A simple radiometric method has been developed for evaluating the effect of drugs on the metabolism of M. lepraemurium. The method is based on the measurement of the 14CO2 produced through bacterial metabolism of acetate-U-14C. Seventeen drugs were tested: bacitracin, cephaloridine, chloramphenicol, cycloserine, dactinomycin, DDS, ethionamide, INH, kanamycin, methenamine mandelate, nitrofurantoin, oxacillin, polymyxin B, rifampicin, streptomycin, sulfadimethoxine and vancomycin. The drugs which caused most marked inhibition were chloramphenicol, INH, ethionamide and nitrofurantoin in order of increasing effectiveness. The radiometric study which is completed in 15 days permits direct study of the drug effect on the metabolism of M. lepraemurium and a more rapid screening of antileprosy drugs than has previously been possible. Currently, these observations are being extended to studies of the structure-activity relationships of antileprosy drugs and the metabolism and drug susceptibility of M. leprae in vitro.

Background: Catheter ablation (CA) is recommended for treating paroxysmal/persistent atrial fibrillation (AF) as an alternative to antiarrhythmic drugs after failure or intolerance, or as first-line in limited cases. This study has described patients affected by AF and treated or not with CA, from the perspective of the Italian National Healthcare System (INHS).

Methods: From the healthcare administrative data collected in the ReS (Ricerca e Salute) database, from 2016 to 2017, patients with main/secondary diagnosis of AF (index date) were split into two cohorts by presence/absence of CA procedure in the same hospital discharge form. The cohorts were characterized by gender, age, comorbidities. Consumptions (DDD) of antiarrhythmic, anticoagulant, antiplatelet and antihypertensive drugs, hospitalizations for AF, hemorrhagic stroke/intracranial hemorrhage, ischemic stroke/transient ischemic attack, extra cranial major bleeding and heart failure, outpatient specialist care and healthcare costs paid by the INHS were assessed.

Results: Out of >5 million inhabitants in 2016-2017, 33,940 patients were hospitalized with a diagnosis of AF, 990 (2.9%) were treated with CA in the same hospitalization (32,950 without CA). Patients with CA were mostly males (66.8%; 48.5% without CA). On average, they were aged (±SD) 65±12 (78±11 without CA) and affected by one comorbidity (≥3 in patients without CA). During the observational period, beta-blockers were the most prescribed to both cohorts, followed by antiarrhythmic drugs to patients with CA and by direct oral anticoagulants to those without. The 29.7% of subjects with CA were hospitalized due to relevant cardiovascular diagnoses during the previous year (7.4% without CA) and 93.4% in the first follow-up year (29.7% without CA). The 80-90% of cohorts resorted to the outpatient specialist care. Electrocardiograms and the cardiology visits were performed to the 62.5% and 31.1% of the cohort with CA (39.5% and 13% without CA) in the first follow-up year. On average, the INHS spent about € 4000 in the previous year and around € 10,000 in the first follow-up year per patient of both cohorts, while around € 3000 and € 4000 for a patient respectively with and without CA. At least half of the total costs were due to hospitalizations, followed by pharmaceuticals and outpatient specialist care.

Conclusions: This study confirm a post-CA suboptimal monitoring.

<A<em>b</em>stractText>Dia<em>b</em>etes represents a relevant pu<em>b</em>lic health pro<em>b</em>lem worldwide due to its growing prevalence and socioeconomic <em>b</em>urden, principally due to the development of macrovascular and microvascular complications as well as to the continuous launch of new and even more expensive drugs. The aim of our study is to evaluate the economic impact of dulaglutide, a weekly GLP-1 receptor agonist, on the treatment of dia<em>b</em>etic patients as an alternative to <em>b</em>oth high dose sulphonylureas and insulin <em>b</em>asalization at the failure of oral therapies alone. We carried out a cost-effectiveness analysis developed considering the economic implications of recent clinical studies regarding cardiovascular risk drug effects and especially of REWIND studies outcomes, focusing on the impact of weight changes on HRQoL.</A<em>b</em>stractText><p><div>(<em>b</em>)Material and Method</<em>b</em>)</div>In our analysis, we have applied the cost-utility technique to the a<em>b</em>ove reported clinical outcomes and compared the glo<em>b</em>al costs of dulaglutide versus sulfonylurea or <em>b</em>asal insulin, all in add-on with metformin. We have chosen gliclazide, as a sulfonylurea and A<em>b</em>asaglar^®, the less expensive among <em>b</em>asal insulin analogues. A<em>b</em>asaglar was titrated to 20 IU, corresponding to the mean dosage used in the treatment of type II dia<em>b</em>etic patients. The model aims to estimate total direct costs related to the a<em>b</em>ove-reported treatments and find out the real gap in costs <em>b</em>etween dulaglutide, the apparently cheaper gliclazide and <em>b</em>asal insulin glargine (IGlargine) <em>b</em>ased on the Italian National Healthcare System (<em>INHS</em>).</p><A<em>b</em>stractText>The total cost of dulaglutide has resulted in €859.66 higher than gliclazide (€1,579.73 vs €720.07) and <em>b</em>asal insulin, although less significantly, reporting a difference of €396.54 (€1,579.73 vs 1,183.19). Except for the purchase cost, dulaglutide has reported reduced costs compared to insulin IGlargine and gliclazide. Dulaglutide showed lower self-monitoring <em>b</em>lood glucose and hypoglycaemia costs, a significant reduction in costs related to cardiovascular complications, as well as savings in costs in other drugs. Dulaglutide can <em>b</em>e considered a cost-effective antidia<em>b</em>etic therapy, due to the positive impact on the quality of life induced <em>b</em>y weight reduction, despite the higher annual cost per patient, mainly influenced <em>b</em>y drug purchase cost.</A<em>b</em>stractText><A<em>b</em>stractText>In this cost-utility analysis, dulaglutide has shown to <em>b</em>e a cost-effective treatment option from the Italian healthcare system perspective as add-on therapy to metformin in patients with inadequately controlled type 2 dia<em>b</em>etes mellitus. Study findings can provide stakeholders valua<em>b</em>le evidence to support the adoption of this cost-effective second- or third-line therapy compared to gliclazide or <em>b</em>asal insulin glargine. Dulaglutide cost-effectiveness has <em>b</em>een particularly evident in the comparison with <em>b</em>asal insulin glargine, indicating that, in patients who have treatment indication, this therapy may <em>b</em>e preferred to <em>b</em>asalization avoiding related complications and costs.</A<em>b</em>stractText>

