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Marika T Leving,1 Job FM van Boven,2– 4 Sinthia Z Bosnic-Anticevich,5,6 Joyce van Cooten,1 Jaime Correia de Sousa,7 Biljana Cvetkovski,5 Richard Dekhuijzen,8 Lars Dijk,1 Marina García Pardo,9 Asparuh Gardev,10 Rados&lstrok;aw Gawlik,11 Iris van der Ham,1 Elisabeth Sophia Hartgers-Gubbels,10 Ymke Janse,1 Federico Lavorini,12 Tiago Maricoto,13 Jiska Meijer,1 Boyd Metz,1 David B Price,14,15 Miguel Roman-Rodríguez,9 Kirsten Schuttel,1 Nilouq Stoker,1 Ioanna Tsiligianni,16 Omar S Usmani,17 Janwillem H Kocks1,2,15,18 1General Practitioners Research Institute, Groningen, the Netherlands; 2University Medical Centre Groningen, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen, the Netherlands; 3University Medical Centre Groningen, Department of Clinical Pharmacy & Pharmacology, University of Groningen, Groningen, the Netherlands; 4Medication Adherence Expertise Centre of the Northern Netherlands (MAECON), Groningen, the Netherlands; 5Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia; 6Sydney Local Health District, Sydney, Australia; 7Life and Health Sciences Research Institute (ICVS), PT Government Associate Laboratory, School of Medicine, University of Minho, Braga, Portugal; 8Radboud University Medical Centre, Nijmegen, Netherlands; 9Primary Care Respiratory Research Unit, Instituto De Investigación Sanitaria De Baleares (IdISBa), Palma de Mallorca, Spain; 10Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 11Department of Internal Medicine, Allergology, Clinical Immunology, Medical University of Silesia, Katowice, Poland; 12Department of Experimental and Clinical Medicine, Careggi University Hospital, Florence, Italy; 13Faculty of Health Sciences, University of Beira Interior, Covilha, Portugal; 14Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 15Observational and Pragmatic Research Institute, Singapore; 16Department of Social Medicine, Health Planning Unit, Faculty of Medicine, University of Crete, Rethymno, Greece; 17Airway Disease, National Heart and Lung Institute (NHLI), Imperial College London and Royal Brompton Hospital, London, UK; 18Department of Pulmonology, University of Groningen, University Medical Centre Groningen, Groningen, the NetherlandsCorrespondence: Janwillem H Kocks, General Practitioners Research Institute, Professor Enno Dirk Wiersmastraat 5, Groningen, 9713 GH, the Netherlands, Tel +31 50 211 3898, Email janwillem@gpri.nlPurpose: To assess the relationship between suboptimal Peak Inspiratory Flow (sPIF), inhalation technique errors, and non-adherence, with Healthcare Resource Utilisation (HCRU) in Chronic Obstructive Pulmonary Disease (COPD) patients receiving maintenance therapy via a Dry Powder Inhaler (DPI).Patients and methods: The cross-sectional, multi-country PIFotal study included 1434 COPD patients (≥ 40 years) using a DPI for maintenance therapy. PIF was measured with the In-Check DIAL G16, and sPIF was defined as a typical PIF lower than required for the device. Inhalation technique was assessed by standardised evaluation of video recordings and grouped into 10 steps. Patients completed the “Test of Adherence to Inhalers” questionnaire. HCRU was operationalised as COPD-related costs for primary healthcare, secondary healthcare, medication, and total COPD-related costs in a 1-year period.Results: Participants with sPIF had higher medication costs compared with those with optimal PIF (cost ratio [CR]: 1.07, 95% CI [1.01, 1.14]). Multiple inhalation technique errors were associated with increased HCRU. Specifically, “insufficient inspiratory effort” with higher secondary healthcare costs (CR: 2.20, 95% CI [1.37, 3.54]) and higher total COPD-related costs (CR: 1.16, 95% CI 1.03– 1.31). “no breath-hold following the inhalation manoeuvre (< 6 s)” with higher medication costs (CR: 1.08, 95% CI [1.02, 1.15]) and total COPD-related costs (CR 1.17, 95% CI [1.07, 1.28]), and “not breathing out calmly after inhalation” with higher medication costs (CR: 1.19, 95% CI [1.04, 1.37]). Non-adherence was not significantly associated with HCRU.Conclusion: sPIF and inhalation technique errors were associated with higher COPD-related healthcare utilisation and costs in COPD patients on DPI maintenance therapy.Keywords: chronic obstructive pulmonary disease, Dry Powder Inhaler, health economics, cost analysis, healthcare resource utilisation

