The impact of the COVID-19 pandemic on TB notifications in Ukraine in 2020.

BACKGROUND: We assessed the impact of the COVID-19 pandemic on TB notifications in Ukraine, stratified by multiple subgroups. DESIGN/METHODS: We analyzed data from Ukraine's National TB Program from January 2015 to December 2020 using interrupted time series models. We compared observed cases to counterfactual estimated cases had the pandemic not occurred and estimated trends through December 2020 nationally and by various demographics. We compared the proportions of individuals who underwent drug susceptibility testing (DST) in February 2020 and April 2020 to assess the pandemic impact on drug resistance testing. RESULTS: In April 2020, there were 39% (95% CI 36-42) fewer TB notifications than the estimated counterfactual (3,060 estimated; 95% CI 2,918-3,202; 1,872 observed). We observed a greater decrease in notifications among refugees/migrants compared with non-refugees/migrants (64%, 95% CI 60-67 vs. 39%, 95% CI 36-42), and individuals aged <15 years compared with those aged ≥15 years (60%, 95% CI 57-64 vs. 38%, 95% CI 36-41). We also observed a decrease in the proportion of individuals receiving DST for several drugs. CONCLUSIONS: These findings underscore the challenges to TB prevention and care during disruption and may be generalizable to the current wartime situation, especially considering the substantial increase in refugees within and leaving Ukraine.

CONTEXTE: Nous avons évalué l'impact de la pandémie de COVID-19 sur les notifications de TB en Ukraine, stratifiées en plusieurs sous-groupes. CONCEPTION/MÉTHODES: Nous avons analysé les données du Programme national de lutte contre la TB de l'Ukraine de janvier 2015 à décembre 2020 à l'aide de modèles de séries chronologiques interrompues. Nous avons comparé les cas observés aux cas contrefactuels estimés si la pandémie n'avait pas eu lieu et les tendances estimées jusqu'en décembre 2020 à l'échelle nationale et selon divers groupes démographiques. Nous avons comparé les proportions de personnes ayant subi un test de sensibilité aux médicaments (DST) en février 2020 et avril 2020 pour évaluer l'impact de la pandémie sur les tests de résistance aux médicaments. RÉSULTATS: En avril 2020, il y avait 39% (IC à 95% 36­42) de notifications de TB de moins que le contrefactuel estimé (3 060 estimés ; IC à 95% 2 918­3 202 ; 1 872 observés). Nous avons observé une plus grande diminution des notifications chez les réfugiés/migrants par rapport aux non-réfugiés/migrants (64%, IC à 95% 60­67 contre 39%, IC à 95% 36­42), et les personnes âgées de <15 ans par rapport à celles âgées de ≥15 ans (60% ; IC à 95% 57­64 contre 38% ; IC à 95% 36­41). Nous avons également observé une diminution de la proportion de personnes recevant le DST pour plusieurs médicaments. CONCLUSIONS: Ces résultats soulignent les défis de la prévention et des soins de la TB pendant les perturbations et peuvent être généralisés à la situation actuelle en temps de guerre, en particulier compte tenu de l'augmentation substantielle du nombre de réfugiés à l'intérieur et à l'extérieur de l'Ukraine.

Remaining challenges in catheter ablation of accessory pathways: rare entity of coronary sinus diverticulum-associated pathways.

INTRODUCTION: A limited number of case reports of coronary sinus (CS) diverticula complicating catheter ablation have been published. METHODS AND RESULTS: We retrospectively analysed 2245 patients who underwent ablation of an accessory pathway (AP) at our institution between 1/11/1993 and 31/10/2016. Eight patients (0.36%) were found to have a CS diverticulum in venography. APs showed a mean antegrade conduction time of 276 ± 23 ms (range 220-310 ms) and a mean retrograde conduction of 301 ± 45 ms (230-350 ms). Four patients had 1 (n = 2), 2 (n = 1), or 3 (n = 1) previously failed ablation attempts. Pathways could not be ablated with a conventional 4 mm tip catheter in 7 of 8 cases. In seven patients, ablation was successful, in two using an 8-mm ablation catheter, in two using cryoablation, and in the remaining three with an irrigated tip ablation catheter. After failed femoral approach, one 9-year-old female was successfully ablated via the right jugular vein. In one 75-year-old female, ablation was not successful. During a mean follow-up of 8.9 ± 6.4 years, all patients remained free of recurrences. CONCLUSION: In inferoseptal pathways, especially with previous failed ablation attempts, venographies of the CS should be performed. After successful ablation long-term prognosis is excellent.