<A<em>b</em>stractText>To assess the pharmacokinetics of isoniazid (<em>INH</em>) at 10 mg/kg/day among Indian children.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div><em>INH</em> levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1-15 years on daily anti-tu<em>b</em>erculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after <em>INH</em> administration. The maximum concentration (C<su<em>b</em>)max</su<em>b</em>)) and area under the curve (AUC<su<em>b</em>)0-24</su<em>b</em>)) were determined. The normal therapeutic range for C<su<em>b</em>)max</su<em>b</em>) is 3-5 μg/ml. An AUC of <10.52 μg•h/ml for <em>INH</em> is low.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The mean C<su<em>b</em>)max</su<em>b</em>) was 8.3 ± 4.28 μg/ml and was attained in 1.22 ± 0.5 h, with a median time to C<su<em>b</em>)max</su<em>b</em>) (T<su<em>b</em>)max</su<em>b</em>)) of 1 h. The mean AUC for <em>INH</em> was 46.23 ± 34.82 μg•h/ml. Children aged 1-4.9 years, 5-10 years and >10 years had a mean C<su<em>b</em>)max</su<em>b</em>) of respectively 9.87 ± 5.75 μg/ml, 7.62 ± 3.37 μg/ml and 7.21 ± 2.50 μg/ml (<i>P =</i> 0.08) and a mean AUC of respectively 60.97 ± 49.90 μg•h/ml, 38.95 ± 22.28 μg•h/ml and 36.09 ± 13.56 μg•h/ml (<i>P =</i> 0.29). The mean C<su<em>b</em>)max</su<em>b</em>) in children taking fixed-drug com<em>b</em>inations and individual drugs was respectively 9.07 ± 4.67 μg/ml and 7.43 ± 3.71 μg/ml (<i>P =</i> 0.26); the mean AUC was respectively 50.48 ± 38.38 μg•h/ml and 41.20 ± 30.52 μg•h/ml (<i>P =</i> 0.44). Two children had hepatitis.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>Most Indian children had higher than normal <em>INH</em> AUC and C<su<em>b</em>)max</su<em>b</em>) values<i>.</i> It is necessary to determine the ideal dose of <em>INH</em> in Indian children using the genotypic acetylator status of the patients and pharmacokinetic toxicity analysis.</p>

OBJECTIVE

Tumor necrosis factor (TNF) blockers increase the risk of tuberculosis infection. National recommendations in France for prevention of latent tuberculosis recommend treatment by rifampicin (RIF) 600 mg/day and isoniazid (INH) 300 mg/day for 3 months. However, its toxicity is unknown in this context and is a subject of debate.

OBJECTIVE

To assess (a) frequency of prescription, (b) reasons for prescription, (c) tolerance of INH/RIF for prevention of tuberculosis.

METHODS

Systematic retrospective study of medical records of one tertiary rheumatology unit, from 2002 to 2007, of all patients who were prescribed INH/RIF before receiving TNF blockers.

METHODS

patients'demographic characteristics, reasons of prescription, tolerance and levels of aminotransferase before and during INH/RIF treatment.

METHODS

Descriptive and determination of risk factors of hepatotoxicity by multivariate logistic regression.

RESULTS

Of 1028 patients treated by TNF blockers between 2002 and 2007, 216 (21.1%) received INH/RIF treatment. Of 93 patients with complete data, 17 (18.2%) presented hepatotoxicity of which only one above 10 times the upper limit of the norm. Fourteen (15.0%) had other side effects. Ten (10.7%) patients had to interrupt INH/RIF for intolerance. Factors predicting intolerance were male sex, aminotransferases before treatment, a higher body mass index and leflunomide comedication.

CONCLUSIONS

This systematic case review indicates a high rate of necessity for preventive treatment by INH/RIF, and in particular for positive skin tests. This association had a high rate of hepatotoxicity without severe consequences. A better screening of patients before preventive therapy is needed.

