high risk of performance, detection and pseudoreplication bias were identified. Future studies should explore the application of ultrasound on human OA chondrocytes cultures to potentiate the applicability of ultrasound towards cartilage regeneration of knee with OA.

Influenza vaccination strategy in acute coronary syndromes: the VIP-ACS trial.

AIMS: To evaluate whether a strategy of double-dose influenza vaccination during hospitalization for an acute coronary syndrome (ACS) compared with standard-dose outpatient vaccination (as recommended by current guidelines) would further reduce the risk of major cardiopulmonary events. METHODS AND RESULTS: Vaccination against Influenza to Prevent cardiovascular events after Acute Coronary Syndromes (VIP-ACS) was a pragmatic, randomized, multicentre, active-comparator, open-label trial with blinded outcome adjudication comparing two strategies of influenza vaccination following an ACS: double-dose quadrivalent inactivated vaccine before hospital discharge vs. standard-dose quadrivalent inactivated vaccine administered in the outpatient setting 30 days after randomization. The primary outcome was a hierarchical composite of all-cause death, myocardial infarction, stroke, unstable angina, hospitalization for heart failure, urgent coronary revascularization, and hospitalization for respiratory causes, analysed by the win ratio method. Patients were followed for 12 months. During two influenza seasons, 1801 participants were included at 25 centres in Brazil. The primary outcome was not different between groups, with 12.7% wins in-hospital double-dose vaccine group and 12.3% wins in the standard-dose vaccine group {win ratio: 1.02 [95% confidence interval (CI): 0.79-1.32], P = 0.84}. Results were consistent for the key secondary outcome, a hierarchical composite of cardiovascular death, myocardial infarction and stroke [win ratio: 0.94 (95% CI: 0.66-1.33), P = 0.72]. Time-to-first event analysis for the primary outcome showed results similar to those of the main analysis [hazard ratio 0.97 (95% CI: 0.75-1.24), P = 0.79]. Adverse events were infrequent and did not differ between groups. CONCLUSION: Among patients hospitalized with an ACS, double-dose influenza vaccination before discharge did not reduce cardiopulmonary outcomes compared with standard-dose vaccination in the outpatient setting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04001504.

Evaluation of 68Ga-DOTATATE uptake at the pituitary region and the biochemical response to somatostatin analogs in acromegaly.

PURPOSE: Acromegaly is associated with many comorbidities and increased mortality. The first-line treatment is transsphenoidal surgery. However, many patients also need adjuvant drug treatment after surgery. Somatostatin analog (SSA), which suppresses GH secretion by somatotrophs by binding to the SSTR2 receptor, is the first choice. Nevertheless, 50% of patients are partially or totally resistant to SSA, so predictive factors of response are helpful to individualize drug treatment. 68GaDOTATATE PET/CT has emerged as the gold-standard method in the diagnosis and follow-up of gastroenteropancreatic neuroendocrine tumors, which also express SSTR. Our objective was to evaluate whether 68Ga-DOTATATE uptake (SUV max) at the pituitary region of patients on SSA therapy would be useful as a drug response predictor without the need of tumoral tissue. METHODS: Fifteen acromegalics patients on SSA treatment for at least 6 months were underwent to 68Ga-DOTATATE PET/CT at the nuclear medicine service. There was an SSA complete response group (n = 5), defined as GH < 1 µg/L and IFG-1 in the normal range for gender and age, and a group that did not meet these criteria (n = 10). RESULTS: As a result, we did not find out a significantly higher SUV max in the complete response group (p = 0.0576) to SSA. However, we found a significant inverse relationship between postoperative GH values and the SUVmax at the sella turcica (p = 0.0188), probably reflecting tumor SSTR2 expression. CONCLUSION: Thus, after this initial evaluation, 68GaDOTATATE PET/CT should be better studied to assess its usefulness in the follow-up of acromegalic patients.

Soil fungi enable the control of gastrointestinal nematodes in wild bovidae captive in a zoological park: a 4-year trial.

