Lower Treatment Success Rates Research Articles

Predictors of mortality among multidrug-resistant tuberculosis patients after decentralization of services in Tanzania from 2017 to 2019: retrospective cohort study

BackgroundMultidrug-resistant tuberculosis (MDR-TB) presents persistent global health challenges, characterized by low treatment success rates among patients enrolled for treatment. The World Health Organization recommends decentralization to improve outcomes. This study aims to assess predictors of mortality among MDR-TB patients after decentralization of services in Tanzania. This was a retrospective cohort study involving all MDR-TB patients enrolled in treatment in all 31 regions in Tanzania from 2017 to 2019. The overall mortality rate among MDR-TB patients was calculated using the incidence rate. Additionally, independent factors of MDR-TB mortality were determined using multivariable cox proportional hazards models.ResultsThe study followed 985 patients for a total of 12,929 months. During this time, it found that approximately 12 out of every 1000 patients died each month. Specifically, the death rates were about 18 out of 1000 patients at 6 months, 8 out of 1000 at 12 months, and 7 out of 1000 at 24 months. Patients who had both MDR-TB and HIV, as well as those who were malnourished, had a lower chance of surviving at 6, 12, and 24 months. Malnourished patients had almost three times the risk of dying [adjusted hazard ratio (aHR) 2.96, with a 95% confidence interval (CI) of 2.10–4.19], while those with HIV had nearly double the risk [aHR 1.91, with a 95% CI of 1.37–2.65].ConclusionIn summary, our study on MDR-TB patient outcomes in Tanzania between 2017 and 2019 reveals a pattern of high mortality rates within the first 6 months of treatment. Furthermore, malnutrition and HIV co-infection were found to be significant predictors of mortality. To decrease mortality, it is crucial to closely monitor patients during the initial 6 months of treatment, especially those who are malnourished or co-infected with HIV, and ensure they receive appropriate and timely care. Additionally, further investigation is needed to find out what may be contributing to possible rise in mortality rate.

Predictors of Therapy Success in Weekly Adalimumab for Refractory Uveitis: A Retrospective Cohort Study

PurposeTo determine predictors of treatment success after dose escalation of adalimumab, including measurement of anti-adalimumab antibodies as a predictor of success DesignRetrospective clinical cohort study SettingSingle-center academic institution Study PopulationPatients with noninfectious uveitis who were inadequately controlled or developed recurrent disease on biweekly adalimumab and required dose escalation or therapy modification Observation ProceduresPatients who had anti-adalimumab antibodies checked with resultant low to intermediate levels were compared to patients who had no testing performed prior to adalimumab dose escalation. Of note, patients with testing and resultant high levels of anti-adalimumab antibodies were not escalated. Predictors of escalation success and utility of antibody testing prior to escalation were analyzed using Kaplan Meier survival analysis and Cox proportional hazard models. Main Outcome MeasuresTreatment success defined as anterior chamber grade ≤0.5+ cell, topical corticosteroids ≤1 drop/day, oral prednisone ≤5 mg/day, resolution of macular edema, and resolution of angiographic signs of inflammation without any addition or escalation of therapy. Results24 patients had antibodies tested with low to intermediate levels (average: 32.3 ng/mL, range: 0 – 154), while 41 did not have antibody testing. A greater treatment success rate post escalation was observed among the “low antibody” group compared to the “no testing” group (HR: 2.63, standard error: 1.19, p=0.031, 95% CI 1.09 – 6.37). Among the entire cohort, patients with panuveitis (n = 14) had a lower treatment success rate compared to the reference of anterior uveitis (n = 26) (HR: 0.09, standard error: 0.11, p = 0.05, 95% CI 0.01 – 0.99). ConclusionsPatients with low anti-adalimumab antibodies had a greater treatment success compared to patients in whom antibodies were not checked. This suggests a utility to checking antibodies prior to dose escalation and that low levels of antibodies may confer a success advantage. Overall, patients with panuveitis had a lower rate of success after escalation while patients with anterior uveitis patients had a very high rate of success suggesting that certain disease characteristics may guide clinicians when determining who to escalate versus changing therapy.

