Global adoption of 6-month drug-resistant TB regimens: Projected uptake by 2026.

BACKGROUND: The WHO has issued a call to action urging countries to accelerate the rollout of new WHO-recommended shorter all-oral treatment regimens for drug-resistant TB (DR-TB), which remains a public-health crisis. The all-oral, 6-month BPaL/M regimen comprises 3-4 drugs: pretomanid used in combination with bedaquiline and linezolid, with or without moxifloxacin. This regimen has been recommended by the WHO for use in DR-TB patients instead of ≥9-month (up to 24-month) regimens. This study aims to project this regimen's use, along with its components bedaquiline, pretomanid and linezolid, and other treatments for DR-TB globally through 2026. It is intended to guide global health stakeholders in planning and budgeting for DR-TB interventions. Projected usage could help estimate cost of the individual components of DR-TB regimens over time. METHODS: Semi-structured interviews were conducted with national TB programme participants in key countries to gather intelligence on established plans and targets for use of various DR-TB treatment regimens from 2023 to 2026. These data informed development of projections for the global use of regimens and drugs. RESULTS: Consistent global growth in the use of shorter regimens in DR-TB treatment was shown: BPaLM reaching 126,792 patients, BPaL reaching 43,716 patients, and the 9-11-month all-oral bedaquiline-based regimen reaching 13,119 patients by 2026. By 2026, the longer all-oral regimen is projected to be used by 19,262 patients, and individualised treatment regimens by 15,344 patients. CONCLUSION: The study shows BPaL/M will be used in majority of DR-TB patients by 2024, reaching 78% by 2026. However, national efforts to scale-up, case-finding, monitoring, drug-susceptibility testing, and implementation of new treatments will be essential for ensuring they are accessible to all eligible patients in the coming years and goals for ending TB are met. There is an urgent need to engage communities in capacity building and demand generation.

Comparative effectiveness of adding delamanid to a multidrug-resistant tuberculosis regimen comprised of three drugs likely to be effective.

Clarity about the role of delamanid in longer regimens for multidrug-resistant TB is needed after discordant Phase IIb and Phase III randomized controlled trial results. The Phase IIb trial found that the addition of delamanid to a background regimen hastened culture conversion; the results of the Phase III trial were equivocal. We evaluated the effect of adding delamanid for 24 weeks to three-drug MDR/RR-TB regimens on two- and six-month culture conversion in the endTB observational study. We used pooled logistic regression to estimate the observational analogue of the intention-to-treat effect (aITT) adjusting for baseline confounders and to estimate the observational analogue of the per-protocol effect (aPP) using inverse probability of censoring weighting to control for time-varying confounding. At treatment initiation, 362 patients received three likely effective drugs (delamanid-free) or three likely effective drugs plus delamanid (delamanid-containing). Over 80% of patients received two to three Group A drugs (bedaquiline, linezolid, moxifloxacin/levofloxacin) in their regimen. We found no evidence the addition of delamanid to a three-drug regimen increased two-month (aITT relative risk: 0.90 (95% CI: 0.73-1.11), aPP relative risk: 0.89 (95% CI: 0.66-1.21)) or six-month culture conversion (aITT relative risk: 0.94 (95% CI: 0.84, 1.02), aPP relative risk: 0.93 (95% CI: 0.83, 1.04)). In regimens containing combinations of three likely effective, highly active anti-TB drugs the addition of delamanid had no discernible effect on culture conversion at two or six months. As the standard of care for MDR/RR-TB treatment becomes more potent, it may become increasingly difficult to detect the benefit of adding a single agent to standard of care MDR/RR-TB regimens. Novel approaches like those implemented may help account for background regimens and establish effectiveness of new chemical entities.

Waste polystyrene foam-derived sorbent for determining bisphenol-A from canned beverages.