Idiopathic ventricular outflow tract arrhythmias from the great cardiac vein: challenges and risks of catheter ablation.

INTRODUCTION: Catheter ablation for idiopathic ventricular arrhythmia is well established but epicardial origin, proximity to coronary arteries, and limited accessibility may complicate ablation from the venous system in particular from the great cardiac vein (GCV). METHODS: Between April 2009 and October 2010 14 patients (56 ± 15 years; 9 male) out of a total group of 117 patients with idiopathic outflow tract tachycardias were included undergoing ablation for idiopathic VT or premature ventricular contractions (PVC) originating from GCV. All patients in whom the PVC arose from the GCV were subject to the study. In these patients angiography of the left coronary system was performed with the ablation catheter at the site of earliest activation. RESULTS: Successful ablation was performed in 6/14 (43%) and long-term success was achieved in 5/14 (36%) patients. In 4/14 patients (28.6%) ablation was not performed. In another 4 patients (26.7%), ablation did not abolish the PVC/VT. In the majority, the anatomical proximity to the left coronary system prohibited effective RF application. In 3 patients RF application resulted in a coronary spasm with complete regression as revealed in repeat coronary angiography. CONCLUSION: A relevant proportion idiopathic VT/PVC can safely be ablated from the GCV without significant permanent coronary artery stenosis after RF application. Our data furthermore demonstrate that damage to the coronary artery system is likely to be transient.

Risk stratification in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiomyopathy characterized by myocyte death and fibrofatty replacement mostly in the right ventricle. It is a leading cause of sudden cardiac death (SCD) in individuals under the age of 35 years. The main goal in the treatment of the disease is the prevention of SCD. An implantable cardioverter-defibrillator (ICD) is the only proven life-saving therapeutic option able to improve survival in ARVC patients. This therapy is not free from side effects and it accounts for a relatively high rate of morbidity because of the occurrence of inappropriate ICD interventions and of complications, both at implantation and during the follow-up. In recent years, the approach to ICD implantation has been changing on the basis of new emerging data on risk stratification. The usefulness of ICD implantation for secondary prevention has been definitively proven; the most challenging question is how to treat patients with no history of previous cardiac arrest or hemodynamically unstable ventricular tachycardia (VT). The value of ECG abnormalities, syncope, VT, and right/left ventricular involvement as predictors of SCD has been assessed in different studies with the purpose of better defining risk stratification in ARVC. Nevertheless, in spite of the growing amount of data, primary prevention in ARVC patients remains mostly an individual decision.

[Current status and problems of the entirely subcutaneous ICD (S-ICD®)]. / Gegenwärtiger Stand und Probleme vollständig subkutaner ICD-Systeme (S-ICD®).

Prevention of sudden cardiac death is one of the most important tasks of cardiology. Transvenous ICD-systems have impressively proven their effectiveness in numerous randomized trials. Transvenous systems have their limitations due to frequent long-term lead complications. Having been available for a few years, the entirely subcutaneous ICD-system (S-ICD®, Boston Scientific, USA, former Cameron Health, USA) seems to be a promising alternative despite the lack of prospective data. The implantation of the SICD® can be performed easily; lead complications are rare because of the totally subcutaneous implantation. The detection and therapy of life-threatening tachyarrhythmias seems to be safe, although inappropriate therapies are a common problem in cases of insufficient ECG screening. S-ICD® is no alternative to the transvenous system due to limited programming options and the lack of stimulation, but it is an interesting supplement of ICD therapy.