Effectiveness of ceftazidime/avibactam as a continuous infusion in critically ill patients with OXA-48-producing Klebsiella pneumoniae infection

Introduction. Ceftazidime/avibactam, a novel beta-lactam antibiotic, demonstrates time-dependent bacterial killing; thus, new reports advocate its administration as a continuous infusion, as opposed to bolus or prolonged infusion application. Methods. Critically ill COVID-19 patients (n=10) superinfected with OXA-48-producing Klebsiella pneumoniae susceptible to ceftazidime/avibactam were treated with ceftazidime/avibactam as a continuous infusion for an average of 10 days. The treatment regimen included an initial loading dose, followed by a continuous infusion of ceftazidime/avibactam. These patients were immunocompromised because of severe COVID-19, treatment with corticosteroids, and some solid organ transplant recipients (n=2), all with high disease severity scores. Discussion. Considering the published literature to this date, this is the one of first reports describing the real-life results of using a continuous infusion of ceftazidime/avibactam in the treatment of OXA-48-producing K. pneumoniae superinfection in critically ill COVID-19 patients. Microbiological effectiveness of treatment, evidenced by negativization of microbiological samples, was achieved in eight cases (80%) overall, but in patients with sepsis and urinary tract infection, the cure rate was 100%. Conclusion. The reasons for the low treatment success rates in pneumonia caused by OXA-48-producing K. pneumoniae could be explained by the concurrent severe COVID-19 pneumonia.

Effectiveness of smoking cessation intervention based on the ABC Approach in patients with TB.

Urban setting in the Philippines. To assess the effectiveness of the ABC Approach developed by The Union as a tobacco-smoking cessation intervention for TB patients at a primary healthcare level in an urban setting in the Philippines. We set up an intervention group whose patients with TB received the ABC approach and a control group of patients with TB receiving only routine health education in Manila, The Philippines. We collected smoking status and the domestic secondhand-smoking (SHS) status data from patients with TB at months 0, 2, 4, 6, 8, and 12. TB treatment outcome data were also collected. Patients with TB (n = 2,174) were enrolled upon TB registration. Smoking rates were consistently low in the intervention group (3.9% vs. 8.7% at Month 6). The odds ratios of both tobacco-smoking status and domestic SHS status in the intervention group were significantly lower than those in the control group (tobacco-smoking status: P < 0.001, domestic SHS status: P < 0.01). TB treatment success rates were similar between the groups (85.0% vs. 87.3%; P = 0.201). The ABC approach successfully reduced tobacco-smoking rates, maintained low domestic SHS rates and TB treatment success rates in the Philippines.

Medical management of early pregnancy loss with mifepristone and misoprostol in emergency departments compared to a Complex Family Planning office: Implementation of a COVID-19 institutional policy change

ObjectivesTo evaluate the implementation of mifepristone and misoprostol for medical management of early pregnancy loss (EPL) in emergency departments (EDs) by comparing efficacy, complication, and follow-up rates for patients treated in EDs to those in the Complex Family Planning (CFP) outpatient office. Study DesignIn COVID-19's first wave, we expanded medication management of EPL to our EDs. This retrospective study evaluated 72 patients receiving mifepristone and misoprostol for EPL from 4/1/2020-3/31/2021, comparing treatment success, safety outcomes, and follow-up rates by location. We did not perform a power calculation. ResultsThirty-three (46%) patients received care in the ED and 39 (54%) at CFP. Treatment success was lower in the ED (23, 70%) compared to CFP (34, 87.2%), but after adjusting for insurance status and type of pregnancy (miscarriage, uncertain viability, unknown location) this was not significant: aOR 0.48 (95%CI 0.13-1.81), p=0.28. More ED patients underwent emergent interventions (3 vs 0). Complications in the ED cohort included two emergent uterine aspirations, one uterine artery embolization, and two blood transfusions. Among these, two cases were attributed to misdiagnosis (a cesarean scar and a cervical ectopic pregnancy interpreted as incomplete miscarriages) and one to guideline nonadherence (anticoagulated patient). No complications occurred in the CFP group. Follow-up rates were over 80% in both groups. More ED patients engaged in telehealth follow-up (67% vs 18.0%, p≤0.0001). ConclusionsIn this small sample, we observed a trend toward lower rates of treatment success following medication management of EPL in the ED, compared to the CFP office. This analysis highlights that both correctly making uncommon diagnoses and adhering to new guidelines presented challenges during our implementation process. IMPLICATIONSImplementing mifepristone and misoprostol for EPL in our EDs achieved lower rates of pregnancy resolution compared to outpatient management. Complex uncommon diagnoses and implementing new care pathways in EDs may have contributed to complications and highlight opportunities for improvement. Additional studies are needed to further quantify safety outcomes for EPL management in EDs. TWEETABLE ABSTRACTED provision of mifepristone and misoprostol for early pregnancy loss during COVID-19 was less effective than outpatient care. There were more serious complications in the ED group due to misdiagnosis and guideline nonadherence.