Background: Correct inhaler use depends on a complex interplay of factors, including device preparation and generating sufficient inspiratory flow. It is currently unknown which inhalation technique errors can be considered critical in Chronic Obstructive Pulmonary Disease (COPD) patients on Dry Powder Inhaler (DPI) maintenance therapy., Objective: To investigate the association between inhalation technique errors and health status or exacerbations in patients with COPD. Additionally, the association between the number of errors and COPD outcomes was determined., Methods: The PIFotal study is a cross-sectional multi-country observational study in a primary care setting, including 1434 COPD patients aged ≥ 40 years (50.1% female; mean age 69.2 yrs) using a DPI for their maintenance therapy. Inhalation technique was video recorded and scored by two independent researchers using inhaler-specific checklists. Health status was assessed with two questionnaires; the Clinical COPD Questionnaire (CCQ) and the COPD Assessment Test (CAT). The number of moderate and severe exacerbations in the past 12 months was recorded. Critical errors were identified based on their association with health status or exacerbations through multi-level prediction models adjusted for identified confounding., Results: Errors in inhalation technique steps 'Breathe in', 'Hold breath', and 'Breathe out calmly after inhalation' were significantly associated with poorer CCQ and CAT outcomes and thus deemed critical. None of the errors were significantly associated with moderate exacerbations. Patients with errors 'Preparation', 'Hold inhaler in correct position during inhalation', and 'Breathe in' had significantly more severe exacerbations, and therefore these errors were also deemed critical. 81.3% of patients with COPD made at least one critical error. Specific combinations of errors were associated with worse outcomes. The more inhalation technique errors identified, the poorer the health status and the higher the exacerbation rate., Conclusion: In this study, we identified multiple critical inhalation technique errors in COPD patients using DPIs each associated with poorer outcomes. Explorative analysis revealed that specific combinations of errors may be of clinical relevance, especially those related to the inhalation manoeuvre. COPD outcomes worsened with increasing error count. These results warrant further prospective longitudinal studies to establish the effect of correcting these errors on COPD control., Trial Registration: https://clinicaltrials.gov/ct2/show/NCT04532853 (31/08/2020)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Smart inhalers are electronic monitoring devices which are promising in increasing medication adherence and maintaining asthma control. A multi-stakeholder capacity and needs assessment is recommended prior to implementation in healthcare systems. This study aimed to explore perceptions of stakeholders and to identify anticipated facilitators and barriers associated with the implementation of smart digital inhalers in the Dutch healthcare system. Data were collected through focus group discussions with female patients with asthma (n = 9) and healthcare professionals (n = 7) and through individual semi-structured interviews with policy makers (n = 4) and smart inhaler developers (n = 4). Data were analysed using the Framework method. Five themes were identified: (i) perceived benefits, (ii) usability, (iii) feasibility, (iv) payment and reimbursement, and (v) data safety and ownership. In total, 14 barriers and 32 facilitators were found among all stakeholders. The results of this study could contribute to the design of a tailored implementation strategy for smart inhalers in daily practice., (© 2023. The Author(s).)

