Clinical outcome of idiopathic juvenile ventricular arrhythmias in 25 dogs.

INTRODUCTION/OBJECTIVES: Juvenile ventricular arrhythmias in the absence of structural heart disease have been characterized in a small number of canine breeds with limited long-term follow up. The objective of this study was to describe the clinical outcome of dogs with JVA presenting to a university teaching hospital. ANIMALS, MATERIALS, METHODS: Twenty five dogs, less than two years old with idiopathic ventricular arrhythmias were retrospectively identified via a medical record search. Young dogs with ventricular arrhythmias were excluded if they had structural heart disease, systemic illness, or an abnormal troponin (if performed). Electrocardiographic and Holter monitor data was evaluated for arrhythmia frequency and complexity at the time of diagnosis and over time. Long-term follow up was achieved through client and primary veterinarian contact. RESULTS: Breeds included German Shepherd (eight), Boxer (four), Great Dane (three), mixed breed (two) and one each of the following: Anatolian Shepherd, French Bulldog, golden retriever, Great Pyrenees, Labrador retriever, Shiloh Shepherd, miniature Poodle and Siberian Husky. The average age at diagnosis was 7.9 months (range, 2-22 months). The overall median survival was 10.96 years (range, 1.75-15.66 years). There was an average reduction in the number of ventricular beats by 86.7 % per year (P value -0.0257) based on Holter data. CONCLUSION: In most cases, idiopathic juvenile ventricular arrhythmias had a favorable long-term prognosis with reduced ectopy over time in this case series. Juvenile ventricular arrhythmias remains a diagnosis of exclusion but can be considered in a broader range of dog breeds than previously described.

Causes of loss to follow-up from drug-resistant TB treatment in Khayelitsha, South Africa.

Patients initiated on drug-resistant TB(DR-TB) treatment in 2019 in Khayelitsha, South Africa, with a loss to follow-up outcome were evaluated to better understand reasons for loss to follow-up and to determine if any had returned to care. Of a total of 187 patients, 28 (15%) were lost to follow-up (LTFU), 24 (86%) of whom were traced: 20/24 (83%) were found when they re-presented to facilities and 8/28 (29%) were linked back to DR-TB care. People with DR-TB continue to seek care even after being LTFU; thus better coordination between different components of the healthcare system are required to re-engage with these patients. Interventions to mitigate the socio-economic challenges of people on DR-TB treatment are needed. Many people who were LTFU and symptomatic were willing to re-engage with DR-TB care, which highlights the importance of for compassionate interventions to welcome them back.

Les patients placés sous traitement pour TB pharmacorésistante (DR-TB) en 2019 à Khayelitsha, Afrique du Sud, et ayant été perdus de vue ont été évalués afin de mieux comprendre les raisons de la perte de vue et de déterminer si certains étaient de nouveau suivis. Sur 187 patients, 28 (15%) ont été perdus de vue, dont 24 (86%) ont été retrouvés : 20/24 (83%) ont été retrouvés lorsqu'ils se sont de nouveau présentés en consultation et 8/28 (29%) ont été réinsérés dans le parcours de soins de la DR-TB. Les patients atteints de DR-TB sont toujours en demande de soins, même après avoir été perdus de vue. Ainsi, une meilleure coordination entre les différentes composantes du système de santé est nécessaire afin de rétablir le lien avec ces patients. Des interventions visant à atténuer les problèmes socio-économiques des patients sous traitement pour DR-TB sont nécessaires. De nombreux patients symptomatiques ayant été perdus de vue étaient enclins à reprendre leur traitement de la DR-TB. Il est donc important de mettre en place des programmes compassionnels afin de les réinsérer dans le parcours de soins.

Early mortality during rifampicin-resistant TB treatment.