The control of gastrointestinal nematodes among ruminants maintained in zoological parks remains difficult due to infective stages develop in the soil. For the purpose to improve the possibilities of the control of gastrointestinal nematodes (genera Trichostrongylus, Nematodirus, Chabertia and Haemonchus) affecting wild captive bovidae ruminants belonging to the subfamilies Antilopinae, Caprinae, Bovinae and Reduncinae, commercial pelleted feed enriched with a blend of 104-105 spores of both filamentous fungi Mucor circinelloides + Duddingtonia flagrans per kg meal was provided for a period of 3.5 years. All animals were dewormed at the beginning of the trial and also when exceeding a cut-off point of 300 eggs per gram of feces (EPG). The anthelmintic efficacy ranged between 96 and 100%. The need for repeating the administration of parasiticide treatment disappeared at the 24th month of study in the Antilopinae individuals, and at the 8th month in the Caprinae, Bovinae and Reduncinae. No side-effects were observed on the skin or in the digestive, respiratory or reproductive system. It was concluded that this strategy provides a sustainable tool for preventing the contamination of paddocks where captive ruminants are maintained, decreasing the risk of infection by gastrointestinal nematodes and consequently the need of frequent deworming.

Compact, low-threshold squeezed light source.

Strongly squeezed light finds many important applications within the fields of quantum metrology, quantum communication and quantum computation. However, due to the bulkiness and complexity of most squeezed light sources of today, they are still not a standard tool in quantum optics labs. We have taken the first steps in realizing a compact, high-performance 1550 nm squeezing source based on commercially available fiber components combined with a free-space double-resonant parametric down-conversion source. The whole setup, including single-pass second-harmonic generation in a waveguide, fits on a 30 cm×45 cm breadboard and produces 9.3 dB of squeezing at a 5 MHz sideband-frequency. The setup is currently limited by phase noise, but further optimization and development should allow for a 19" sized turn-key squeezing source capable of delivering more than 10 dB of squeezing.

Can chronic stretching change the muscle-tendon mechanical properties? A review.

It is recognized that stretching is an effective method to chronically increase the joint range of motion. However, the effects of stretching training on the muscle-tendon structural properties remain unclear. This systematic review with meta-analysis aimed to determine whether chronic stretching alter the muscle-tendon structural properties. Published papers regarding longitudinal stretching (static, dynamic and/or PNF) intervention (either randomized or not) in humans of any age and health status, with more than 2 weeks in duration and at least 2 sessions per week, were searched in PubMed, PEDro, ScienceDirect and ResearchGate databases. Structural or mechanical variables from joint (maximal tolerated passive torque or resistance to stretch) or muscle-tendon unit (muscle architecture, stiffness, extensibility, shear modulus, volume, thickness, cross-sectional area, and slack length) were extracted from those papers. A total of 26 studies were selected, with a duration ranging from 3 to 8 weeks, and an average total time under stretching of 1165 seconds per week. Small effects were seen for maximal tolerated passive torque, but trivial effects were seen for joint resistance to stretch, muscle architecture, muscle stiffness, and tendon stiffness. A large heterogeneity was seen for most of the variables. Stretching interventions with 3- to 8-week duration do not seem to change either the muscle or the tendon properties, although it increases the extensibility and tolerance to a greater tensile force. Adaptations to chronic stretching protocols shorter than 8 weeks seem to mostly occur at a sensory level.

Analysis of a Minimally Invasive Intracranial Pressure Signals During Infusion at the Subarachnoid Spinal Space of Pigs.

OBJECTIVE: We developed a new minimally invasive method for intracranial pressure monitoring (ICPMI). The objective of this project is to verify the similarities between the ICPMI and the invasive method (ICPInv), for different components of the intracranial pressure signal-namely, the mean value (trend) as well as its pulsatile component. MATERIALS AND METHODS: A 9 kg anesthetized pig was used for simultaneous ICP monitoring with both methods. ICP was increased by performing ten infusions of 6 ml 0.9% saline into the spinal subarachnoid space, using a catheter implanted in the lumbar region. For correlation analysis, the signals were decomposed into two components-trend and pulsatile signals. Pearson correlation coefficient was calculated between ICPInv and ICPMI. RESULTS: During the infusions, the correlation between the pulsatile components of the signals was above 0.5 for most of the time. The signal trends showed a good agreement (correlation above 0.5) for most of the time during infusions. CONCLUSIONS: The ICPMI signal trends showed a good linear agreement with the signal obtained invasively. Based on the waveform analysis of the pulsatile component of ICP, our results indicate the possibility of using the minimally invasive method for assessing the neuroclinical state of the patient.

Analysis of a Non-invasive Intracranial Pressure Monitoring Method in Patients with Traumatic Brain Injury.