[Totally subcutaneous cardioverter-defibrillator (S-ICD®) : recent experience and future perspectives]. / Komplett subkutaner Kardioverter-Defibrillator (S-ICD®) : Aktuelle Erfahrungen und Ausblick.

The implantable cardioverter defibrillator (ICD) is an established therapy for patients at risk of sudden cardiac death. Nevertheless the endocardial electrode in conventional systems plays a major role in long-term complications (difficult removal, risk of endocarditis, etc.). The totally subcutaneous ICD (S-ICD®, Cameron Health, San Clemente, CA, USA) represents a new and particularly significant development in ICD therapy which, since it requires no electrode in or on the heart, results in significantly fewer perioperative and long-term complications (e.g., thromboembolism and endocarditis risk). Although we see an indication for primary and secondary prevention, patients need to be informed about the limited data from randomized trials with the S-ICD®. As there is no permanent pacing option, patients in whom a pacemaker is indicated are not appropriate candidates for S-ICD®. In addition, patients with ventricular tachycardias that can be terminated by antitachycardic pacing are not recommended for the device. In the present article, we report our initial experience with the 18 patients implanted with the S-ICD® to date, comment on the available studies and offer a critical perspective.

[The ICD as primary prevention. Rare indications]. / ICD-Therapie zur Primärprävention. Seltene Indikationen.

The most frequent cause of sudden cardiac death (SCD) is underlying coronary artery disease. Healthy appearing young individuals are affected in a minority of cases. These individuals are usually diagnosed with electrical or genetically determined structural heart disease. Arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, long and short QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and early repolarization syndrome are generally considered rare underlying causes of SCD in these young patients. Affected patients typically present with syncope or cardiac arrest. Occasionally, disease is diagnosed during family screening. Risk stratification is difficult in this patient population. Risk of sudden death has to be weighed individually against risks associated with an implantable cardioverter defibrillator (ICD) in these young patients.

Diastolic filling pattern and left ventricular diameter predict response and prognosis after cardiac resynchronisation therapy.

OBJECTIVE: To investigate predisposing factors for cardiac resynchronisation therapy (CRT) response. DESIGN: Single-centre study. SETTING: University hospital in Germany. PATIENTS: 122 consecutive patients with heart failure (mean (SD) age 65 (11) years; ischaemic/non-ischaemic 41%/55%; New York Heart Association (NYHA) class 3.1 (0.3); left ventricular ejection fraction 24.4 (8.1)%; QRS width 170 (32) ms, quality of life (QoL) 43.5 (19.2)) with an indication for CRT and demonstrated left ventricular dyssynchrony by echocardiography including tissue Doppler imaging. INTERVENTIONS: Besides laboratory testing of clinical variables, results of ECG, echocardiography including tissue Doppler imaging, invasive haemodynamics, measures of QoL and of exercise capacity were obtained before CRT implantation and during follow-up. MAIN OUTCOME MEASURE: Responders were predefined as patients with improvement by one or more NYHA functional class or reduction of left ventricular end-systolic volume by 10% or more during follow-up. Mean (SD) follow-up was 418 (350) days. RESULTS: Overall, 70.5% of patients responded to CRT. Responders had a significantly improved survival compared with non-responders (96.2% vs 45.5%, log-rank p<0.001). On univariate analysis, left ventricular end-diastolic diameter, left ventricular end-systolic diameter (LVESD), E/A ratio, a restrictive filling pattern, mean pulmonary artery pressure, pulmonary capillary pressure, N-terminal pro-brain natriuretic peptide and Vo(2)max were significant predictors of outcome. On multivariate analyses, LVESD (p = 0.009; F = 7.83), pulmonary capillary pressure (p = 0.015, F = 6.61) and a restrictive filling pattern (p = 0.026, F = 5.707) remained significant predictors of response. CONCLUSIONS: Despite treatment according to present guidelines nearly 30% of patients had no benefit from CRT treatment in a clinical setting. On multivariate analyses, patients with an increased left ventricular end-systolic diameter and concomitant diastolic dysfunction had a significantly worse outcome.