Polystyrene-based products are widely used in industrial and daily activities, but their subsequent disposal can negatively affect the environment. This work focuses on reducing polystyrene waste into useful material. A waste-derived polystyrene sorbent (WDPS) was fabricated and successfully applied to determine bisphenol-A in canned beverages. High-performance liquid chromatography with a diode-array detection (HPLC-DAD) was applied to quantify bisphenol-A. Good linearity at a concentration range of 2.5-50 µg L-1 was achieved. The limit of detection was 0.93 ± 0.02 µg L-1. Good precision (RSDs < 1.6 %, 4 concentrations, n = 6) in spiked coconut juice samples were obtained. The contamination of BPA in canned beverage samples were found in the range of 6.3 ± 0.2 µg L-1 to 27.0 ± 1.0 µg L-1 with recoveries in the range of 70.4 ± 1.6 % to 82.4 ± 0.4 %. This proposed method also offers reduced polystyrene waste, reuse as a sorbent, and recycling after use.

Paraneoplastic Pemphigus: A Striking Complication of Undiagnosed Lymphoma.

A 49-year-old male with no past medical history presented with acute-onset painful mucosal erosions along with flaccid bullae on his trunk, scalp, and intertriginous areas. The patient initially underwent a skin biopsy which demonstrated suprabasilar acantholysis and lichenoid interface dermatitis. This was followed by a computed tomography scan which identified a large abdominal lymph node. Core needle biopsy of this node demonstrated follicular lymphoma. Lastly, indirect immunofluorescence (IIF) in rat bladder was positive (titer 1 : 10,240). This finding confirmed the diagnosis of paraneoplastic pemphigus (PNP) in the setting of follicular lymphoma. The patient's cutaneous disease was treated with a combination of intravenous immunoglobulin and methylprednisolone, along with intravenous rituximab, with a resolution of his cutaneous symptoms. His lymphoma was treated with six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), with an interval decrease in his tumor burden. PNP is an autoimmune-mediated mucocutaneous disease associated with underlying neoplasm, most commonly non-Hodgkin lymphoma or chronic lymphocytic leukemia. Affected patients develop variable autoantibodies to antigens on keratinocytes and the basement membrane zone. Severe intractable stomatitis is characteristic, in addition to polymorphous cutaneous eruptions including bullae and erosions. Mortality rates can reach up to 90% due to malignancy, sepsis, or bronchiolitis obliterans, an irreversible and often lethal cause of pulmonary insufficiency. We highlight PNP manifesting in a patient with lymphoma, who responded well to the skin- and malignancy-directed treatments. PNP is an exceedingly rare diagnosis that should be considered in a patient with intractable stomatitis.

Safety and Effectiveness Outcomes From a 14-Country Cohort of Patients With Multi-Drug Resistant Tuberculosis Treated Concomitantly With Bedaquiline, Delamanid, and Other Second-Line Drugs.

BACKGROUND: Concomitant use of bedaquiline (Bdq) and delamanid (Dlm) for multi-drug/rifampicin resistant tuberculosis (MDR/RR-TB) has raised concerns about a potentially poor risk-benefit ratio. Yet this combination is an important alternative for patients infected with strains of TB with complex drug resistance profiles or who cannot tolerate other therapies. We assessed safety and treatment outcomes of MDR/RR-TB patients receiving concomitant Bdq and Dlm, along with other second-line anti-TB drugs. METHODS: We conducted a multi-centric, prospective observational cohort study across 14 countries among patients receiving concomitant Bdq-Dlm treatment. Patients were recruited between April 2015 and September 2018 and were followed until the end of treatment. All serious adverse events and adverse events of special interest (AESI), leading to a treatment change, or judged significant by a clinician, were systematically monitored and documented. RESULTS: Overall, 472 patients received Bdq and Dlm concomitantly. A large majority also received linezolid (89.6%) and clofazimine (84.5%). Nearly all (90.3%) had extensive disease; most (74.2%) had resistance to fluoroquinolones. The most common AESI were peripheral neuropathy (134, 28.4%) and electrolyte depletion (94, 19.9%). Acute kidney injury and myelosuppression were seen in 40 (8.5%) and 24 (5.1%) of patients, respectively. QT prolongation occurred in 7 patients (1.5%). Overall, 78.0% (358/458) had successful treatment outcomes, 8.9% died, and 7.2% experienced treatment failure. CONCLUSIONS: Concomitant use of Bdq and Dlm, along with linezolid and clofazimine, is safe and effective for MDR/RR-TB patients with extensive disease. Using these drugs concomitantly is a good therapeutic option for patients with resistance to many anti-TB drugs.

