Characterisation of patients referred to a tertiary-level inherited cardiac condition clinic with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC).

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) or arrhythmogenic cardiomyopathy is a rare inherited disease with incomplete penetrance and an environmental component. Although a rare disease, ARVC is a common cause of sudden cardiac death in young adults. Data on the different stages of ARVC remains scarce. The purpose of this study is to describe the initial presentation and cardiac phenotype of definite and non-definite ARVC for patients seen at a tertiary service. METHODS: This is a single centre, observational cohort study of patients with definite and non-definite ARVC seen at the Inherited Cardiac Conditions services at University Hospital Birmingham (UHB) in the period 2010-2021. Patients were identified by interrogation of digital health records, medical history, imaging and by examining 12-lead electrocardiograms (ECG). RESULT: The records of 1451 patients were reviewed; of those, 165 patients were at risk of ARVC (mean age 41 ± 17 years, 56% male). 60 patients fulfilled task force criteria for definite ARVC diagnosis (n = 40, 67% males), and 38 (72%) of them carried a known pathogenic variant. The remaining 105 patients (50% males) were non-definite, and of these 45 (62%) carried a known pathogenic variant. Patients in the definite group were more symptomatic, with palpitations (57% vs. 17%), syncope (35% vs. 6%) and shortness of breath (28% vs. 5%, p < 0.001). T-wave inversion in V1-V3 and epsilon waves were observed only in the definite group. Both PR interval and QRS duration were longer in the definite (170 ± 34 ms and 100 ± 19 ms, p < 0.001) compared to (149 ± 25 and 91 ± 14 ms, p = 0.005). Patients with definite ARVC had significantly larger RV end diastolic areas and significantly reduced biventricular function (RVEDA = 27 ± 10 cm2, RVFAC = 37 ± 11% and EF = 56 ± 12%) compared to the non-definite group (RVEDA = 18 ± 4 cm2, RVFAC 49 ± 6% and LVEF 64 ± 7%, p < 0.001). Sustained ventricular tachycardia (VT) occurred more frequently in the definite group compared to the non-definite group (27% vs. 2%, p < 0.001). Ventricular fibrillation was observed in the definite group only (8 of 60 patients, 13%). CONCLUSION: Our study showed differences between definite and non-definite ARVC patients in terms of clinical, electrophysiological and imaging features. Major adverse cardiac events occurred more commonly in the definite group, but also were observed in non-definite ARVC. This single centre observational cohort study forms a basis for further prospective multicentre interventional studies.

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).

Diverse clinical and social circumstances: developing patient-centred care for DR-TB patients in South Africa.

OBJECTIVE: To describe the medical, socio-economic and geographical profiles of patients with rifampicin-resistant TB (RR-TB) and the implications for the provision of patient-centred care. SETTING: Thirteen districts across three South African provinces. DESIGN: This descriptive study examined laboratory and healthcare facility records of 194 patients diagnosed with RR-TB in the third quarter of 2016. RESULTS: The median age was 35 years; 120/194 (62%) of patients were male. Previous TB treatment was documented in 122/194 (63%) patients and 56/194 (29%) had a record of fluoroquinolone and/or second-line injectable resistance. Of 134 (69%) HIV-positive patients, viral loads were available for 68/134 (51%) (36/68 [53%] had viral loads of >1000 copies/ml) and CD4 counts were available for 92/134 (69%) (20/92 [22%] had CD4 <50 cells/mm3). Patients presented with varying other comorbidities, including hypertension (13/194, 7%) and mental health conditions (11/194, 6%). Of 194 patients, 44 (23%) were reported to be employed. Other socio-economic challenges included substance abuse (17/194, 9%) and ill family members (17/194, 9%). Respectively 13% and 42% of patients were estimated to travel more than 20 km to reach their diagnosing and treatment-initiating healthcare facility. CONCLUSIONS: RR-TB patients had diverse medical and social challenges highlighting the need for integrated, differentiated and patient-centred healthcare to better address specific needs and underlying vulnerabilities of individual patients.