Reactivity of anomeric 1alpha- and 1beta-pentofuranosyl azide derivatives in ammonia chemical ionization.

Electron impact (EI), fast atom bombardment (FAB) and ammonia chemical ionization [CI(NH3)] mass spectrometry were applied with the aim of differentiating between the anomeric 1alpha- and 1beta-azidopentofuranosyl derivatives. Calculated ammonium affinities [AA(M)] and proton affinities [PA(M)] show that beta-anomers have higher affinities for H+ and NH4+ ions than alpha-azides. Protonated molecules, obtained by CI(NH3) of azidofuranosyl derivatives, lose HN3 giving abundant furanosyl (S+) ions. Ammonia solvation of MH+ ions competes with the previous reaction producing the [SNHN2NH3]+ ion, a competitive product to the ammonium-attached [SN3NH4]+ ion. The fragmentation pathways of the stable and metastable [MNH4]+, MH+ ions, and several other important fragment ions, were determined using mass analyzed ion kinetic energy spectrometry (MIKES). The abundance of the [SN3NH4]+ and/or [SNHN2NH3]+ ions was found to correlate inversely with the exothermicity of ammonia solvation of the MH+ ion. The abundance of the fragment ions [SNHNH3]+, [SNH3]+ and SNH+ in some examples correlates with the exothermicity of the corresponding [MNH4]+ and MH+ parent ion formation. The fragment ions SNH3+ and SNHNH3+ can be formed, at least in part, in the ammonia solvation reaction of the S+ and SNH+ ions taking place within the high-pressure region of the CI ion source.

Synthesis, Characterization and Antiviral Properties of Pd(II) Complexes With Penciclovir.

With the aim to improve and extend the antiviral activity of the antiherpic drug penciclovir, to a wider spectrum of viruses, we have synthesized and characterized new binary and ternary complexes of Pd(II) of formulae cis-(pen)(2)PdCl(2) and cis,[(nucl)(2)Pd(pen)(2)]Cl(2), where nucl = guanosine, inosine, cytidine or penciclovir. The characterization was mainly based on IR and (1)H NMR spectroscopy, and the results showed that in all prepared complexes, penciclovir coordinates to the metal through N7. The far-i.r. spectrum of the complex cis-(pen)(2)PdCl(2) confirmed the cis- geometry around Pd(II). All the prepared complexes were markedly active against HSV-1 and HSV-2 strains, but not against thymidine kinase-deficient HSV-1 strains.

Stereoselective synthesis of 1,2-cis- and 2-deoxyglycofuranosyl azides from glycosyl halides.

Protected 1,2-cis glycofuranosyl azides with alpha-D-ribo, beta-D-arabino and 2-deoxy-2-fluoro-beta-D-arabino configurations were efficiently prepared from the appropriate 1,2-trans glycosyl halides bearing non-participating 0-2 substituent by inversion with sodium azide under phase transfer catalytic conditions (80-85% yields, 90-96% de). The same method failed to result in sufficiently good beta-selectivity starting from 2-deoxy-3,5-di-O-(p-toluoyl)-alpha-D-ery-thro-pentofuranosyl chloride (5alpha) (40% de). The selectivity in favour of the protected 2-deoxy-beta-D-erythro-pentofura-nosyl azides was greatly improved (74-80% de) by treating 5alpha and its p-chlorobenzoyl analog 6alpha with cesium or potassium azide in dimethylsulfoxide at room temperature (83-85% yields).

Studies on the origin of stereoselectivity in the synthesis of 1,2-trans glycofuranosyl azides.