OBJECTIVE: We aimed to compare the invasive (iICP) and a non-invasive intracranial pressure (nICP) monitoring methods in patients with traumatic brain injury, based on the similarities of the signals' power spectral densities. MATERIALS AND METHODS: We recorded the intracranial pressure of seven patients with traumatic brain injury admitted to Hospital São João, Portugal, using two different methods: a standard intraparenchymal (iICP) and a new nICP method based on mechanical extensometers. The similarity between the two monitoring signals was inferred from the Euclidean distance between the non-linear projection in a lower dimensional space (ISOMAP) of the windowed power spectral densities of the respective signals. About 337 h of acquisitions were used out of a total of 608 h. The only data exclusion criterion was the absence of any of the signals of interest. RESULTS: The averaged distance between iICP and nICP, and between arterial blood pressure (ABP) and nICP projections in the embedded space are statistically different for all seven patients analysed (Mann-Whitney U, p < 0.05). CONCLUSIONS: The similarity between the iICP and nICP monitoring methods was higher than the similarity between the nICP and the recordings of the radial ABP for all seven patients. Despite the possible differences between the shape of the ABP waveform at radial and parietal arteries, the results indicate-based on the similarities of iICP and nICP as functions of time-that the nICP method can be applied as an alternative method for ICP monitoring.

Oral findings in secondary syphilis.

BACKGROUND: Syphilis is a sexually transmitted disease caused by Treponema pallidum. However, there are of hematogenic and vertical transmission. All health care professionals must be aware of the manifestations of this condition, such as oral lesions. OBJECTIVES: This study to analyze and compare four clinical cases of syphilis that were diagnosed based on lesions in the oral cavity with published literature. MATERIAL AND METHODS: Four patients with a confirmed sorologic and clinical diagnosis of syphilis were examined, confirmated from manifestation of oral lesions together with analysis of serological laboratory tests and histopathological analyses. RESULTS: Lesions were found in classic sites such as lips, tongue and skin. However, there were also lesions on the hard palate, and labial commissure, which correspond to less than 5% of the syphilis oral manifestations. CONCLUSIONS: The practice of unprotected oral sex may result in infection and development of syphilis. The acknowledgment of the oral manifestations of syphilis in all its period of training for health professionals is of basic importance, the association of clinical features, histopathological findings and serological tests are required to complete the diagnosis and correct treatment.

A survey of zoonotic pathogens carried by house mouse and black rat populations in Yucatan, Mexico.

The house mouse (Mus musculus) and the black rat (Rattus rattus) are reservoir hosts for zoonotic pathogens, several of which cause neglected tropical diseases (NTDs). Studies of the prevalence of these NTD-causing zoonotic pathogens, in house mice and black rats from tropical residential areas are scarce. Three hundred and two house mice and 161 black rats were trapped in 2013 from two urban neighbourhoods and a rural village in Yucatan, Mexico, and subsequently tested for Trypanosoma cruzi, Hymenolepis diminuta and Leptospira interrogans. Using the polymerase chain reaction we detected T. cruzi DNA in the hearts of 4·9% (8/165) and 6·2% (7/113) of house mice and black rats, respectively. We applied the sedimentation technique to detect eggs of H. diminuta in 0·5% (1/182) and 14·2% (15/106) of house mice and black rats, respectively. Through the immunofluorescent imprint method, L. interrogans was identified in 0·9% (1/106) of rat kidney impressions. Our results suggest that the black rat could be an important reservoir for T. cruzi and H. diminuta in the studied sites. Further studies examining seasonal and geographical patterns could increase our knowledge on the epidemiology of these pathogens in Mexico and the risk to public health posed by rodents.

Using melanopsin to study G protein signaling in cortical neurons.

Our understanding of G protein-coupled receptors (GPCRs) in the central nervous system (CNS) has been hampered by the limited availability of tools allowing for the study of their signaling with precise temporal control. To overcome this, we tested the utility of the bistable mammalian opsin melanopsin to examine G protein signaling in CNS neurons. Specifically, we used biolistic (gene gun) approaches to transfect melanopsin into cortical pyramidal cells maintained in organotypic slice culture. Whole cell recordings from transfected neurons indicated that application of blue light effectively activated the transfected melanopsin to elicit the canonical biphasic modulation of membrane excitability previously associated with the activation of GPCRs coupling to Gαq-11 Remarkably, full mimicry of exogenous agonist concentration could be obtained with pulses as short as a few milliseconds, suggesting that their triggering required a single melanopsin activation-deactivation cycle. The resulting temporal control over melanopsin activation allowed us to compare the activation kinetics of different components of the electrophysiological response. We also replaced the intracellular loops of melanopsin with those of the 5-HT2A receptor to create a light-activated GPCR capable of interacting with the 5-HT2A receptor interacting proteins. The resulting chimera expressed weak activity but validated the potential usefulness of melanopsin as a tool for the study of G protein signaling in CNS neurons.

Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase.