Profile and risk factors of pre-XDR-TB and XDR-TB patients in a national reference hospital for Sumatra region of Indonesia.

The low treatment rate, low treatment success rate and high mortality rate of patients with pre-extensively drug-resistant tuberculosis (pre-XDR-TB) and extensively drug-resistant TB (XDR-TB) need serious attention. The aim of this study was to describe the profiles of patients with pre-XDR-TB and XDR-TB cases and to determine associated risk factors of their incidence in Indonesia. A retrospective case-control study was conducted at H. Adam Malik General Hospital in Medan, North Sumatra of which all sensitive-drug TB (SD-TB), pre-XDR-TB, and XDR-TB patients aged 18 years or older treated between October 2019 to June 2022 were included. Chi-squared test or Kruskal Wallis test and multiple logistic regression were used to determine the risk factors associated with pre-XDR-TB and XDR-TB incidence. A total 16 patients of case group (15 pre-XDR-TB and one XDR-TB) and 116 SD-TB patients (control group) were included in the final analysis. Out of total patients within case group, 62.5% were male, 43.8% aged between 56-65 years, 62.5% graduated from high school or equivalent, and 25% were unemployed. The majority of patients had no comorbid (62.5%), had history of anti-TB treatment (93.8%), and had secondary resistance (93.8%). Multivariate analysis indicated that age (OR: 10.01; 95%CI: 1.49- 66.91, p=0.018) and previous history of anti-TB treatment (OR: 216.25; 95%CI: 18.62- 2511.60, p<0.001) were significantly associated with incidence of pre-XDR-TB and XDR-TB. This study highlights that having previous history of anti-TB treatment and older age are the predictors of the incidence of pre-XDR-TB and XDR-TB.

Comparison of outcomes between fungal and non-fungal periprosthetic joint infections in total knee arthroplasty.

Fungal periprosthetic joint infections (PJIs) are rare, but their diagnosis and treatment are highly challenging. The purpose of this study was to investigate the clinical outcomes of patients with fungal PJIs treated with two-stage exchange knee arthroplasty combined with prolonged antifungal therapy. We reviewed our institutional joint arthroplasty database and identified 41 patients diagnosed with fungal PJIs and treated with two-stage exchange arthroplasty after primary total knee arthroplasty (TKA) between January 2001 and December 2020, and compared them with those who had non-fungal PJIs during the same period. After propensity score matching based on age, sex, BMI, American Society of Anesthesiologists grade, and Charlson Comorbidity Index, 40 patients in each group were successfully matched. The surgical and antimicrobial treatment, patient demographic and clinical characteristics, recurrent infections, survival rates, and relevant risk factors that affected joint survivorship were analyzed. We defined treatment success as a well-functioning arthroplasty without any signs of a PJI, and without antimicrobial suppression, at a minimum follow-up of two years from the time of reimplantation. The fungal PJI group demonstrated a significantly worse treatment success rate at the final follow-up than the non-fungal PJI group (65.0% (26/40) vs 85.0% (34/40); p < 0.001). The mean prosthesis-free interval was longer in the fungal PJI group than in the non-fungal PJI group (6.7 weeks (SD 5.8) vs 4.1 weeks (SD 2.5); p = 0.020). The rate of survivorship free from reinfection was worse in the fungal PJI group (83.4% (95% confidence interval (CI) 64.1 to 92.9) at one year and 76.4% (95% CI 52.4 to 89.4) at two years) than in the non-fungal PJI group (97.4% (95% CI 82.7 to 99.6) at one year and 90.3% (95% CI 72.2 to 96.9) at two years), but the differences were not significant (p = 0.270). Cox proportional hazard regression analysis identified the duration of the prosthesis-free interval as a potential risk factor for failure (hazard ratio 1.128 (95% CI 1.003 to 1.268); p = 0.043). Fungal PJIs had a lower treatment success rate than non-fungal PJIs despite two-stage revision arthroplasty and appropriate antifungal treatment. Our findings highlight the need for further developments in treating fungal PJIs.