BACKGROUND: Data suggest that treatment with newer TB drugs (linezolid [LZD], bedaquiline [BDQ] and delamanid [DLM]), used in Khayelitsha, South Africa, since 2012, reduces mortality due to rifampicin-resistant TB (RR-TB).METHODS: This was a retrospective cohort study to assess 6-month mortality among RR-TB patients diagnosed between 2008 and 2019.RESULTS: By 6 months, 236/2,008 (12%) patients died; 12% (78/651) among those diagnosed in 2008-2011, and respectively 8% (49/619) and 15% (109/738) with and without LZD/BDQ/DLM in 2012-2019. Multivariable analysis showed a small, non-significant mortality reduction with LZD/BDQ/DLM use compared to the 2008-2011 period (aOR 0.79, 95% CI 0.5-1.2). Inpatient treatment initiation (aOR 3.2, 95% CI 2.4-4.4), fluoroquinolone (FQ) resistance (aOR 2.7, 95% CI 1.8-4.2) and female sex (aOR 1.5, 95% CI 1.1-2.0) were also associated with mortality. When restricted to 2012-2019, use of LZD/BDQ/DLM was associated with lower mortality (aOR 0.58, 95% CI 0.39-0.87).CONCLUSIONS: While LZD/BDQ/DLM reduced 6-month mortality between 2012 and 2019, there was no significant effect overall. These findings may be due to initially restricted LZD/BDQ/DLM use for those with high-level resistance or treatment failure. Additional contributors include increased treatment initiation among individuals who would have otherwise died before treatment due to universal drug susceptibility testing from 2012, an effect that also likely contributed to higher mortality among females (survival through to care-seeking).

Clinical perspectives on treatment of rifampicin-resistant/multidrug-resistant TB.

Rapid diagnostics, newer drugs, repurposed medications, and shorter regimens have radically altered the landscape for treating rifampicin-resistant TB (RR-TB) and multidrug-resistant TB (MDR-TB). There are multiple ongoing clinical trials aiming to build a robust evidence base to guide RR/MDR-TB treatment, and both observational studies and programmatic data have contributed to advancing the treatment field. In December 2019, the WHO issued their second 'Rapid Communication´ related to RR-TB management. This reiterated their prior recommendation that a majority of people with RR/MDR-TB receive all-oral treatment regimens, and now allow for specific shorter duration regimens to be used programmatically as well. Many TB programs need clinical advice as they seek to roll out such regimens in their specific setting. In this Perspective, we highlight our early experiences and lessons learned from working with National TB Programs, adult and pediatric clinicians and civil society, in optimizing treatment of RR/MDR-TB, using shorter, highly-effective, oral regimens for the majority of people with RR/MDR-TB.

Implementing novel regimens for drug-resistant TB in South Africa: what can the world learn?

Worldwide uptake of new drugs in the treatment of rifampicin-resistant tuberculosis (RR-TB) has been extremely low. In June 2018, ahead of the release of the updated WHO guidelines for the management of RR-TB, South Africa announced that bedaquiline (BDQ) would be provided to virtually all RR-TB patients on shorter or longer regimens. South Africa has been the global leader in accessing BDQ for patients with RR-TB, who now represent 60% of the global BDQ cohort. The use of BDQ within a shorter modified regimen has generated the programmatic data underpinning the most recent change in WHO guidelines endorsing a shorter, injectable-free regimen. Progressive policies on access to new drugs have resulted in improved favourable outcomes and a reduction in mortality among RR-TB patients in South Africa. This supported global policy change. The strategies underpinning these bold actions include close collaboration between the South African National TB Programme and partners, introduction of new TB diagnostic tools in closely monitored conditions and the use of locally generated programmatic evidence to inform country policy changes. In this paper, we summarise a decade´s work that led to the bold decision to use a modified, short, injectable-free regimen with BDQ and linezolid under carefully monitored programmatic conditions.

Adverse events among people on delamanid for rifampicin-resistant tuberculosis in a high HIV prevalence setting.