Over 1400 patients using dry powder inhalers (DPIs) to deliver COPD maintenance therapies were recruited across Europe and Australia. Their peak inspiratory flow (PIF) was measured, inhaler technique was observed, and adherence to treatment assessed. From relating the findings with patient health status, and thereby identifying critical errors, key clinical recommendations for primary care clinicians were determined, namely - measure PIF before prescribing a DPI to ensure inhalation manoeuvre ability is well-matched with the device. Some patients could benefit from inhalation training whereas others should have their DPI changed for one better suited to their inspiratory ability or alternatively be prescribed an active device (such as a soft mist inhaler or pressurized metered dose inhaler). Observing the inhalation technique was valuable however this misses suboptimal PIF (approaching one fourth of patients with a satisfactory observed manoeuvre had a suboptimal PIF for their DPI). Assess adherence as deliberate non-adherence can point to a mismatch between a patient and their inhaler (deliberate non-adherence was significantly associated with PIFs below the minimum for the DPI). In-person observation of inhalation technique was found to be inferior to video rating based on device-specific checklists. Where video assessments are not possible, observation training for healthcare professionals would therefore be valuable particularly to improve the ability to identify the critical errors associated with health status namely 'teeth and lips sealed around mouthpiece', 'breathe in' and 'breathing out calmly after inhalation'. However, it is recommended that observation alone should not replace PIF measurement in the DPI selection process.Trial registration: https://clinicaltrials.gov/ct2/show/NCT04532853 ., (© 2022. The Author(s).)

Concentration dependency of phenotypic and genotypic isoniazid-rifampicin resistance emergence was investigated to obtain a mechanistic understanding on how anti-mycobacterial drugs facilitate the emergence of bacterial populations that survive throughout treatment. Using static kill curve experiments, observing two evolution cycles, it was demonstrated that rifampicin resistance was the result of non-specific mechanisms and not associated with accumulation of drug resistance encoding SNPs. Whereas, part of isoniazid resistance could be accounted for by accumulation of specific SNPs, which was concentration dependent. Using a Hollow Fibre Infection Model it was demonstrated that emergence of resistance did not occur at concentration-time profiles mimicking the granuloma. This study showed that disentangling and quantifying concentration dependent emergence of resistance provides an improved rational for drug and dose selection although further work to understand the underlying mechanisms is needed to improve the drug development pipeline., (© 2022. The Author(s).)

The study aimed to determine the associations of Peak Inspiratory Flow (PIF), inhalation technique and adherence with health status and exacerbations in participants with COPD using DPI maintenance therapy. This cross-sectional multi-country observational real-world study included COPD participants aged ≥40 years using a DPI for maintenance therapy. PIF was measured three times with the In-Check DIAL G16: (1) typical PIF at resistance of participant's inhaler, (2) maximal PIF at resistance of participant's inhaler, (3) maximal PIF at low resistance. Suboptimal PIF (sPIF) was defined as PIF lower than required for the device. Participants completed questionnaires on health status (Clinical COPD Questionnaire (CCQ)), adherence (Test of Adherence to Inhalers (TAI)) and exacerbations. Inhalation technique was assessed by standardised evaluation of video recordings. Complete data were available from 1434 participants (50.1% female, mean age 69.2 years). GOLD stage was available for 801 participants: GOLD stage I (23.6%), II (54.9%), III (17.4%) and IV (4.1%)). Of all participants, 29% had a sPIF, and 16% were shown able to generate an optimal PIF but failed to do so. sPIF was significantly associated with worse health status (0.226 (95% CI 0.107-0.346), worse units on CCQ; p = 0.001). The errors 'teeth and lips sealed around mouthpiece', 'breathe in', and 'breathe out calmly after inhalation' were related to health status. Adherence was not associated with health status. After correcting for multiple testing, no significant association was found with moderate or severe exacerbations in the last 12 months. To conclude, sPIF is associated with poorer health status. This study demonstrates the importance of PIF assessment in DPI inhalation therapy. Healthcare professionals should consider selecting appropriate inhalers in cases of sPIF., (© 2022. The Author(s).)

The development of vaccines and effective diagnostic methods for bovine tuberculosis requires an understanding of the immune response against its causative agent, Mycobacterium bovis. Although this disease is primarily investigated and diagnosed through the assessment of cell-mediated immunity, the role of B cells and antibodies in bovine tuberculosis has been relatively undervalued and understudied. Current evidence indicates that circulating M. bovis-specific antibodies are not effective in controlling the disease. However, local humoral immune responses may contribute to either defence or pathology. Recent studies in animal models and cattle vaccine trials suggest a potential beneficial role of B cells in tuberculosis control. This review discusses the role of B cells and antibodies in bovine tuberculosis and explores antibody-based diagnostics for the disease, including traditional techniques, such as different ELISA, new platforms based on multiple antigens and point-of-care technologies. The high specificity and sensitivity values achieved by numerous antibody-based tests support their use as complementary tests for the diagnosis of bovine tuberculosis, especially for identifying infected animals that may be missed by the official tests. [ABSTRACT FROM AUTHOR]