OBJECTIF: Décrire les profils médicaux, socioéconomiques et géographiques des patients atteints de TB résistante à la rifampicine (RR-TB) et les implications en matière de soins centrés sur le patient. CONTEXTE: Treize districts de trois provinces d'Afrique du Sud. MÉTHODE: Cette étude descriptive a analysé les dossiers médicaux et de laboratoire de 194 patients ayant reçu un diagnostic de RR-TB au troisième trimestre de 2016. RÉSULTATS: L'âge médian était de 35 ans ; 120/194 (62%) patients étaient des hommes. Un traitement antituberculeux antérieur était documenté chez 122/194 (63%) patients, et 56/194 (29%) avaient une résistance à la fluoroquinolone et/ou à un agent injectable de deuxième ligne documentée. Sur 134 (69%) patients infectés par le VIH, les charges virales étaient disponibles pour 68/134 (51%) patients (36/68 [53%] avaient des charges virales >1 000 copies/ml) et les taux de CD4 étaient disponibles pour 92/134 (69%) patients (20/92 [22%] avaient un taux de CD4 <50 cellules/mm3). Les patients présentaient diverses autres comorbidités, dont hypertension (13/194, 7%) et troubles psychiques (11/194, 6%). Sur les 194 patients, 44 (23%) avaient un emploi. Les autres problèmes socioéconomiques comprenaient la toxicomanie (17/194, 9%) et le fait d'avoir un membre de sa famille malade (17/194, 9%). Respectivement 13% et 42% des patients parcouraient plus de 20 km pour se rendre à leur centre de diagnostic et au centre de soins responsable de l'instauration du traitement. CONCLUSIONS: Les patients atteints de RR-TB avaient divers problèmes médicaux et sociaux. Ces résultats soulignent le besoin de soins intégrés, différenciés et centrés sur le patient afin de mieux répondre aux besoins spécifiques et aux vulnérabilités sous-jacentes de chaque patient.

Drug-resistant tuberculosis patient care journeys in South Africa: a pilot study using routine laboratory data.

SETTING: Thirteen districts in Eastern Cape (EC), KwaZulu-Natal (KZN) and Western Cape (WC) Provinces, South Africa.OBJECTIVE: To pilot a methodology for describing and visualising healthcare journeys among drug-resistant tuberculosis (DR-TB) patients using routine laboratory records.DESIGN: Laboratory records were obtained for 195 patients with laboratory-detected rifampicin-resistant TB (RR-TB) during July-September 2016. Health facility visits identified from these data were plotted to visualise patient healthcare journeys. Data were verified by facility visits.RESULTS: In the 9 months after the index RR-TB sample was collected, patients visited a mean of 2.3 health facilities (95% CI 2.1-2.6), with 9% visiting ≥4 facilities. The median distance travelled by patients from rural areas (116 km, interquartile range [IQR] 50-290) was greater than for urban patients (51 km, IQR 9-140). A median of 21% of patient's time was spent under the care of primary healthcare facilities: this was respectively 6%, 37% and 39% in KZN, EC and WC. Journey patterns were generally similar within districts. Some reflected a semi-centralised model of care where patients were referred to regional hospitals; other journeys showed greater involvement of primary care.CONCLUSION: Routine laboratory data can be used to explore DR-TB patient healthcare journeys and show how the use of healthcare services for DR-TB varies in different settings.

Opportunities from a new disease for an old threat: Extending COVID-19 efforts to address tuberculosis in South Africa.

The COVID-19 pandemic and phased nationwide lockdown have impacted negatively on individuals with tuberculosis (TB) and routine TB services. Through a literature review and the perspective of members of a national TB Think Tank task team, we describe the impact of the pandemic and lockdown on TB patients and services as well as the potential long-term setback to TB control in South Africa (SA). Strategies to mitigate risk and impact are explored, together with opportunities to leverage synergies from both diseases to the benefit of the National TB Programme (NTP). With the emergence of COVID-19, activities to address this new pandemic have been prioritised across all sectors. Within the health system, the health workforce and resources have been redirected away from routine services towards the new disease priority. The social determinants of health have deteriorated during the lockdown, potentially increasing progression to TB disease and impacting negatively on people with TB and their households, resulting in additional barriers to accessing TB care, with early reports of a decline in TB testing rates. Fewer TB diagnoses, less attention to adherence and support during TB treatment, poorer treatment outcomes and consequent increased transmission will increase the TB burden and TB-related mortality. People with TB or a history of TB are likely to be vulnerable to COVID-19. Modifications to current treatment practices are suggested to reduce visits to health facilities and minimise the risks of COVID-19 exposure. The COVID-19 pandemic has the potential to negatively impact on TB control in TB-endemic settings such as SA. However, there are COVID-19-related health systems-strengthening developments that may help the NTP mitigate the impact of the pandemic on TB control. By integrating TB case finding into the advanced screening, testing, tracing and monitoring systems established for COVID-19, TB case finding and linkage to care could increase, with many more TB patients starting treatment. Similarly, integrating knowledge and awareness of TB into the increased healthcare worker and community education on infectious respiratory diseases, behavioural practices around infection prevention and control, and cough etiquette, including destigmatisation of mask use, may contribute to reducing TB transmission. However, these potential gains could be overwhelmed by the impact of increasing poverty and other social determinants of health on the burden of TB.