MIR-145's Regulatory Role in Breast Cancer Progression

Delayed diagnosis of breast cancer results in lower treatment success rates and lower survival rates. Every year millions of women are diagnosed with breast cancer and many of them die from this disease. However, the discovery of biomarkers that enable early diagnosis should increase the success of treatment processes and extend survival times. In recent years, studies have been carried out to use microRNAs as biomarkers in the early detection of breast cancer. Research shows that microRNAs can serve as potential biomarkers for the diagnosis and prognosis of breast cancer. In addition to ongoing research on the possible use of microRNAs as biomarkers for early breast cancer diagnosis, our study also analyzed the possible use of miR-145 as a biomarker in breast cancer. In our study, RNA samples were isolated from blood serum samples of 200 breast cancer patients and 100 people in the healthy control group, and the specific expression levels of miR-145 were determined using RT-qPCR technique. As a result of these analyses, it was found that miR-145 had lower expression levels in breast cancer patients than in healthy controls. After further investigation of the biomarker potential of miR-145 in a larger group of breast cancer patients, it will be used as a target biomarker for early breast cancer diagnosis.

Risk Factors for the Development of New-Onset Persistent Atrial Fibrillation: Subanalysis of the VITAL Study.

Sustained forms of atrial fibrillation (AF) are associated with lower treatment success rates and poorer prognosis compared with paroxysmal AF. Yet, little is known about risk factors that predispose to persistent AF on initial presentation. Our objective was to define risk factors associated with new-onset persistent AF. We prospectively examined the differential associations between lifestyle, clinical, and socioeconomic risk factors and AF pattern (persistent versus paroxysmal) at the time of diagnosis among 25 119 participants without a history of cardiovascular disease, AF, or cancer in the VITAL rhythm study (Vitamin D and Omega-3). During a median follow-up of 5.3 years, 900 participants developed AF and 346 (38.4%) were classified as persistent at the time of diagnosis. In multivariable competing risk models, increasing age, male sex, White race, height, weight, body mass index ≥30 kg/m2, hypertension, current or past smoking, alcohol intake ≥2 drinks/day, postcollege education, and randomized treatment with vitamin D were significantly associated with incident persistent AF. Compared with paroxysmal AF, increasing age, male sex, weight, body mass index ≥30 kg/m2, and postcollege education were more strongly associated with persistent AF in multivariable models regardless of whether interim cardiovascular disease and heart failure events were censored. In a prospective cohort without baseline AF or cardiovascular disease, over one-third of AF at the time of diagnosis is persistent. Older age, male sex, postcollege education, and obesity were preferentially associated with persistent AF and represent a high-risk AF subset for population-based intervention.

Sequenced treatment alternatives to relieve adolescent depression (STAR-AD): a multicentre open-label randomized controlled trial protocol

BackgroundAdolescent major depressive disorder (MDD) is a prevalent mental health problem with low treatment success rates. Whether fluoxetine or fluoxetine combined with cognitive-behavioural therapy (CBT) is the more effective initial treatment for adolescent MDD remains controversial, and few studies have investigated whether treatment switching or augmentation is preferred when the initial treatment is not working well.MethodsWe developed a multicentre open-label Sequential Multiple Assignment Randomized Trial (SMART) design, consisting of two phases lasting 8 weeks each. In phase 1 (at baseline), patients will be recruited and grouped in fluoxetine group or fluoxetine combined with CBT group by patient self-selection. In phase 2 (after 8 weeks of treatment), the nonresponders will be randomly assigned to six groups, in which participants will switch to sertraline, vortioxetine, or duloxetine or added aripiprazole, olanzapine, or lithium carbonate to fluoxetine. After the full 16 weeks of treatment, we will assess the long-term sustainability of the treatment effects by evaluating participants during their subsequent naturalistic treatment. The primary outcome will be the response rate, determined by the Children’s Depression Rating Scale-Revised (CDRS-R). Secondary outcomes include the change in scores on the Beck Depression Inventory (BDI), the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and the Safe Assessment.DiscussionThe results from this study will aid clinicians in making informed treatment selection decisions for adolescents with MDD.Trial registrationThis protocol was registered at ClinicalTrials.gov with Identifier: NCT05814640.