A simple gelatin aerogel tablet sorbent for the effective vortex assisted solid phase extraction of polycyclic aromatic hydrocarbons from tea samples.

A gelatin aerogel tablet was used as a vortex assisted solid phase extraction (VA-SPE) sorbent for the determination of polycyclic aromatic hydrocarbons (PAHs), benzo(a)anthracene (BaA), benzo(b)fluoranthene (BbF), and benzo(a)pyrene (BaP) in tea samples. They have been quantified by a high-performance liquid chromatography with a diode array detector (HPLC-DAD). The method shows good linearity (R2 = 0.999) at concentrations of 5.00-200 ng L-1, with the limits of detection of 1.65 ± 0.02, 1.81 ± 0.02, and 2.06 ± 0.03 ng L-1 for BaA, BbF, and BaP, respectively. Good reproducibility (RSDs < 0.24%, n = 6), good precision (RSDs < 6.3%), and excellent reusability (n = 40, RSDs < 0.17%) were achieved. The tablet can extract PAHs within 1.5 min with good recoveries (70.10 ± 0.74% - 119.3 ± 4.1%). This method, which is simple, rapid, ecofriendly, and inexpensive, requires low consumption of organic solvent, and has potential application in food safety.

An Uninformed Decision-Making Process for Cesarean Section: A Qualitative Exploratory Study among the Slum Residents of Dhaka City, Bangladesh.

The decision-making process and the information flow from physicians to patients regarding deliveries through cesarean section (C-section) has not been adequately explored in Bangladeshi context. Here, we aimed to explore the extent of information received by mothers and their family members and their involvement in the decision-making process. We conducted a qualitative exploratory study in four urban slums of Dhaka city among purposively selected mothers (n = 7), who had a cesarean birth within one-year preceding data collection, and their family members (n = 12). In most cases, physicians were the primary decision-makers for C-sections. At the household level, pregnant women were excluded from some crucial steps of the decision-making process and information asymmetry was prevalent. All interviewed pregnant women attended at least one antenatal care visit; however, they neither received detailed information regarding C-sections nor attended any counseling session regarding decisions around delivery type. In some cases, pregnant women and their family members did not ask health care providers for detailed information about C-sections. Most seemed to perceive C-sections as risk-free procedures. Future research could explore the best ways to provide C-section-related information to pregnant women during the antenatal period and develop interventions to promote shared decision-making for C-sections in urban Bangladeshi slums.

Pyrazinamide resistance and pncA mutations in drug resistant Mycobacterium tuberculosis clinical isolates from Myanmar.

Pyrazinamide (PZA) is an important anti-tuberculosis drug, which is active against semi-dormant bacilli and used as a component of first-line drugs and drug-resistant tuberculosis regimens. Mutations in pncA and its promoter region are main cause of PZA resistance. There are limited PZA susceptibility data as there is no routine drug susceptibility testing (DST) for PZA. This study was aimed to determine the proportion of PZA resistance among rifampicin-resistant tuberculosis patients and to identify mutations which are responsible for PZA resistance in pncA and its promoter region. Liquid-based DST was performed to detect PZA susceptibility on 192 culture positive rifampicin-resistant isolates collected from National Tuberculosis Reference Laboratory. Sequencing on pncA including its promoter region was performed and analysis was done on 157 isolates. Phenotypic PZA resistance was detected in 58.9% of isolates. Sixty-five different mutations were distributed in pncA or promoter region of 82 isolates. Sensitivity and specificity of pncA sequencing in detection of PZA resistance showed 89.8% and 95.6% respectively. High proportion of PZA resistance among rifampicin-resistant cases highlighted the need for effective treatment regimen development for PZA-resistant MDR-TB. It is also suggested that routine PZA susceptibility test should be incorporated to treatment monitoring regimen and National Drug Resistance surveys.