T helper type 17 (Th17) cytokines have been implicated in the pathogenesis of neuromyelitis optica (NMO). As humanized anti-interleukin (IL)-6R (tocilizumab) immunoglobulin (Ig)G has been used as disease-modifying therapy for NMO, the objective of our study was to investigate the role of endogenous IL-6 on NMO-derived CD4(+) T cell behaviour. High production of IL-6, IL-17 and IL-21 by CD4(+) T-cells was detected in NMO patients. Further, IL-21 and IL-6 levels were related directly to the level of neurological disabilities. The addition of anti-IL-6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL-6, IL-17 and IL-21 release by CD4(+) T cells. In contrast, the production of IL-10 was amplified in those cell cultures. Further, anti-IL-6R monoclonal antibodies (mAb) also potentiated the ability of glucocorticoid in reducing Th17 cytokines. Finally, the in-vivo and in-vitro IL-6 levels were significantly higher among those patients who experienced clinical relapse during 2-year follow-up. In summary, our results suggest a deleterious role of IL-6 in NMO by favouring, at least in part, the expansion of corticoid-resistant Th17 cells.

Early developmental exposure to high fructose intake in rats with NaCl stimulation causes cardiac damage.

PURPOSE: Metabolic syndrome (MS) increases the risk of type 2 diabetes and cardiovascular disease. High consumption of fructose is a proposed cause of increased MS, manifested through hypertension, obesity, insulin resistance, and dyslipidemia. High NaCl also increases the risk of CD. The purpose of this study is to evaluate the influence of fructose and sodium on autonomic dysfunction and its relation with CD in MS. Fructose overload was started at weaning and continued through adulthood. METHODS: Male Wistar rats (21 days) were divided into four groups: Control (C), fructose consumption (10%, F), NaCl consumption (salt 1% for the 10 last days, S), and fructose and NaCl (FS), and monitored for 8 weeks. Metabolic evaluations consisted of Lee index, glycemia, insulin and glucose tolerance tests, triglycerides, and total cholesterol measurements. Cardiovascular parameters measured were arterial pressure (AP) and cardiac function performed by echocardiography. They also measured the influence of renin angiotensin (RAS) and autonomic nervous systems by drug blockage with losartan, atropine, and atenolol. RESULTS: Energy analysis showed no change between groups. Fructose overload induced a MS state, confirmed by insulin resistance, glucose intolerance, and dyslipidemia. Fasting glucose was increased in F and FS rat groups compared with C and S groups. AP was higher in F, S, and FS groups in comparison with the C group. The hypotensive response after sympathetic blockade was increased in F, S, and FS versus C. The cardiac vagal tonus was reduced in F and FS animal groups. The intrinsic heart rate was decreased in the FS group (372 ± 9 bpm) compared with the C group (410 ± 13 bpm). The morphometric measurements evaluated through left ventricular diameter during diastole and the left ventricular diameter during systole decreased in the FS group (16 and 26%, respectively). Diastolic function was reduced in F and FS. The depressor response induced by losartan was increased in the F group in comparison with other groups. However, there was a uniform increase in plasma ACE activity in all treated groups compared with the C group. CONCLUSIONS: Data suggest that early exposure to high fructose intake produced marked alterations in metabolic and cardiovascular function. When stimulated by NaCl, the fructose-fed subjects showed further impairment in cardiac function.

Pain reduction and improvement of function following ultrasound-guided intra-articular injections of triamcinolone hexacetonide and hyaluronic acid in hip osteoarthritis.

The scientific literature has shown positive results regarding intra-articular injections of hyaluronic acid in osteoarthritic joints. When injecting in the hip joint, the guidance of ultrasound can provide higher injection accuracy and repeatability. However, due to the methodological limitations in the current available literature, its recommendation in the current practice is still controversial. This study shows that ultrasound-guided intra-articular injections of triamcinolone hexacetonide and hyaluronic acid can improve pain, function and quality of life in patients with symptomatic and radiographic hip osteoarthritis. In addition, the administration of triamcinolone hexacetonide and hyaluronic acid to the hip joint in these patients can delay the need for interventional surgery.

Effects of hip and head position on ankle range of motion, ankle passive torque, and passive gastrocnemius tension.