OS10.6.A GLIOBLASTOMA CELLS IMITATE NEURON’S EXCITABILITY IN ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES

Abstract BACKGROUND Glioblastoma (GBM) is a highly lethal cancer with a low treatment success rate due to its inter- and intra-patient molecular and physiological heterogeneity, and its complex interaction with brain tissue. Neuron-to-brain tumor-synaptic-communications (NBTSCs) are believed to contribute to glioma progression and tumor-induced epilepsy. However, the physiology of these synaptic interactions in the tumor-infiltrated human neocortex remains largely uncharacterized. In this study, we investigated the intrinsic electrical properties of cells and NBTSCs in the tumor-infiltrated human cortex. MATERIAL AND METHODS We established a unique experimental workflow that enables us to investigate glioma cells in acute and cultured human tumor-infiltrated brain slices. We utilized an adeno-associated virus-assisted gene delivery technique to selectively express fluorescence proteins in a cell-type specific manner. By performing fluorescence-guided whole-cell patch clamp recording, we characterized the electrophysiological properties of glioma cells and neurons under the tumor microenvironment. RESULTS We observed that glioma cells from tumor-infiltrated human brain samples display relatively depolarized -32.59 + 3.16 mV resting membrane potential and high input resistance of 1.73 + 0.43 GΩ, with 44.44% of glioma cells exhibit spikelets or distorted-action potentials upon current injection. Consistent with previous studies, some glioma cells (11.8%) from both acute and cultured human brain slices exhibit spontaneous excitatory postsynaptic currents (sEPSC). In addition, the tumor-infiltrated microenvironment significantly influences the proximal neurons’ physiology and the neuronal microcircuitry. Neurons within the tumor region show abnormal intrinsic electrical properties, depolarized resting membrane potential (-37.66 + 4.32 mV), and a significant reduction in spontaneous synaptic input frequency. CONCLUSION Collectively, we consolidate the existence of NBTSCs in human cancer patients and unprecedentedly reveal that glioma cells exhibit neuron-like excitability, which is contrary to the common understanding that they are considered as non-excitable. Under the tumor microenvironment, neurons display hyperexcitability. Our newly established organotypic human brain slice culture platform provides potential grounds for exploring further the biological characteristics of gliomas. SUPPORT/DISCLOSURE This study is supported by grants to AK (DCCC Consortium grant number R295-A16770 funded by the Danish Comprehensive Cancer Center); to MC (Lundbeck-NIH grant number R325-2019 funded by the Lundbeck Foundation, DFF-1 project 37741 funded by the Independent Research Fund Denmark).

The impact of comorbidities on tuberculosis treatment outcomes in Poland: a national cohort study.

Tuberculosis (TB) is a complex disease associated with other medical conditions, that may affect disease severity. This study aimed to investigate the impact of comorbidities on treatment outcomes and mortality rates in patients with TB in Poland. We analyzed a national cohort of 19,217 adult TB patients diagnosed between 2011 and 2016 in Poland. We compared treatment success rates and mortality rates in patients with comorbidities and those without to assess the impact of various comorbidities on these outcomes. Odds ratios (OR) were calculated to quantify the association between comorbidities and TB treatment outcomes. Patients with comorbidities had lower treatment success rates and higher mortality rates. Diabetes was identified as a significant risk factor for increased TB mortality (OR = 1.9) and mortality from all other causes (OR = 4.5). Similar associations were found for alcoholism (OR = 8.3 and OR = 7.1), immunosuppressive therapy (OR = 5.7 and OR = 5.9), and cancer (OR = 3.4 and OR = 15.4). HIV and tobacco use were associated with an increased risk of mortality from causes other than TB, with odds ratios of 28.6 and 2.2, respectively. The overall treatment success rate in the study population was 88.0%, with 9.2% of patients failing to achieve treatment success and 2.8% dying. Comorbidities such as diabetes, alcoholism, substance addiction, immunosuppressive therapy, cancer, and tobacco use increased the risk of tuberculosis treatment failure. Patients with comorbidities face a higher risk of unsuccessful treatment outcomes and increased mortality. It is essential to implement integrated management strategies that address both TB and comorbid conditions to improve treatment success rates and reduce mortality.