Evaluation of the cross-neutralization capacity of Thai green pit viper antivenom against venom of Myanmar green pit viper.

Green pit viper (Trimeresurus sp.) bite occurred throughout Myanmar, but there is no specific antivenom produced in the country for related envenomation. Instead, Myanmar Russell's viper antivenom (Anti-MRV) was often misused because of prolonged clotting time was observed from both species. Thai green pit viper antivenom (Anti-TGPV) raised against Trimeresurus albolabris was found to be effective against venoms of more than ten Trimeresurus sp. from Thailand, Malaysia and Indonesia. The present study compared the neutralization capacities of Anti-TGPV and Anti-MRV towards the venom from T. erythrurus from Myanmar. Anti-TGPV was more efficacious than Anti-MRV in cross-neutralizing the lethal and haemorrhagic activities of the venom by a potency of a least 1.4 times higher. Although Anti-TGPV effectively cross-neutralized the coagulation activity of the venom, Anti-MRV failed to do so. Immunodiffusion and immunoblot experiments showed that Anti-TGPV cross-reacted with more protein components of the venom than Anti-MRV. In conclusion, Anti-TGPV is a better choice for patients bitten by Myanmar green pit viper, but further clinical investigation is required. The current findings highlight the development of a specific antivenom against Myanmar green pit viper venom.

Quality of Malaria Treatment Provided under 'Better Health Together' Project in Ethnic Communities of Myanmar: How Are We Performing?

Malaria accounted for 18% of all deaths in the ethnic communities of Myanmar. In this cross-sectional study, we assessed the extent of and factors associated with receipt of quality malaria treatment services provided by integrated community malaria volunteer (ICMV) under six ethnic health organisations. Data of people with malaria diagnosed by rapid diagnostic tests during 2017-2018 were extracted from the ICMV registers. Documentation of prescribing a complete course of drugs was used to assess quality. Of 2881 people with malaria, village-based ICMV diagnosed and treated 2279 (79%) people. Overall, 2726 (95%) people received correct drugs in the correct dose and adequate duration appropriate to malaria species, age and pregnancy status while 1285 (45%) people received 'correct and timely (within 24 h of fever)' treatment. Children under five years, those with severe malaria, mixed infection and falciparum malaria were less likely to receive the correct treatment. When compared to health posts, village-based ICMVs and mobile teams performed better in providing correct treatment and mobile teams in providing 'correct and timely' treatment. This calls for ensuring the early presentation of people to health workers within 24 h of undifferentiated fever through health promotion initiatives. Future studies should assess adherence to medication and clinical improvement.

Delay in diagnosis and treatment among adult multidrug resistant tuberculosis patients in Yangon Regional Tuberculosis Center, Myanmar: a cross-sectional study.

BACKGROUND: Delays in diagnosis and treatment initiation may allow the emergence of new cases by transmission to the community, and is one of the challenges facing programme management of drug resistance in Myanmar. This study aimed to explore delays in diagnosis and treatment initiation, and associated factors among patients with multidrug-resistant tuberculosis. METHODS: A cross-sectional study was conducted at Yangon Regional Tuberculosis Centre, Myanmar. Data were collected by face-to-face interviews and treatment-card reviews of all adult patients who had registered and started treatment with the standard regimen from May to November, 2017. Delay time was categorized by using median cut-off and analyzed using SPSS version 23.0. Logistic regression analysis was performed to assess the relative impact of predictor variables on diagnosis and treatment delays. RESULTS: A total of 210 patients participated in this study. The median diagnosis delay was 9 days, IQR 3 (8-11) and 58.6% of the patients experienced a long diagnosis delay. Below middle school education (adjusted odds ratio [AOR] = 2.75, 95% CI = 1.22-6.21), non-permanent salaried employment (AOR = 3.03, 95% CI = 1.32-6.95), co-existing diabetes mellitus (AOR = 5.06, 95% CI = 1.97-13.01) and poor awareness (AOR = 2.99, 95% CI = 1.29-6.92) were independent predictors of long diagnosis delay. The median treatment delay was 13 days, IQR 9 (8-17) and 51% of the patients experienced long treatment delay. Age 31-50 years (AOR = 4.50, 95% CI = 1.47-13.97) and age > 50 years (AOR = 9.40, 95% CI = 2.55-34.83), history with MDR-TB patient (AOR = 3.16, 95% CI = 1.29-7.69), > 20 km away from a Regional TB Centre (AOR = 14.33, 95% CI = 1.91-107.64) and poor awareness (AOR = 4.62, 95% CI = 1.56-13.67) were independent predictors of long treatment delay. CONCLUSIONS: Strengthening comprehensive health education, enhancing treatment adherence counseling, providing more Xpert MTB/RIF machines, expanding decentralized MDR-TB treatment centers, ensuring timely sputum transportation, provision of a patient support package immediately after confirmation, and strengthening contact-tracing for all household contacts with MDR-TB patients and active tuberculosis screening were the most effective ways to shorten delays in MDR-TB diagnosis and treatment initiation.