Nonresonant and resonant transient, photochemical hole-burned (HB) spectra are presented for primary electron donor states of a novel bacterial reaction center (Zn-RC) of Rhodobacter sphaeroides, containing six Zn-bacteriochlorophylls (Zn-BChls). A "Zn-β-RC" in which the Zn-BChl in the bacteriopheophytin (BPhe)-binding site on the A side (H(A)) has the Zn penta-coordinated, was also studied. The fifth ligand comes from a histidine introduced by site-directed mutagenesis. Formation of the P(+)Q(A)(-) state was observed in both types of RC, although under identical experimental conditions a significantly deeper P(-) band (corresponding to the lower-energy, special pair, excitonic component) was revealed in the Zn-RC. Assuming a similar lifetime of the P(+)Q(A)(-) state, the quantum yield of P(+)Q(A)(-) formation decreased by ~60% in the Zn-β-RC (compared to the Zn-RC), as was seen in a comparison of analogous (Mg) BChl-containing wild type and β-RCs of Rb. sphaeroides [Kirmaier et al. Science1991, 251, 922]. However, the average (weakly frequency-dependent) low-temperature electron transfer (ET) rates of the Zn-RC and Zn-β-RC (measured from zero phonon holes in resonant transient HB spectra) were both ~1 ps and similar to a rate previously measured in the Rb. sphaeroides native RC [Johnson et al. J. Phys. Chem. 1989, 93, 5953]. Electron transfer rates observed in this work on the Zn-RC yielded a P870* decay rate in good agreement with recent room-temperature, time-domain data [Lin et al. Proc. Natl. Acad. Sci. 2009, 106, 8537]. A lack of correlation observed between the holes near 810 and 883 nm, accounting for electrochromically induced shifts of the Zn-BChl transitions in the B(A,B) and H(A,B) binding sites, produced by formation of the P(+)BHQ(A)(-) state, indicates that the 810 nm bleach does not correspond to the P(+) (upper excitonic component of the dimer) band and is mostly contributed to by a shift of the B(B) absorption band. ZPH-action spectra indicated inhomogeneous broadening (Γ(inh)) of ~110 cm(-1) (Zn-RC) and ~130 cm(-1) (Zn-β-RC). Experimentally determined Γ(inh) decreased the number of variables in theoretical fits of the absorption and frequency-dependent shapes of resonant HB spectra, leading to more reliable Huang-Rhys factors for both low-frequency phonons and a pseudolocalized phonon, ω(SP), often referred to as the special pair marker mode.

<A<em>b</em>stractText>To compare the pharmacokinetics of isoniazid (<em>INH</em>) at doses 5 and 10 mg/kg/day.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div><em>INH</em> concentrations were estimated <em>b</em>y high-performance liquid chromatography in 24 Indian children aged 1 to 15 years on antitu<em>b</em>erculosis therapy. Blood samples were collected at 0, 2, 4, 6, 8 hours after administration of <em>INH</em>. Patients were randomly given <em>INH</em> at 5 or 10 mg/kg/day and maximum concentrations (C<su<em>b</em>)max</su<em>b</em>) ) and area under the curve (AUC<su<em>b</em>)(0-8)</su<em>b</em>) ) were determined in each group. The 2-hour concentration of <em>INH</em> was used as C<su<em>b</em>)max</su<em>b</em>) for this study.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Mean (standard deviation) C<su<em>b</em>)max</su<em>b</em>) was reached in 2 hours and was 2.68 ± 1.19 µg/mL in 5 mg/kg/day group and 8.86 ± 3.94 µg/mL in 10 mg/kg/day group (P < .05). The normal therapeutic range at 2-hour concentrations for <em>INH</em> in adults achieving good clinical response is <em>b</em>etween 3 and 5 µg/mL. Among 5 mg/kg/day, only 4 (33%) patients had <em>INH</em> concentrations within the 2-hour concentrations therapeutic range whereas in 10 mg/kg/day group, 11 (91%) patients achieved C<su<em>b</em>)max</su<em>b</em>) higher than the 2-hour concentrations therapeutic range and 1 (9%) patient had C<su<em>b</em>)max</su<em>b</em>) within the 2-hour concentrations therapeutic range. The mean AUC<su<em>b</em>)(0-8)</su<em>b</em>) in 5 mg/kg/day group was 10.04 ± 6.12 and 35.93 ± 25.37 µg·h/mL in 10 mg/kg/day group (P = .0001).</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>Children on daily <em>INH</em> 10 mg/kg/day have higher AUC and C<su<em>b</em>)max</su<em>b</em>) than the required therapeutic range whereas over 65% of children with daily 5 mg/kg/day <em>INH</em> therapy failed to achieve the optimal therapeutic range.</p>

(<em>b</em>)Aim:</<em>b</em>) To evaluate the potential of three <em>b</em>enzohydrazones ((<em>b</em>)1</<em>b</em>)-(<em>b</em>)3</<em>b</em>)), four acylhydrazones derived from isoniazid (<em>INH</em>-acylhydrazones) ((<em>b</em>)4</<em>b</em>)-(<em>b</em>)7</<em>b</em>)) and one hydrazone ((<em>b</em>)8</<em>b</em>)) as antitu<em>b</em>erculosis agents.(<em>b</em>) Materials & methods:</<em>b</em>) Inhi<em>b</em>itory and <em>b</em>actericidal activities were determined for the reference <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> (<i>Mt<em>b</em></i>) strain and clinical isolates. Cytotoxicity, drug com<em>b</em>inations and ethidium <em>b</em>romide accumulation assays were also performed. (<em>b</em>)Results:</<em>b</em>) The tested compounds ((<em>b</em>)1</<em>b</em>)-(<em>b</em>)8</<em>b</em>)) presented excellent antitu<em>b</em>erculosis activity with surprisingly inhi<em>b</em>itory (0.12-250 μg/ml) and <em>b</em>actericidal values, even against multidrug-resistant <i>Mt<em>b</em></i> clinical isolates. Compounds showed high selectivity index, with values reaching 1833.33, and a limited spectrum of activity. Some of the compounds ((<em>b</em>)2</<em>b</em>) & (<em>b</em>)8</<em>b</em>)) are also great inhi<em>b</em>itors of <em>b</em>acillus efflux pumps. (<em>b</em>)Conclusion:</<em>b</em>) Benzohydrazones and <em>INH</em>-acylhydrazones may <em>b</em>e considered scaffolds for the development of new anti-<i>Mt<em>b</em></i> drugs.