The stereoselectivity of the 1,2-trans directed, Lewis acid-catalysed azidation of peracylated furanoses was found to depend on the reactivity of the azide donor (azide nucleophilicity) and the configuration at the anomeric centre relative to the neighbouring 2-O-acyl group. Reactions of 1,2-trans glycosyl esters with highly nucleophilic azide donors, generated from SnCl4 and Me3SiN3, were stereospecific. The results are interpreted in terms of the rapid reaction of the azide species with bicyclic 1,2-acyloxonium (1,2-O-alkyliumdiyl-D-glycofuranose) ions, which were the primarily formed reactive intermediates. When using 1,2-cis glycosyl esters as starting materials the selectivity was reduced (90-94% de); the same is true with 1,2-trans counterparts if less nucleophilic Me3SiN3 in combination with Me3SiOTf catalyst was used. This occurred due to the appearance of the more reactive but less selective oxocarbenium (glycofuranoxonium) ions either as primarily formed reactive intermediates in the former case or after equilibration with acyloxonium ions in the latter case. Protected 1,2-trans beta-D-glycofuranosyl azides with ribo, xylo and 3-deoxy-erythro-pento configurations were best prepared from the corresponding glycosyl esters using 0.05 equivalents of SnCl4, i.e., under anomerization-free conditions. Azidation of methyl glycofuranosides proceeds with inferior (80-90% de) and less predictable selectivity irrespective of the starting anomeric configuration.

Synthesis and antiviral activities of 2-substituted azino-3-(D-arabinofuranosyl)-5-carboxymethylene-thiazolidine-4-ones.

2-(1-Isopropylidene)azino-3-beta and 3-alpha-D-arabinofuranosyl-5-methoxycarbonylmethylenethiazolidine-4-ones (III) and (IV) have been synthesized by condensation of benzylated alpha-chloro-D-arabinofuranose (V) with o-(trimethylsilyl)-2-(1-isopropilidene)azino-5-methoxycarbonylmethylen- thiazolidine-4-one (VI) in the presence of SnCl4 or molecular sieves. Condensation of benzoylated alpha, beta-bromo-D-arabinose (VII) with (VI) led exclusively to the alpha anomer (VIII). 2-(1-Isopropylidene)azino-3-alpha-D-arabinofuranosyl-5-carbamoylmethylene- thiazolidine-4-one (IX) has been synthesized from (IV) (R, R1, R2 = CH3). 1H-N.M.R. and 13C-N.M.R. data confirmed the structures of (III) and (IV) (R, R1, R2 = CH3 and R, R1 = CH3, R2 = Ph). Antiviral activities were tested on monolayer cultures of KB-cells. Whereas previously tested beta-D-ribofuranosyl derivatives had moderate activity, alpha and/or beta-D-arabinofuranosyl derivatives are totally inactive against herpes simplex and poliovirus.

Conformation and structure of 2-amino-8-(beta-D-ribofuranosyl)imidazo [1,2-a]-s-triazin-4-one(5-aza-7-deaza guanosine), a potent antiviral nucleoside.

The crystal and molecular structure of one imidazo[1,2-a]-s-triazine nucleoside and its antiviral activity are described. The crystal structure of 2-amino-8-(beta-D-ribofuranosyl)imidazo[1,2-a]-s-triazin-4-one monohydroate (C10H13N5O5.H2O) was solved by X-ray counter data. The compound crystallizes in the monoclinic space group P21 with cell dimensions a = 7.353 (1), b = 6.465 (1), c = 13.701 (1) A, B = 104.64 (1) degrees. The structure was solved by direct methods and refined by full matrix least-squares technique to a final value of the conventional R-factor of 0.049 using 1998 observed intensities. The orientation of the base relative to the sugar ring defined in terms of rotating about the C(1')-N(8) glycosyl bond is anti (47.8 degrees). The ribose moiety exhibits C(2')-endo, E conformation. The conformation around C(4')-C(5') is gauche-. Molecular packing is dominated by hydrogen bonds. Base stacking occurs long the b axis. 5-Aza-7-deazaguanosine has shown a marked antiviral activity in vitro against herpes simplex virus despite the fact that N(3) is effective as the hydrogen acceptor only.