Ankle joint range of motion (ROM) is notably influenced by the position of the hip joint. However, this result remains unexplained. Thus, the aim of this study was to test if the ankle passive torque and gastrocnemius muscle tension are affected by the hip and the head positions. The torque and the muscle shear elastic modulus (measured by elastography to estimate muscle tension) were collected in nine participants during passive ankle dorsiflexions performed in four conditions (by combining hip flexion at 90 or 150°, and head flexed or neutral). Ankle maximum dorsiflexion angle significantly decreased by flexing the hip from 150 to 90° (P < 0.001; mean difference 17.7 ± 2.5°), but no effect of the head position was observed (P > 0.05). Maximal passive torque and shear elastic modulus were higher with the hip flexed at 90° (P < 0.001). During submaximal ROM, no effects of the head and hip positioning (P > 0.05) were found for both torque and shear elastic modulus at a given common ankle angle among conditions. Shifts in maximal ankle angle due to hip angle manipulation are not related neither to changes in passive torque nor tension of the gastrocnemius. Further studies should be addressed to better understand the functional role of peripheral nerves and fasciae in the ankle ROM limits.

Stretching Effects: High-intensity & Moderate-duration vs. Low-intensity & Long-duration.

This study examined whether a high-intensity, moderate-duration bout of stretching would produce the same acute effects as a low-intensity, long-duration bout of stretching. 17 volunteers performed 2 knee-flexor stretching protocols: a high-intensity stretch (i. e., 100% of maximum tolerable passive torque) with a moderate duration (243.5 ± 69.5-s); and a low-intensity stretch (50% of tolerable passive torque) with a long duration (900-s). Passive torque at a given sub-maximal angle, peak passive torque, maximal range of motion (ROM), and muscle activity were assessed before and after each stretching protocol (at intervals of 1, 30 and 60 min). The maximal ROM and tolerable passive torque increased for all time points following the high-intensity stretching (p<0.05), but not after the low-intensity protocol (p>0.05). 1 min post-stretching, the passive torque decreased in both protocols, but to a greater extent in the low-intensity protocol. 30 min post-test, torque returned to baseline for the low-intensity protocol and had increased above the baseline for the high-intensity stretches. The following can be concluded: 1) High-intensity stretching increases the maximal ROM and peak passive torque compared to low-intensity stretching; 2) low-intensity, long-duration stretching is the best way to acutely decrease passive torque; and 3) high-intensity, moderate-duration stretching increases passive torque above the baseline 30 min after stretching.

Fine-mapping butyrophilin family genes revealed several polymorphisms influencing viral genotype selection in hepatitis C infection.

Host-viral genetic interaction has a key role in hepatitis C infection (HCV) and maybe in the viral selection. In a preliminary GWAS analysis, we identified BTN3A2 rs9104 to be associated with HCV genotype 1. Therefore, our aim was to determine the influence of BTN family on the selection of HCV genotype. We performed a fine-mapping analysis of BTN gene region in a cohort of chronic HCV infection (N=841), validating significant results in another independent chronic HCV infection cohort (N=637), according to selection of viral genotype. BTN3A2 rs9104, BTN3A2 rs733528, BTN2A1 rs6929846, BTN2A1 rs7763910 and BTN3A3 rs13220495 were associated with viral genotype selection. Interestingly, BTN3A2 rs9104 GG genotype was closely related to genotype 1 infection (80.7% (394/488) compared with genotype 3 infection (53.5% (23/43); P=0.0001) in patients harboring IL28B-CT/TT genotype, although this effect was not observed in IL28B-CC genotype. Similarly, BTN3A3 rs13220495 CC genotype was linked to genotype 3 infection (100% (32/32)) compared to genotype 1 (87.3% (137/157); P=0.028) in patients harboring IL28B-CC genotype, but did not in IL28B-CT/TT genotype. Genetic variants in the butyrophilin family genes may alter susceptibility to infection, selecting HCV genotype and influencing disease progression. BTN3A2 rs9104 was strongly associated with genotype 1 infection and the haplotype BTN3A3 rs13220495 CC+IL28B genotype CC was universal in patients with hepatitis C genotype 3a.

Impact of tuberculosis treatment length and adherence under different transmission intensities.

Tuberculosis (TB) is a leading cause of human mortality due to infectious disease. Treatment default is a relevant factor which reduces therapeutic success and increases the risk of resistant TB. In this work we analyze the relation between treatment default and treatment length along with its consequence on the disease spreading. We use a stylized model structure to explore, systematically, the effects of varying treatment duration and compliance. We find that shortening treatment alone may not reduce TB prevalence, especially in regions where transmission intensity is high, indicating the necessity of complementing this action with increased compliance. A family of default functions relating the proportion of defaulters to the treatment length is considered and adjusted to a particular dataset. We find that the epidemiological benefits of shorter treatment regimens are tightly associated with increases in treatment compliance and depend on the epidemiological background.