First-line antituberculosis drugs, namely, isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA), contribute to diverse pathological complications. Testicular toxicity is one such complication. Berberis aristata DC is an herb with potentially curative characteristics. The aim of this study was to test whether extract of Berberis aristata DC (Berberidaceae) has curing potential against testicular toxicity. Characterization of extract was done using ultra-performance liquid chromatography along with acute toxicity testing. Antioxidant activity of extract was checked by DPPH inhibition assay and H2O2 scavenging assay. Rats were dosed once daily for 28 days in groups: control group (saline), toxicant group (30.85 mg/kg body weight INH + 61.7 mg/kg body weight RIF + 132.65 mg/kg body weight PZA), treatment groups (TB drugs + 150/300 mg/kg body weight extract) and standard group (TB drugs +100 mg/kg body weight silymarin). Spectrophotometric evaluations of lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD), glutathione-S-transferase (GST), and catalase (CAT) content in testes were done using standard protocols. DNA fragmentation and histopathological studies were performed to check the damage at the cellular level. Acute toxicity studies revealed LD50>> 5 g/Kg body weight of B. aristata extract. IC50 for DPPH free-radical scavenging activity and H2O2 scavenging assay were 44.78 µg/mL and 85.28 µg/mL, respectively. Results revealed significant increase in thiobarbituric acid reactive substances, decrease in glutathione and different antioxidants levels, DNA fragmentation pattern, and changes in histology in toxicant group. All the changes were absent in high-dose (300 mg/kg body weight) extract treatment group. This work proved that B. aristata extract has protective efficacy against testicular damage caused by anti-TB drugs.

(<em>b</em>)Background:</<em>b</em>) Hereditary angioedema (HAE) is caused <em>b</em>y mutations in the C1 inhi<em>b</em>itor (C1-<em>INH</em>) gene Serpin Family G Mem<em>b</em>er 1(<i>SERPING1</i>), which results in either the decreased synthesis of normal C1-<em>INH</em> (C1-<em>INH</em>-HAE type I) or expression of unfunctional C1-<em>INH</em> (C1-<em>INH</em>-HAE type II). In recent studies, emotional stress was reported <em>b</em>y patients as the most common trigger factor for C1-<em>INH</em>-HAE attacks. Moreover, patients reported considera<em>b</em>le distress over the significant varia<em>b</em>ility and uncertainty with which the disease manifests, in addition to the impact of physical symptoms on their overall quality of life. (<em>b</em>)O<em>b</em>jective:</<em>b</em>) We did a systematic review of the literature to shed light on the advancements made in the study of how stress and psychological processes impact C1-<em>INH</em>-HAE. (<em>b</em>)Methods:</<em>b</em>) All of the articles on C1-<em>INH</em>-HAE were analyzed up to Decem<em>b</em>er 2019. Both medical data <em>b</em>ases and psychological data <em>b</em>ases were examined. The keywords (KWs) used for searching the medical and psychological data <em>b</em>ases were the following: "hereditary angioedema," "psychology," "stress," "anxiety," and "depression." (<em>b</em>)Results:</<em>b</em>) Of a total of 2549 articles on C1-<em>INH</em>-HAE, 113 articles were retrieved from the literature search <em>b</em>y using the related KWs. Twenty-one of these articles were retrieved, examined, and classified. (<em>b</em>)Conclusion:</<em>b</em>) Although the literature confirmed that stress may induce various physical diseases, it also warned against making simplistic statements a<em>b</em>out its incidence that did not take into account the complexity and multicausality of factors that contri<em>b</em>ute to C1-<em>INH</em>-HAE expression.

<p><div>(<em>b</em>)BACKGROUND</<em>b</em>)</div>Tu<em>b</em>erculosis (TB), especially drug-resistant TB, is a glo<em>b</em>al pu<em>b</em>lic health pro<em>b</em>lem. This study aimed to validate a new molecular diagnostic test, the FluoroType^® MTBDR.</p><p><div>(<em>b</em>)METHOD</<em>b</em>)</div>Samples underwent routine diagnostic procedures (fluorescence microscopy, culture, species differentiation and phenotypic drug suscepti<em>b</em>ility testing). Left over samples stored at -20° underwent DNA extraction using the Fluorolyse^® kit, followed <em>b</em>y FluoroType^® MTBDR and Genotype MTBDRplus testing.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>A total of 350 respiratory and 59 lymph node samples were included in the study; 71 respiratory and 16 lymph node samples were culture positive for M. tu<em>b</em>erculosis complex (MTBC). The sensitivity of the FluoroType^® MTBDR to detect MTBC DNA was 91.4% (95%CI 82.3-96.8%), 68.4% (95%CI 43.4-87.4%) and 62.5%, (95%CI 35.4-84.8%) for respiratory, smear negative respiratory and lymph node samples respectively. The correlating sensitivities of the GenoType MTBDRplus were 85.9% (95%CI 75.6-93.0%), 52.6% (95%CI 28.9-75.6%) and 56.3% (29.9-80.2). Sensitivity of the FluoroType^® MTBDR to detect RMP and <em>INH</em> resistance for respiratory samples was 96.5% (95%CI 82.2-99.9) and 70% (95%CI 45.7-88.1), respectively. The GenoType MTBDRplus revealed sensitivities of 97.1% (95% 85.1-99.9) 70.6% (95%CI 52.5-84.9) for detection of RMP and <em>INH</em> resistance. Indeterminate results were 13/64 (20.3%), 23/64 (35.9%) and 16/64 (25.0%) for rpoB, katG and inhA using the FluoroType^® MTBDR.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>The FluoroType^® MTBDR has a high sensitivity to detect MTBC DNA. However, the high proportion of indeterminate results across all three genes needs to <em>b</em>e addressed.</p>