Eradication of Helicobacter pylori Infection Using 7-day PCR-based Tailored Therapy

Background/Aims: Standard triple therapy (STT; proton pump inhibitor [PPI]+clarithromycin+amoxicillin) used for Helicobacter pylori (H. pylori) eradication has shown low treatment success rates in recent years, which is most likely attributable to increased clarithromycin resistance. In this study, we compared treatment success rates of tailored therapy (TT) using real-time polymerase chain reaction (RT-PCR) and empirical STT.Methods: This retrospective study included 650 patients with H. pylori infection, who visited Eunpyeong St. Mary’s Hospital in Korea; 343 patients received TT based on RT-PCR assays, and 307 patients received STT. Eradication success was defined as a negative &lt;sup&gt;13&lt;/sup&gt;C-urea breath test result 4~8 weeks after treatment completion. Patients who failed first-line therapy and those with clarithromycin resistance received bismuth-containing quadruple therapy (BQT; PPI+bismuth+metronidazole+tetracycline).Results: Intention-to-treat analysis showed that H. pylori eradication rates were higher in patients who received RT-PCR–based TT than in those who were treated using empirical STT (80.5% [190/236] vs. 70.4% [216/307], P=0.069). Per-protocol (PP) analysis showed similar results (84.4% [190/225] vs. 74.7% [216/289], P=0.007). PP analysis showed that 7-day TT treatment was associated with a higher eradication rate than that observed with 10- to 14-day STT (85.2% [178/209] vs. 73.8% [59/80], P=0.029). The clarithromycin resistance rate was 27.9% (87/312). The eradication success rate was 89.2% (74/83) in patients with clarithromycin resistance, who received BQT as first-line therapy.Conclusions: The treatment success rate was higher in patients who received 7-day RT-PCR–based TT than in those who were administered 10- to 14-day empirical treatment.

Low treatment success rate among previously treated persons with drug-susceptible pulmonary tuberculosis in Kampala, Uganda

RationaleIn 2017, the treatment regimen for previously treated persons with tuberculosis (TB) changed to a shorter regimen that lasts six months and consists of Isoniazid, Rifampicin, Pyrazinamide, and Ethambutol. Few studies have examined treatment success rate (TSR) among previously treated persons with TB including the associated factors. ObjectiveTo determine TSR and the associated factors among previously treated persons with bacteriologically confirmed pulmonary TB on a six-month treatment regimen in Kampala, Uganda. MethodsWe retrieved data (January 2012 and December 2021) across six TB clinics in the Kampala Metropolitan area for all previously treated persons with bacteriologically confirmed pulmonary TB. TSR was defined as cure or treatment completion. Frequencies and percentages for categorical data, and the mean and standard deviation for numerical data were computed. Multivariable modified Poisson regression analysis was performed to identify factors associated with TSR, reported as adjusted risk ratio (aRR) with a 95% confidence interval (CI). Measurements and main resultsWe enrolled 230 participants with a mean age of 34.8±10.6 years. TSR was 52.2% and was associated with Mycobacterium tuberculosis (MTB) sputum smear load of ≥2+ (1–10 or >10 Acid Fast Bacilli (AFB)/Field) (aRR = 0.51; 95% CI, 0.38–0.68), TB/human immunodeficiency virus (HIV) (aRR = 0.67; 95% CI, 0.51–0.88) or unknown HIV serostatus (aRR = 0.42; 95% CI, 0.26–0.68), and digital community-based directly observed therapy short-course (DOTS) (aRR = 0.42; 95% CI, 0.20–0.88). ConclusionsThe TSR among previously treated persons with bacteriologically confirmed pulmonary TB on a six-month treatment regimen is suboptimal. TSR is less likely for people with TB/HIV co-infection or unknown HIV serostatus, high MTB sputum smear load, and on digital community-based DOTs. We recommend strengthening of TB/HIV collaborative activities and people with TB with high MTB sputum smear load should receive targeted treatment support, and the contextual barriers to digital community DOTS should be addressed.

Vanoxerine kills mycobacteria through membrane depolarization and efflux inhibition.