Delay in treatment initiation and treatment outcomes among adult patients with multidrug-resistant tuberculosis at Yangon Regional Tuberculosis Centre, Myanmar: A retrospective study.

BACKGROUND: Myanmar faces a health security threat, with an increasing number of multidrug-resistant tuberculosis (MDR-TB) cases. Long delays in the initiation of treatment are a barrier to MDR-TB control. OBJECTIVES: The main objectives of this study were (1) to identify the determinants of delay in treatment initiation after MDR-TB diagnosis, and (2) to explore the effects of treatment delay on disease infectivity, severity, treatment adherence, and treatment outcomes. METHODS: This retrospective study reviewed 330 MDR-TB treatment cards for patients enrolled for treatment at Yangon Regional Tuberculosis Centre, in 2014. RESULTS: Median treatment delay was 105 days, interquartile range (IQR) 106 (61-167) days; (51.5%) of patients experienced a long treatment delay (≥ 105 days). Regarding the determinants of treatment delay, this study identified important patient-healthcare system interaction factors. Significant risk factors of long treatment delay included female sex, age > 30 years, and prior contact with patients with MDR-TB. Patients with long treatment delays were significantly different from those with short delays, in terms of having high sputum smear grade, resistance to more than two main drugs (isoniazid and rifampicin), and long culture conversion time. In this study, delay in the initiation of treatment was associated with poor treatment outcome, but this was not statistically significant after adjusting for other risk factors. Median treatment-delay times were longer among patients with poor outcomes (144 days) than those with successful outcomes (102 days). CONCLUSIONS: Post-diagnosis delays in the initiation of treatment among MDR-TB patients were significantly long. The study results showed that inadequate MDR-TB treatment initiation center, centralization of treatment initiation, limitation of human resources, were health-system factors delaying timely treatment initiation and implementation of an effective TB-control program. Our findings highlight the need for immediate interventions to reduce treatment delay and improve treatment outcomes, including scaling up diagnostic capacity with Xpert MTB/RIF at township level, expansion of decentralized MDR-TB treatment initiation centers, ensuring a productive health workforce comprising trained health personnel, and providing health education and treatment-adherence counseling to patients and family members.

Molecular cloning, expression and chromosomal localization of mouse MM-1.

The protooncogene product Myc associates with many proteins. The isolation of the mouse MM-1; c-Myc binding protein (Myc-Modulator 1) cDNA is described. The cDNA contains a 462 bp open reading frame that encodes a polypeptide of 154 amino acid residues. The deduced amino acid sequence indicates that mouse MM-1 has a 99% identity with the sequence of human MM-1. The expression of mouse MM-1 mRNA was detected in the fetal liver, but its level was 3-fold higher than that in the normal adult liver, and was slightly increased after a partial hepatectomy. It is expressed widely in a variety of adult mouse tissues. Thus, MM-1 may play a role in liver development and growth. A bioinformatics analysis indicates that mouse MM-1 gene consists of 6 exons. Furthermore, the chromosomal location of the mouse MM-1 gene was on the F2-F3 band of chromosome 15, as determined by fluorescence in situ hybridization.