<p><div>(<em>b</em>)Background</<em>b</em>)</div>A new direct microplate-<em>b</em>ased colorimetric drug suscepti<em>b</em>ility test that omits the initial isolation of <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> from sputum specimens was evaluated.</p><p><div>(<em>b</em>)Methods</<em>b</em>)</div>A total of 51 <i>M. tu<em>b</em>erculosis</i> acid fast <em>b</em>acilli (AFB) smear-positive sputum specimens were inoculated directly into drug-free and serial dilutions of drug-containing Middle<em>b</em>rook 7H9 <em>b</em>roth media. With this direct resazurin micro plate assay (REMA) method, resazurin dye was used as a growth indicator in microplate wells. The minimum inhi<em>b</em>itory concentrations (MIC) of isoniazid (<em>INH</em>) and rifampicin (RIF) were compared with those of the 'gold standard' a<em>b</em>solute concentration method (ACM). The turnaround time (TAT) of the direct REMA and the ACM were also determined.</p><A<em>b</em>stractText>At the selected cut-off points (<em>INH</em>: 0.0625 μg/mL; RIF: 0.125 μg/mL), good drug suscepti<em>b</em>ility test results were o<em>b</em>tained for <em>INH</em> and RIF with an average sensitivity, specificity and accuracy of 90%, 100% and 97%, respectively, with a TAT of 15 days. The REMA method also correctly classified the resistant isolates with positive predictive values of 95% and negative predictive values of 98% for the two drugs.</A<em>b</em>stractText><p><div>(<em>b</em>)Conclusions</<em>b</em>)</div>The direct REMA was relia<em>b</em>le in routine diagnostic la<em>b</em>oratories for the drug suscepti<em>b</em>ility testing of <i>M. tu<em>b</em>erculosis</i> and the rapid detection of multi-drug-resistant tu<em>b</em>erculosis.</p>

<A<em>b</em>stractText>Mozam<em>b</em>ique is a high-<em>b</em>urden tu<em>b</em>erculosis (TB) country where TB/HIV co-infection and drug resistant TB (DR-TB) incidence is increasing. Whole genome sequencing (WGS) comprehensively descri<em>b</em>es the molecular epidemiology of TB, allows prediction of DR-TB phenotypes, lineages strains identification and <em>b</em>etter understanding of transmission chains.</A<em>b</em>stractText><A<em>b</em>stractText>To descri<em>b</em>e genetic diversity of DR-TB Myco<em>b</em>acterium tu<em>b</em>erculosis isolated in Beira, Mozam<em>b</em>ique.</A<em>b</em>stractText><p><div>(<em>b</em>)METHODS</<em>b</em>)</div>Descriptive cross-sectional study with 35 M. tu<em>b</em>erculosis isolates, resistant to at least one first-line drug on molecular drug-suscepti<em>b</em>ility tests (DST). Variant identification, DR prediction and phylogenetic analysis provided <em>b</em>y WGS, drug-suscepti<em>b</em>ility pattern compared to line-pro<em>b</em>e assay (LPA): Genotype MTBDR^TMplus and MTBDR^TMsl.</p><A<em>b</em>stractText>Lineage 4 (L4) was the most prevalent: 25 (71.4%) isolates; 5 (14.3%) L1 and 5 (14.3%) L2. WGS showed 33/35 (94.3%) isolates resistant to at least one drug, two pan-suscepti<em>b</em>le isolates that were previously diagnosed as DR-TB with genotype MTBDRplus. Concordance <em>b</em>etween WGS and LPA: 88.6% for isoniazid (<em>INH</em>), 85.7% to rifampicin (RPM), 91.4% for quinolones and 100% to second line injecta<em>b</em>le drugs. There were three possi<em>b</em>le TB transmission chains, 10 strains showing recent transmission.</A<em>b</em>stractText><A<em>b</em>stractText>WGS provided relia<em>b</em>le information a<em>b</em>out the most frequent lineages related to DR-TB in Beira, Mozam<em>b</em>ique: L4.3 (LAM), L2 (Beijing) and L1 (EAI) and possi<em>b</em>le recent transmission chain.</A<em>b</em>stractText>

The discrepancy rates of drug susceptibility testing (DST) results between solid and liquid media have been reported to range from 2.4 to 7.4% for isoniazid. Most isolate with isoniazid DST discrepancies between solid and liquid media test as susceptible on solid medium and resistant in liquid medium, however, the optimal management of patients with discordant testing is unknown. This study was conducted to evaluate the effect of treatment regimen on treatment outcomes when patients with rifampicin-susceptible pulmonary tuberculosis have isoniazid resistance (INH-R) in liquid medium but isoniazid susceptibility (INH-S) on solid medium.

This study was retrospectively conducted by reviewing patient medical records on the liquid compared to solid culture based phenotypic testing at Samsung Medical Center between January 2009 and December 2015. The study population which have INH-R in liquid medium and INH-S on solid medium was divided into two groups: group A (n = 30), which included patients treated for INH-S tuberculosis by discontinuing pyrazinamide (and ethambutol), and group B (n = 56), which included patients treated for INH-R tuberculosis by continuing pyrazinamide and/or adding fluoroquinolone. Unfavorable outcomes included treatment failure and relapse.