The polymerase chain reaction (PCR) was evaluated in a trial which, with respect to the positive-to-negative ratio, approximated the situation of a diagnostic laboratory in a tuberculosis-endemic area. Three hundred sputum samples were included in the study, of which one-third were known to contain mycobacteria as judged by direct microscopy. The repetitive insertion sequence IS 6110/IS 986 of Mycobacterium tuberculosis was used as a target. The samples were spiked with DNA from a modified IS 6110/IS 986 sequence, which gives rise to PCR products easily distinguished from PCR products amplified from chromosomal Mycobacterium tuberculosis DNA. This allowed identification of samples that contained substances inhibitory to the Taq polymerase. The detection limit of the assay was 0.05 pg to 0.5 pg of purified Mycobacterium tuberculosis DNA, corresponding to 10 to 100 organisms. The sensitivity and specificity of the PCR was compared with that of conventional microscopy and culture. It was concluded that this method is fast and sensitive, but that culture currently is crucial for assessing viability and thus infectivity. [ABSTRACT FROM AUTHOR]

Histidine-requiring auxotrophs of Mycobacterium smegmatis were isolated following W-methyl-W-nitro-N'-nitrosoguanidine treatment. One of these mutants, his5, was transformed with an M. smegmatis shuttle cosmid library, and complementing clones were isolated at a frequency of approximately 1%. A 2.3 kb fragment was subcloned and sequenced, and found to contain the start of an operon including the hisD gene and part of the hisC gene. No hisG gene was detected upstream of hisD, suggesting that the regulation of histidine biosynthesis in mycobacteria may differ from that of Escherichia coli. The strategy used here will allow the molecular genetics of complex mycobacterial-specific biosynthetic pathways involved in the virulence of pathogenic species to be studied. [ABSTRACT FROM AUTHOR]

The ability to construct defined deletions of Mycobacterium tuberculosis has allowed many genes involved in virulence to be identified. Deletion of nutritional genes leads to varying levels of attenuation, presumably reflecting the need for a particular molecule, and the availability (or lack) of that molecule in vivo. We have previously shown that M. tuberculosis mutants lacking either the trpD or ino1 gene are highly attenuated in mouse models of infection, but can grow when supplemented with tryptophan or inositol, respectively. In this paper we have constructed a double Delta trpDDelta ino1 mutant, and show that this is severely attenuated in SCID mouse and guinea pig models. As the strain will grow in the presence of supplements, we propose that this strain could be used for research and antigen preparative purposes, with reduced risks to laboratory workers.

Mycolic acids are major and specific lipid components of the cell envelope of mycobacteria that include the causative agents of tuberculosis and leprosy, Mycobacterium tuberculosis and Mycobacterium leprae, respectively. Subtle structural variations that are known to be crucial for both their virulence and the permeability of their cell envelope occur in mycolic acids. Among these are the introduction of cyclopropyl groups and methyl branches by mycolic acid S-adenosylmethionine-dependent methyltransferases (MA-MTs). While the functions of seven of the M. tuberculosis MA-MTs have been either established or strongly presumed nothing is known of the roles of the remaining umaA gene product and those of M. smegmatis MA-MTs. Mutants of the M. tuberculosis umaA gene and its putative M. smegmatis orthologue, MSMEG0913, were created. The lipid extracts of the resulting mutants were analyzed in detail using a combination of analytical techniques such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and proton nuclear magnetic resonance spectroscopy, and chemical degradation methods. The M. smegmatis mutants no longer synthesized subtypes of mycolates containing a methyl branch adjacent to either trans cyclopropyl group or trans double bond at the "proximal" position of both alpha- and epoxy-mycolates. Complementation with MSMEG0913, but not with umaA, fully restored the wild-type phenotype in M. smegmatis. Consistently, no modification was observed in the structures of mycolic acids produced by the M. tuberculosis umaA mutant. These data proved that despite their synteny and high similarity umaA and MSMEG0913 are not functionally orthologous.