Mycobacterium tuberculosis is a deadly pathogen, currently the leading cause of death worldwide from a single infectious agent through tuberculosis infections. If the End TB 2030 strategy is to be achieved, additional drugs need to be identified and made available to supplement the current treatment regimen. In addition, drug resistance is a growing issue, leading to significantly lower treatment success rates, necessitating further drug development. Vanoxerine (GBR12909), a dopamine re-uptake inhibitor, was recently identified as having anti-mycobacterial activity during a drug repurposing screening effort. However, its effects on mycobacteria were not well characterized. Herein, we report vanoxerine as a disruptor of the membrane electric potential, inhibiting mycobacterial efflux and growth. Vanoxerine had an undetectable level of resistance, highlighting the lack of a protein target. This study suggests a mechanism of action for vanoxerine, which will allow for its continued development or use as a tool compound.

Tuberculosis literacy and stigma: female activists in five areas with the lowest treatment success rate in Semarang, Indonesia

Background: The Case Detection Rate of Tuberculosis (TB) in Semarang city increased from 2014 to 2018, while the Treatment Success Rate declined. Low literacy can trigger stigma in society, especially among women, resulting in low awareness of suspect TB for treatment. Objectives: The aims are to analyze the correlation between TB literacy and stigma expressed among female health and social activists. Methods: Cross-sectional research was conducted in five public health centers with the lowest Treatment Success Rate (TSR). A valid and reliable self-administered online questionnaire collected data that involved 391 respondents predominantly in the urban areas. Rank Spearman test was used to analyze the data with a confidence interval of 95%. Results: The respondents were mostly elderly (&gt;45 years; 61.6%), health activists with high school graduation, didn't have a family with a health background and did not work. Most of them showed low TB literacy (Me:60; SD±6.62) and high stigma (Me: 76; SD±10.36). They were also difficult to access, understand, assess, and apply information about TB. Age (p.0.03; r.-0.110), being health activist (p.0.081; r.-0.088), and TB literacy (p.0.001; r.0.165) correlated significantly with stigma. Conclusions: Public Health Center's officers require inserting literacy education materials related to stigma to form a comfortable support system for persons with TB.

Second-line drug resistance markers as proxy indicators of time to sputum culture conversion among second-line drug resistant tuberculosis patients tested in Uganda: A cross-sectional study

Background Increased tuberculosis disease burden arises as a result of low treatment success rates stemming from the emergence of second-line drug resistance. We aimed at determining the usefulness of second-line drug (SLD) resistance markers as proxy indicators of time to sputum culture conversion; a renowned predictor of Tuberculosis treatment outcome, among SLD-resistant tuberculosis (TB) patients tested at the Uganda National TB Reference Laboratory (NTRL). Methods A cross-sectional study was conducted on 72 bacteriologically confirmed SLD resistant TB patients with datasets including culture conversion time and second line probe assay mutation profiles between 01/06/2017 and 31/12/2019. The data were then imported into STATA v15 for descriptive statistical analysis, Univariate cox proportional hazard model analysis and Kaplan-Meier survival curves at a 5% level of significance; p-value ≤0.05. Results Results indicate the median time was achieved at 3 (0–12) months across the studied patients. The rrs G1484T mutation associated with conferring drug resistance to injectable agents was observed to have the shortest median conversion time of 1.5 months, longest by the gryB E540D at 5 months. A single mutation in the gryA gene locus showed higher converted proportions 70.8% (58.9–81.0) than those that had two 8.3% (3.1–17.3) or three 2.7% (0.3–10.0) mutations. Conclusions The studied second-line drug resistance markers had no statistically significant association with the time to sputum culture conversion, although increased drug resistance levels reduced the converted proportions and stressed the need to utilize molecular diagnostics data and other crucial variables to better comprehend proxy indicators of SLD resistant tuberculosis management.

Evaluation of treatment regimens and long-term clinical outcomes in patients with isoniazid-resistant pulmonary tuberculosis: a 5-year follow-up.