There were no statistically significant differences between the two groups including demographic data, comorbidities, radiologic data, and treatment duration. However, baseline smear positive rates were more frequent in group A (19/30, 63.3%) than in group B (22/56, 39.3%; P = 0.033). Only three patients had unfavorable outcomes; one was bacteriologically proven treatment failure and the other two were clinically judged as unfavorable outcomes. All of them were in the group A (3/30, 10%); no unfavorable outcomes occurred in the group B (0/56, 0%; P = 0.040).

Unfavorable outcomes were less frequent in the group B than in the group A, indicating that treatment regimen modification according to DST results on liquid medium could improve treatment outcomes in patients with rifampicin-susceptible pulmonary tuberculosis. Further studies are required to confirm these findings to overcome the small number of unfavorable outcomes.

The aim of our study was to genotypically characterise isoniazid (INH) and rifampicin (RMP) resistant Mycobacterium tuberculosis isolates in Sousse, Central Tunisia, using DNA sequencing and multispacer sequence typing (MST). The results show that 27/28 (96.4%) and 1/28 (3.6%) INH-resistant isolates yielded respectively the kat G S315T and the inh A - 15C → T mutations. Two-thirds of RMP-resistant isolates yielded the rpo B D516V mutation and one sixth yielded either H526D or S531L mutations. Genotyping analysis revealed the multiclonal spread of drug-resistant isolates in Central Tunisia. Data presented here complete the previously published map of resistant M. tuberculosis isolates and highlight their regional disparity in Tunisia.

<p><div>(<em>b</em>)<em>B</em>ACKGROUND</<em>b</em>)</div>The genetic diversity of <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> in Quito, Ecuador is not well known.</p><p><div>(<em>b</em>)O<em>B</em>JECTIVE</<em>b</em>)</div>To investigate mutations related to drug resistance and <em>b</em>acterial genotypes in <i>M. tu<em>b</em>erculosis</i> strains in Ecuador.</p><p><div>(<em>b</em>)DESIGN</<em>b</em>)</div>This was a retrospective study of <i>M. tu<em>b</em>erculosis</i> isolates from 104 patients. Isolates were phenotypically resistant to rifampicin (RMP) and/or isoniazid (<em>INH</em>). The genotype was determined using 24-locus myco<em>b</em>acterial interspersed repetitive units-varia<em>b</em>le-num<em>b</em>er tandem repeats (MIRU-VNTR).</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>Isolates showed mutations in the <i>rpo</i><em>B</em> and <i>kat</i>G genes, and the <i><em>inh</em></i>A promoter. In <i>rpo</i><em>B</em>, we found 13 genetic alterations at codons 511, 513, 514, 515, 516, 526 and 531. Forty-six (44.2%) RMP-resistant isolates <em>b</em>elonged to codon 531. In <i>kat</i>G, there were nine genetic alterations at codons 296, 312, 314, 315, 322, 324 and 351. Fifty-three (51%) <em>INH</em>-resistant isolates <em>b</em>elonged to codon 315. Five mutations not previously descri<em>b</em>ed were identified in <i>kat</i>G: Thr324Ser, Thr314Ala, Ala312Pro, Trp351Stop and deleted G at 296 codon. The Latin American Mediterranean (LAM) (33.7%) and Ghana (30.8%) lineages presented most of the main mutations o<em>b</em>served.</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>This is the first report from Ecuador; it descri<em>b</em>es five new mutations in <i>kat</i>G and indicates that LAM is the most prevalent lineage.</p>

<p><div>(<em>b</em>)O<em>b</em>jective</<em>b</em>)</div>To determine the prevalence of MDR-TB and find out the incidence of drug resistance using molecular diagnostic method. Line pro<em>b</em>e assay (LPA) is <em>b</em>ased on the principle of multiplex PCR is used to detect MTB (<i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i>) complex as well as its sensitivity to rifampicin and isoniazid.</p><A<em>b</em>stractText>This is a hospital-<em>b</em>ased prospective o<em>b</em>servational study. The sputum of MDR-TB suspected patients was su<em>b</em>jected to Ziehl-Neelsen staining and smear positive samples were analyzed <em>b</em>y LPA. Decontamination and digestion of the samples was done using the NALC- NaOH method (as defined in RNTCP guidelines). DNA extraction was done from the decontaminated samples using Geno Lyse kit. After DNA extraction, detection of MTB complex and rifampicin and/or <em>INH</em> resistance was done with the help of line pro<em>b</em>e assay (LPA) using GenoType ® MTBDRplus version 2.0.</A<em>b</em>stractText><A<em>b</em>stractText>Out of the 156 smear-positive sputum samples, 140 samples had LPA valid results. The most common age group of positive TB samples in this study was 30-40 years (26.42%). Twenty-five samples (17.85%) were found to <em>b</em>e rifampicin resistant and 22 (15.71%) samples were found resistant to isoniazid. Sixteen patients (11.42%) were detected MDR. Nine patients (6.42%) were monoresistant to rifampicin and six patients (4.28%) were monoresistant to isoniazid. "Sputum positive retreatment cases" had the highest detection rate for MDR TB.</A<em>b</em>stractText><A<em>b</em>stractText>Line pro<em>b</em>e assay is an economical and time saving method for the detection of MDR-TB and serves as a lifesaving tool for early diagnosis and treatment. This calls for a widespread national use of this assay. The detection of around 10% ZN-positive patients, who were not showing MTB complex in LPA may <em>b</em>e a hidden ice<em>b</em>erg for non-tu<em>b</em>ercular myco<em>b</em>acteria.</A<em>b</em>stractText>