SETTING: Patients with rifampicin-resistant tuberculosis (RR-TB) in the township of Khayelitsha, South Africa, were offered delamanid (DLM) within a decentralised RR-TB treatment programme.OBJECTIVE: To describe adverse events (AEs) among HIV-positive and negative people receiving DLM for RR-TB in a programmatic setting.DESIGN: Patients were followed up monthly for blood, electrocardiography and clinical monitoring and AEs were assessed for severity grade, seriousness and relationship to DLM.RESULTS: Fifty-eight patients (55% male; median age 35 years, interquartile range [IQR] 28-42) started DLM; 46 (79%) were HIV-positive, median CD4 count 173 cells/mm³ (IQR 70-294). Fifty (86%) patients experienced ≥1 new or worsening AE after starting DLM, most commonly vomiting, QTcB >450 ms and/or myalgia. Serious and/or severe AEs were experienced by 22 (38%) patients; three HIV-positive patients died (not related to DLM). HIV status was not significantly associated with number (P = 0.089) or severity/seriousness (P = 0.11) of AEs during exposure to DLM. Two (3%) patients had DLM withdrawn due to AEs.CONCLUSION: AEs during RR-TB treatment, both before and during DLM exposure, were common, with relatively few serious/severe AEs considered related to DLM and no significant association with HIV status. Clinical and electrocardiography monitoring should be prioritised in the first two months after starting DLM.

Barriers and solutions to finding rifampicin-resistant tuberculosis cases in older children and adolescents.

Little is known about the barriers to post-exposure management of rifampicin-resistant tuberculosis (RR-TB) in older children and adolescents. We report on implementation lessons from a pilot programme targeting household-exposed individuals aged 6-18 years in Khayelitsha, South Africa. Barriers included misperceptions regarding risk of exposure, multiple research and implementation stakeholders, additional workload for an overburdened healthcare system, logistical issues faced by families, and insufficient human and financial resources. Solutions to these barriers are possible, but creativity and persistence are required. Our experience can guide others looking to roll-out care for children and adolescents exposed to RR-TB.

On connaît mal les entraves à la prise en charge post-exposition de la tuberculose résistante à la rifampicine (RR-TB) chez les enfants plus âgés et les adolescents. Nous rapportons les leçons de la mise en œuvre d'un programme pilote ciblant les individus exposés dans leurs foyers, âgés de 6­18 ans, à Khayelitsha, Afrique du Sud. Les obstacles ont inclus des perceptions erronées à propos du risque d'exposition, la multiplicité des partenaires de recherche et de mise en œuvre, la charge de travail supplémentaire pour un système de santé déjà surchargé, les problèmes logistiques auxquels sont confrontées les familles, et l'insuffisance des ressources humaines et financières. Il y a des solutions possibles à ces obstacles mais elles demandent de la créativité et de la détermination. Notre expérience peut guider ceux qui veulent lancer la prise en charge des enfants et des adolescents exposés à la RR-TB.

Se conoce poco sobre los factores que obstaculizan la atención después de la exposición a un caso de tuberculosis resistente a rifampicina (RR-TB) en los niños mayores y los adolescentes. En el presente artículo se describen las enseñanzas aprendidas durante la ejecución de un programa piloto dirigido a los contactos domiciliarios expuestos entre los 6 y los 18 años de edad, en Khayelitsha, Suráfrica. Entre los obstáculos observados se pueden citar las percepciones equivocadas sobre el riesgo de exposición, la multiplicidad de interesados directos en la investigación y la ejecución, la carga de trabajo adicional en un sistema de salud sobresaturado, los problemas organizativos afrontados por las familias y la insuficiencia de recursos humanos y de financiamiento. Las soluciones a estos problemas son posibles, pero exigen creatividad y persistencia. Esta experiencia puede orientar a otros equipos que intenten poner en marcha la atención de los niños y los adolescentes expuestos a la RR-TB.

Assessing psychological and supportive care needs in glioma patients - feasibility study on the use of the Supportive Care Needs Survey Short Form (SCNS-SF34-G) and the Supportive Care Needs Survey Screening Tool (SCNS-ST9) in clinical practice.