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.

What will it take to eliminate drug-resistant tuberculosis?

Drug-resistant tuberculosis (DR-TB) is challenging to diagnose, treat, and prevent, but this situation is slowly changing. If the world is to drastically reduce the incidence of DR-TB, we must stop creating new DR-TB as an essential first step. The DR-TB epidemic that is ongoing should also be directly addressed. First-line drug resistance must be rapidly detected using universal molecular testing for resistance to at least rifampin and, preferably, other key drugs at initial TB diagnosis. DR-TB treatment outcomes must also improve dramatically. Effective use of currently available, new, and repurposed drugs, combined with patient-centered treatment that aids adherence and reduces catastrophic costs, are essential. Innovations within sight, such as short, highly effective, broadly indicated regimens, paired with point-of-care drug susceptibility testing, could accelerate progress in treatment outcomes. Preventing or containing resistance to second-line and novel drugs is also critical and will require high-quality systems for diagnosis, regimen selection, and treatment monitoring. Finally, earlier detection and/or prevention of DR-TB is necessary, with particular attention to airborne infection control, case finding, and preventive therapy for contacts of patients with DR-TB. Implementing these strategies can overcome the barrier that DR-TB represents for global TB elimination efforts, and could ultimately make global elimination of DR-TB (fewer than one annual case per million population worldwide) attainable. There is a strong cost-effectiveness case to support pursuing DR-TB elimination; however, achieving this goal will require substantial global investment plus political and societal commitment at national and local levels.

Health care gaps in the global burden of drug-resistant tuberculosis.

The drug-resistant tuberculosis (DR-TB) cascade-from estimated or incident cases to numbers successfully treated or disease-free survival-has long been characterised by sharp declines at each step in the cascade. The losses along the cascade vary across different settings, and the reasons why some countries have a higher burden of DR-TB are complex and multifactorial; broadly, weak health systems, inadequate financing and poverty all impact differential access to DR-TB care. Within a human rights framework that mandates the right to health and the right to benefit from scientific progress, the aim of this review is to focus on describing inequities in access to DR-TB care at critical points in the cascade.

Mucosal glucagon-like peptide 1 (GLP-1) responses are mediated by calcitonin gene-related peptide (CGRP) in the mouse colon and both peptide responses are area-specific.

BACKGROUND: Glucagon-like peptide (GLP)-1 is an incretin hormone and its mimetics are proven antidiabetic and antiobesity drugs. GLP-1 exerts antimotility and mucosal proliferative activities but its epithelial ion transport effects are uncharacterized and these may contribute to the gastrointestinal (GI) disturbance, i.e., diarrhea experienced with some GLP-1 mimetics. Our aim was to establish GLP-1 agonist mechanisms and identify potential mucosal mediator(s) in the colonic tissue from C57BL/6J mice. METHODS: A tissue survey of GLP-1 responses (using exendin 4, Ex4) and α-calcitonin gene-related peptide (αCGRP) was undertaken, dividing the mouse colon into eight adjacent mucosal-submucosal preparations. Each preparation was voltage-clamped and changes in short-circuit current (Isc) measured. The involvement of submucosal neurons in GLP-1 agonism was tested using Ex(9-39) and tetrodotoxin (TTX), and CGRP receptors were blocked with BIBN4094. KEY RESULTS: Ex4 responses along the length of the colon were inhibited by the GLP-1 antagonist, Ex(9-39) or TTX, indicating neural mediation in all colonic regions. In the ascending colon, Ex4 increased Isc levels that were abolished by 10 nM BIBN4096, while in the descending colon it reduced Isc levels that were again BIBN4096-sensitive, but at 1 µM. The latter αCGRP response was dependent on epithelial Cl- conductance and Na+ /K+ -ATPase, and was partially (~25%) peptide YY-mediated, but was not nitrergic, somatostatin sst2 , or α2 -adrenoceptor-mediated. CONCLUSIONS AND INFERENCES: GLP-1 modulates epithelial ion transport indirectly by activating CGRP-containing submucosal enteric neurons in the mouse colon. This GLP-1-CGRP response was area-specific and could potentially contribute to the diarrheal side effect of certain GLP-1R therapeutics.