Hereditary angioedema (HAE) is rare disease characterized by recurrent, unpredictable, and debilitating attacks of subcutaneous/submucosal tissue swelling.^1,2 The reported median age of onset of HAE due to C1 inhibitor deficiency/dysfunction (type 1/2; C1-INH-HAE) is 11-12 years.^1,3 Treatment options for pediatric patients are limited, owing to low childhood diagnosis rates and low representation in investigative clinical trials.⁴ We present a multicenter, open-label, single-arm, phase 3 study (NCT01386658) investigating the use of icatibant, a bradykinin B₂ receptor antagonist, to treat HAE attacks in pediatric patients with a confirmed diagnosis of C1-INH-HAE.⁵ In Part 1, patients (aged 2 to <18 years with confirmed diagnosis of C1-INH-HAE) received an icatibant injection in the presence or absence of an attack. Icatibant showed acceptable safety and tolerability, and the treatment response to the first icatibant injection (n = 22) was consistent with that observed in adults, with median time to onset of symptom relief (TOSR) of 1.0 h. The European Medicines Agency subsequently approved icatibant in 2017 for use in pediatric patients aged 2-17 years.

<A<em>b</em>stractText>Ethnopharmacological relevance Senna septemtrionalis (Viv.) H.S. Irwin & Barne<em>b</em>y (Fa<em>b</em>aceae) is a shru<em>b</em> empirically used as diuretic, and for the treatment of neurological disorders. These pharmacological effects have not <em>b</em>een previously evaluated.</A<em>b</em>stractText><A<em>b</em>stractText>To evaluate the diuretic and CNS effects of a standardized ethanol extract of Senna septemtrionalis aerial parts (SSE).</A<em>b</em>stractText><A<em>b</em>stractText>Gas chromatography mass spectrometry was used to perform a chemical analysis with SSE. In all tests, SSE was evaluated from 10 to 100 mg/kg p.o. The diuretic activity of SSE was assessed in mice individually placed in meta<em>b</em>olic cages. After 6 h, the urine volume and the electrolyte excretion (Na and K) were measured. The role of prostaglandins and nitric oxide was assessed administrating mice with indomethacin and N(ω)-nitro-L-arginine methyl ester (L-NAME), prior the administration of 100 mg/kg SSE. The sedative effects of SSE were analyzed with the pento<em>b</em>ar<em>b</em>ital-induced sleeping time test. The effects of SSE on motor coordination in mice were evaluated with the rotarod test. The antidepressant-like activity of SSE was analyzed with the forced swimming test (FST) and the tail suspension test (TST). The role of 5-HT2 receptor, α1-and α2-adrenoceptors, or muscarinic receptors was assessed administrating mice with cyproheptadine, prazosin, yohim<em>b</em>ine, and atropine, respectively, prior the administration of 100 mg/kg SSE in the FST. The anxiolytic-like activity of SSE (10-100 mg/kg p.o.) was assessed using the light-dark test (LDB), the elevated plus maze test (EPM), the cylinder exploratory test, and the open field test (OFT). The anticonvulsant effect of SSE (1-100 mg/kg) was evaluated in mice administered with different convulsant agents: strychnine, pentylenetetrazol (PTZ), isoniazid (<em>INH</em>) or yohim<em>b</em>ine.</A<em>b</em>stractText><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The main compound found in SSE was D-pinitol (42.2%). SSE (100 mg/kg) increased the urinary volume (2.67-fold), as well as the excretion of Na (5.60-fold) and K (7.2-fold). The co-administration of SSE with L-NAME or indomethacin reverted the diuretic activity shown <em>b</em>y SSE alone. SSE lacked sedative effects and did not affect motor coordination in mice. SSE (100 mg/kg) showed higher and similar antidepressant-like effect, compared to 20 mg/kg fluoxetine, in the FST and TST, respectively. The co-administration of SSE with yohim<em>b</em>ine reverted the antidepressant-like activity shown <em>b</em>y SSE alone. SSE (100 mg/kg) showed anxiolytic-like activity in the four models of anxiety, with similar activity with 1.5 mg/kg clonazepam. The seizure-protective effect of SSE was ED<su<em>b</em>)50</su<em>b</em>) = 73.9 ± 8.4 mg/kg (<em>INH</em>) and 40.4 ± 5.2 mg/kg (yohim<em>b</em>ine).</p><A<em>b</em>stractText>The diuretic effects of SSE involve the possi<em>b</em>le contri<em>b</em>ution of prostaglandins and nitric oxide. SSE showed moderate anxiolytic and anticonvulsant effects, whereas the participation of α2-adrenoceptors is pro<em>b</em>a<em>b</em>ly associated in the antidepressant-like effects of SSE.</A<em>b</em>stractText>

(<em>b</em>)Introduction:</<em>b</em>) The aim of this study was to present the follow-up results of 110 patients who were given anti-tumor necrosis factor alpha (TNF-α) therapy for rheumatic and dermatologic diseases in a country with a high rates of active and latent tu<em>b</em>erculosis <em>b</em>acillus infection. (<em>b</em>)Material and Methods:</<em>b</em>) Between Fe<em>b</em>ruary 2008 and January 2015, 110 cases in the age range of 23-77 who are using anti-TNF-α were included in the study retro-prospectively. (<em>b</em>)Results:</<em>b</em>) 52.7% of them (<i>n</i> = 58) were male. The most common diagnoses were rheumatoid arthritis (42.7%) and ankylosing spondylitis (38.2%). Most frequently given treatment were inflixima<em>b</em> 37.3% and etanercept 30.9%, respectively. The 65 patients whose first tu<em>b</em>erculin skin test (TST) value "5 mm and a<em>b</em>ove" was started daily 300 mg <em>INH</em> prophylaxis for 9 months <em>b</em>ut 3 patients had not <em>b</em>een started <em>b</em>ecause of refusing treatment. In only one case chemoprophylaxis has had to <em>b</em>e interrupted <em>b</em>ecause of high liver function test due to the <em>INH</em> prophylaxis. TST conversion was o<em>b</em>served in 14 patients. Further follow-up, it was o<em>b</em>served that 4 patients had TST's positivity. Isoniazide (<em>INH</em>) prophylaxis was started these 18 patients (42.9%). Although <em>INH</em> prophylaxis has <em>b</em>een given in two patients, they developed active tu<em>b</em>erculosis in follow-up. (<em>b</em>)Conclusion:</<em>b</em>) Considering the <em>INH</em> resistance in our country, all patients especially the ones with residual lesion and history of previous exposure, should <em>b</em>e followed up closely during the anti-TNF-α treatment.