Neuro-oncological patients experience high symptom and psychosocial burden. The aim was to test feasibility and practicability of the Supportive Care Needs Survey Short Form (SCNS-SF34-G) and the SCNS-Screening Tool (SCNS-ST9) to assess supportive care needs of neuro-oncological patients in clinical routine. A total of 173 patients, most with a primary diagnosis of high-grade glioma (81%), were assessed first using SCNS-SF34-G in comparison to two well-established patient-reported outcome measures, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQC30 + QLQ-BN20) and Distress Thermometer (DT). In a follow-up assessment, SCNS-ST9 was used in a subgroup (n = 90). Questionnaires were completed either with personal guidance offered (group A) or by patients alone (group B). Feasibility was compared between instruments and groups for possible associations with patient and treatment-related factors. Missing values occurred in similar frequencies in all instruments. Errors in completion occurred in SCNS-SF34-G in 20% and in SCNS-ST9 in 16%; difficulties in completion were observed more often in SCNS-SF34-G and SCNS-ST9 (39%) compared to DT and EORTC (13%, p < .001). Distress was found to be associated with difficulties in completion of SCNS (OR 1.4, [95% CI 1.1-1.9], p = .013). SCNS-SF34 and SCNS-ST9 are suitable tools for glioma patients as long as personal guidance is offered.

The devil we know: is the use of injectable agents for the treatment of MDR-TB justified?

For decades, second-line injectable agents (IAs) have been the cornerstone of treatment for multidrug-resistant tuberculosis (MDR-TB). Although evidence on the efficacy of IAs is limited, there is an expanding body of evidence on the serious adverse events caused by these drugs. Here, we present the results of a structured literature review of the safety and efficacy of IAs. We review the continued widespread use of these agents in the context of therapeutic alternatives-most notably the newer TB drugs, bedaquiline and delamanid-and from the context of human rights, ethics and patient-centered care. We conclude that there is limited evidence of the efficacy of IAs, clear evidence of the risks of these drugs, and that persons living with MDR-TB should be informed about these risks and provided with access to alternative therapeutic options.

Mass spectrometry to complement standardization of house dust mite and other complex allergenic extracts.

In the United States, the Center for Biologics Evaluation and Research of the US Food and Drug Administration regulates biologics used for diagnosis and treatment of allergic diseases. The Code of Federal Regulations 21CFR680.3(e) states that when measured, the potency of an allergenic extract is assessed according to its allergenic activity. As of 2016, 19 allergenic extracts are standardized for potency in the United States. While these standardized extracts constitute a minority of those available, they treat the most prevalent allergies (e.g. grass and ragweed pollens, dust mites, and cat) and those that induce life-threatening anaphylaxis (e.g. Hymenoptera venom). Standardization for potency enhances safety and efficacy of immunotherapy by minimizing the risks of variations in allergen dosing when switching from one lot of manufactured extract to another, and by providing an objective measure of stability of each lot of allergenic extract over time. Allergenic extracts that have multiple immunodominant allergenic proteins are standardized with little or no information about compositional differences among extracts. Here, we propose application of mass spectrometry towards measurement of compositional differences among extracts that may affect the efficacy and safety of allergen immunotherapy. In addition, we discuss of house dust mite allergen extracts as a prototypical complex extract that may be standardized by mass spectrometry.

Synthesis of heteroatomic bridged paracyclophanes.

Heteroatomic bridged paracyclophanes were obtained by two independent synthetic approaches. The required precursors consist of para R2SiCl (R = Me, iPr) substituted aromatic rings (2 and 4). They were subsequently functionalised by using NH3, [LiPH2(dme)] or LiAl(PH2)4. In the case of the Me-substituted species 2, the reaction with NH3 directly yielded the Si2N bridged paracyclophane 5. The Si2P incorporated derivative 10 was obtained by lithiation of p-C6H4(SiiPr2PH2)2 (9) and subsequent salt metathesis with the chlorosilane 4. The second approach involves the use of GaEt3 in the formation of four membered (GaPn)2 cycles (Pn = N, P). p-[C6H4{SiiPr2N(H)GaEt2}2]2 (11) and p-[C6H4{SiiPr2P(H)GaEt2}2]2 (12) represent the first examples of stable (GaPn)2cis isomers as the trans species did not appear in solution. Although 11 and 12 show a similar coordination pattern, they differ in the orientation of the aromatic systems: in the solid structure, 11 adopts a - for paracyclophanes so far unique - T-shape conformation of the phenyl rings, while 12 shows the predominant coplanar orientation. All cyclophanes were characterized by X-ray diffraction, elemental analysis, NMR and IR spectroscopy.