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.

Time to treatment for rifampicin-resistant tuberculosis: systematic review and meta-analysis.

BACKGROUND: To reduce transmission and improve patient outcomes, rapid diagnosis and treatment of rifampicin-resistant tuberculosis (RR-TB) is required. OBJECTIVE: To conduct a systematic review and meta-analysis assessing time to treatment for RR-TB and variability using diagnostic testing methods and treatment delivery approach. DESIGN: Studies from 2000 to 2015 reporting time to second-line treatment initiation were selected from PubMed and published conference abstracts. RESULTS: From 53 studies, 83 cohorts (13 034 patients) were included. Overall weighted mean time to treatment from specimen collection was 81 days (95%CI 70-91), and was shorter with ambulatory (57 days, 95%CI 40-74) than hospital-based treatment (86 days, 95%CI 71-102). Time to treatment was shorter with genotypic susceptibility testing (38 days, 95%CI 27-49) than phenotypic testing (108 days, 95%CI 98-117). The mean percentage of diagnosed patients initiating treatment was 76% (95%CI 70-83, range 25-100). CONCLUSION: Time to second-line anti-tuberculosis treatment initiation is extremely variable across studies, and often unnecessarily long. Reduced delays are associated with genotypic testing and ambulatory treatment settings. Routine monitoring of the proportion of diagnosed patients initiating treatment and time to treatment are necessary to identify areas for intervention.

Missed opportunities for earlier diagnosis of rifampicin-resistant tuberculosis despite access to Xpert® MTB/RIF.

OBJECTIVE: To assess the proportion of rifampicin-resistant tuberculosis (RR-TB) patients with potential earlier RR-TB diagnoses in Khayelitsha, South Africa. DESIGN: We conducted a retrospective analysis among RR-TB patients diagnosed from 2012 to 2014. Patients were considered to have missed opportunities for earlier diagnosis if 1) they were incorrectly screened according to the Western Cape diagnostic algorithm; 2) the first specimen was not tested using Xpert® MTB/RIF; 3) no specimen was ever tested; or 4) the initial Xpert test showed a negative result, but no subsequent specimen was sent for follow-up testing in human immunodeficiency virus-positive patients. RESULTS: Among 543 patients, 386 (71%) were diagnosed with Xpert and 112 (21%) had had at least one presentation at a health care facility within the 6 months before the presentation at which RR-TB was diagnosed. Overall, 95/543 (18%) patients were screened incorrectly at some point: 48 at diagnostic presentation only, 38 at previous presentation only, and 9 at both previous and diagnostic presentations. CONCLUSIONS: These data show that a significant proportion of RR-TB patients might have been diagnosed earlier, and suggest that case detection could be improved if diagnostic algorithms were followed more closely. Further training and monitoring is required to ensure the greatest benefit from universal Xpert implementation.

A brief psychological intervention for mothers of children with food allergy can change risk perception and reduce anxiety: Outcomes of a randomized controlled trial.

BACKGROUND: Mothers of children with food allergy have increased anxiety, which may be influenced by healthcare professionals' communication of risk. OBJECTIVE: To evaluate a brief psychological intervention for reducing anxiety in mothers of children with food allergy. METHODS: Two hundred mothers of children with food allergy were recruited from allergy clinics. A computer-generated randomization list was used to allocate participants to a single-session cognitive behavioural therapy intervention including a risk communication module, or standard care. Anxiety and risk perception were assessed at 6 weeks and 1 year. Primary outcome was state anxiety at 6 weeks. Secondary outcomes included state anxiety at 1 year, risk perception at 6 weeks and 1 year, and salivary cortisol response to a simulated anaphylaxis scenario at 1 year. RESULTS: We found no significant difference in the primary outcome state anxiety at 6 weeks, with mean 31.9 (SD 10.2) intervention, 34.0 (10.2) control; mean difference 2.1 (95% CI -0.9, 5.0; P=.17). There was significantly reduced state anxiety at 6 weeks in the intervention group, in the subgroup of participants with moderate/high anxiety at enrolment (103/200, 52%), with mean 33.0 (SD 9.3) intervention, 37.8 (SD 10.0) control; mean difference 4.8 (95% CI 0.9, 8.7; P=.016; Cohen's d effect size 0.50). The psychological intervention also reduced risk perception and salivary cortisol response (P=.032; effect size 0.36). CONCLUSION: We found evidence that a brief psychological intervention which incorporates accurate risk information may impact on anxiety, risk perception and physiological stress response in mothers of children with food allergy.