In industrialized countries pellagra may nowadays be induced by inappropriate diet schedules, alcohol abuse, endogenous disorders of metabolism, and also intake or abuse of drugs. In particular, INH, hydantoine, and other anticonvulsive drugs may induce pellagra by causing disorders in vitamin B metabolism. On this pathway disorders of tryptophan metabolism may also occur. We report here on a woman who developed pellagra after long-term abuse of analgetics and psychopharmaca obviously due to disorders in gastrointestinal resorption and liver metabolism. Phenobarbital, salicylic amide, phenacetin, possible also diazepam, induced the disease most likely. The clinical diagnosis was confirmed by low blood levels of niacinamide. Discontinuation of drug medication and systemic application of vitamin preparations were followed by full remission in 6 weeks.

<A<em>b</em>stractText>Early diagnosis and drug suscepti<em>b</em>ility testing are important for anti-tu<em>b</em>erculosis treatment.</A<em>b</em>stractText><p><div>(<em>b</em>)OBJECTIVE</<em>b</em>)</div>To develop a rapid method for detecting <i>Myco<em>b</em>acterium tu<em>b</em>erculosis</i> and drug suscepti<em>b</em>ility <em>b</em>ased on culture and droplet digital polymerase chain reaction (ddPCR).</p><p><div>(<em>b</em>)DESIGN</<em>b</em>)</div><i>M. tu<em>b</em>erculosis</i> in 102 sputum samples was detected using ddPCR, Xpert, quantitative PCR (qPCR) and MGIT™ 960™. The suscepti<em>b</em>ility of ddPCR-positive samples to rifampicin (RMP), isoniazid (<em>INH</em>) and streptomycin (SM) was tested <em>b</em>y measuring changes in DNA quantity over 4 days of culture. For comparison, suscepti<em>b</em>ility of MGIT 960-positive samples was tested using the standard agar proportion method.</p><p><div>(<em>b</em>)RESULTS</<em>b</em>)</div>The sensitivity and specificity of <i>M. tu<em>b</em>erculosis</i> detection using ddPCR and MGIT 960 were respectively 95.7% (95%CI 80.0-99.2) and 88.9% (95%CI 76.7-95.4). Compared with agar proportion, the suscepti<em>b</em>ility of 44 specimens positive on culture-ddPCR showed sensitivity and specificity for RMP, <em>INH</em> and SM of respectively 83.3% (95%CI 50.9-97.1) and 90.6% (95%CI 73.8-97.6); 79.0% (95%CI 53.9-93.0) and 92% (95%CI 72.5-98.6); 94.1% (95%CI 69.2-99.7) and 92.6% (95%CI 74.3-98.7).</p><p><div>(<em>b</em>)CONCLUSION</<em>b</em>)</div>Culture ddPCR could detect <i>M. tu<em>b</em>erculosis</i> within 5 h and drug suscepti<em>b</em>ility within 4 days directly from sputum, which would greatly reduce the la<em>b</em>oratory time needed for tu<em>b</em>erculosis diagnosis.</p>

Publicly funded human immunodeficiency virus (HIV) clinics in Los Angeles County, California, USA.

HIV-infected persons are a high priority group for targeted testing and treatment for Mycobacterium tuberculosis infection in the United States.

To describe rates of isoniazid (INH) initiation and completion among HIV-1 and M. tuberculosis co-infected persons in Los Angeles County.

We conducted a cross-sectional study using routinely collected surveillance data from publicly funded HIV clinics. We examined differences in INH treatment initiation and completion between four clinic categories: the three largest clinics (Clinics A, B, and C) and 'Other' clinics (pooled data for the remaining 10 clinics).

During 2010-2013, 802 (5.3%) of 15 029 HIV-1-infected persons tested positive for M. tuberculosis infection. INH was initiated in 581 (72.4%) persons, of whom 457 (78.7%) completed treatment. We found significant differences between clinics in terms of treatment initiation (range 59.1-93.4%) and completion (range 58.8-82.3%). Overall, 57% (457/802) of HIV and M. tuberculosis co-infected persons completed the recommended treatment (range across clinics 34.8-76.3%).

We identified significant gaps in the treatment for M. tuberculosis infection among HIV-infected persons in Los Angeles County. Interventions are needed to improve initiation and completion of treatment for M. tuberculosis infection in this population.

Vaccination to prevent hepatitis B and tuberculosis (TB) forms a part of the national immunization program in the Kingdom of Saudi Arabia. The hepatitis B vaccination was introduced in the Makkah region in January 1991G. Since then, 25 children have developed post vaccination subcutaneous abscesses at the site of vaccination. Microbiological studies proved these to be of bacillus Calmette-Guerin vaccine (BCG) origin. Ten patients were treated successfully with isoniazid (INH) and rifampicin and 15 with INH alone. Four patients required incision and drainage. Possible reasons for this complication in our patients are discussed.