The conformational IgE epitope profile of soya bean allergen Gly m 4.

BACKGROUND: Birch pollen-related soya allergy is mediated by Gly m 4. Conformational IgE epitopes of Gly m 4 are unknown. OBJECTIVE: To identify the IgE epitope profile of Gly m 4 in subjects with birch pollen-related soya allergy utilizing an epitope library presented by Gly m 4-type model proteins. METHODS: Sera from patients with (n = 26) and without (n = 19) allergy to soya as determined by oral provocation tests were studied. Specific IgE (Bet v 1/Gly m 4) was determined by ImmunoCAP. A library of 59 non-allergenic Gly m 4-type model proteins harbouring individual and multiple putative epitopes for IgE was tested in IgE binding assays. Primary, secondary and tertiary protein structures were assessed by mass spectrometry, circular dichroism and nuclear magnetic resonance spectroscopy. RESULTS: All subjects were sensitized to Gly m 4 and Bet v 1. Allergen-specific serum IgE levels ranged from 0.94 to > 100 kUA /L. The avidities of serum IgE were 5.06 ng (allergic) and 1.8 ng (tolerant) as determined by EC50 for IgE binding to Gly m 4. 96% (46/48) of the protein variants bound IgE. Model proteins had Gly m 4-type conformation and individual IgE binding clustered in six major surface areas. Gly m 4-specific IgE binding could be inhibited to up to 80% by model proteins harbouring individual IgE binding sites in an epitope-wise equimolar fashion. Receiver operating curve analysis revealed an area under fitted curve of up to 0.88 for model proteins and 0.66 for Gly m 4. CONCLUSION AND CLINICAL RELEVANCE: Serum levels and avidity of Gly m 4-specific IgE do not correlate with clinical reactivity to soya. Six IgE-binding areas, represented by 23 amino acids, account for more than 80% of total IgE binding capacity of Gly m 4. Model proteins may be used for epitope-resolved diagnosis to differentiate birch-soya allergy from clinical tolerance.

Epicutaneous immunotherapy with a hypoallergenic Bet v 1 suppresses allergic asthma in a murine model.

BACKGROUND: Due to reduced allergic potency, hypoallergenic variants have been suggested as safer and potentially more efficacious alternative to the corresponding wild-type allergens in allergen-specific immunotherapy. Here, we aimed at investigating the efficacy of recombinant Bet v 1B2, a hypoallergenic folding variant of Bet v 1, in epicutaneous immunotherapy to suppress asthmatic features using a murine model of birch pollen allergy. METHODS AND RESULTS: Before, or after sensitization with rBet v 1 plus ALUMW and intranasal challenges with birch pollen extract, BALB/c mice received epicutaneous immunization (EPI) with rBet v 1, or rBet v 1B2 on their depilated back. Prophylactic EPI with rBet v 1B2, but not with rBet v 1, suppressed serum levels of Bet v 1-specific IgE antibodies and reduced the number of eosinophils and the concentrations of Th2 cytokines in bronchoalveolar lavage. In an established allergic condition, serum levels of Bet v 1-specific IgE antibodies were similar between PBS-treated control mice and EPI-treated mice. However, therapeutic EPI with rBet v 1B2, but not with rBet v 1, significantly suppressed the development of airway inflammation and lung function impairment. CONCLUSION: This study is the first to show the effect of therapeutic EPI with a recombinant form of a hypoallergenic folding variant on the suppression of asthmatic features. Our results suggest that rBet v 1B2 along with its reduced IgE-binding capacity could be a preferred therapeutic allergen than wild-type rBet v 1 in epicutaneous immunotherapy of birch pollen-induced allergic asthma, in particular due to a lower risk of allergic side effect.