Considering its early bactericidal activity, isoniazid (H) is an important first-line agent in tuberculosis (TB) treatment.The aim of this study was to evaluate the treatment regimens and results of H-resistant pulmonary TB patients. We retrospectively evaluated treatment regimens and results of 188 H-resistant pulmonary TB patients who were treated in our center between January 2015 and December 2017. Treatment regimens applied were noted and treatment outcomes were recorded. The long-term results were evaluated. Totally 174 (92.6%) of 188 patients with H-resistant pulmonary TB achieved treatment success. Ninety-seven patients (51.6%)were cured and 77 patients (41.0%) completed treatment. Five patients (2.7%) had treatment failure. Four patients (2.1%) having treatment success relapsed during one-year follow-up. Eighteen patients (9.6%) had unfavorable outcomes, including treatment failure in five (2.7%), death in nine (4.8%), and relapse in four patients (2.1%). The treatment success rate was found to be statistically higher in group 1 (9-month regimen 2HREZ/7HRE) compared with those in group 2 (9HREZ) (97.4% vs. 85.9%; p = 0.010). Group 3 (HREZFQ) and group 1 had statistically significant favorable outcomes, compared to group 2 (group 2 vs. group 3, p = 0.048; group 1 vs. group 2, p = 0.022). Interestingly, no relapse and acquired rifampicin resistance in patients occurred who received an FQ-containing regimen. Our study results show higher treatment success and positive results with the treatment regimen containing FQ and that treatment with HREZ for nine months is associated with a lower treatment success rate.

Effect of retro-walking on pain, functional disability, quality of life and sleep problems in patients with chronic low back pain

IntroductionChronic low back pain is an important clinical, social, economic, and public health problem, with low treatment success rates. Retro-walking works on multiple factors of the causative agents of low back pain. Therefore the aim of the current study was to investigate the effect of retro-walking on pain, functional disability, quality of life and sleep problems in patients with chronic low back pain.MethodsIt was a two parallel arm, single blinded, randomized, controlled clinical trial. Thirty-one patients both males and females with chronic low back pain were recruited from December 2016 till April 2017 out of which twenty-nine completed the study. The experimental group had 16 patients (aged 24.7 ± 5.56 with 22.7 ± 4.28 Body Mass Index) whereas the control group had 15 patients (aged 25.9 ± 5.61with and 22.1 ± 3.15 Body Mass Index). Pain, Functional Disability, Quality of Life and Sleep Problems were measured by Numerical pain rating scale, Oswestry Disability Index, Short Form Health Survey 36 and sleep diary Both the groups received same conventional treatment for three physiotherapy sessions per week for three weeks. Experimental group additionally participated in 15 minutes of retro-walking at the comfortable walking speed which was determined prior to the commencement of the intervention along with the conventional treatment.ResultsAll variables of the sleep diary, i.e., sleeping hours/week [Time effect (&lt;i&gt;p&lt;/i&gt; = 0.004), time × group interaction effect (&lt;i&gt;p&lt;/i&gt; = 0.001)], sleep efficiency [Time effect (&lt;i&gt;p&lt;/i&gt; = 0.024), time × group interaction effect (&lt;i&gt;p&lt;/i&gt; = 0.004)] and restoration post sleep [Time effect (&lt;i&gt;p&lt;/i&gt; = 0.014), time × group interaction effect (&lt;i&gt;p&lt;/i&gt; = 0.034)] showed significant differences in the experimental group. The experimental group also demonstrated significant differences over time (&lt;i&gt;p&lt;/i&gt; = 0.001) in all the other outcome measures such as pain, pain disability, quality of life and sleep patterns and habits.ConclusionsConventional physiotherapy is an effective means of treatment for Chronic Low back pain. However, there was a added advantage of retro-walking as the experimental group showed a faster recovery. Thus, making it an effective treatment adjunct.

Unraveling antibiotic resistance mechanisms in Mycobacterium abscessus: the potential role of efflux pumps

Mycobacterium abscessus is an opportunistic respiratory pathogen in patients with underlying lung disease. It is infamously known for its low treatment success rates because of its resistance to multiple classes of antibiotics. Further insight into M. abscessus resistance mechanisms is needed to improve treatment options. In this in vitro study, the role of efflux pumps in reaction to antibiotic stress is explored, as well as the ability of the putative efflux inhibitors, thioridazine and verapamil, to potentiate the activity of guideline-recommended antibiotics. To evaluate the effects of antibiotic stress on mycobacterial efflux pumps, M. abscessus subspecies abscessus was exposed to amikacin, cefoxitin, clarithromycin, clofazimine, and tigecycline for 24 hours. Transcriptomic responses were measured by RNA sequencing to gain insight into upregulation of efflux pump encoding genes. Subsequently, in time-kill kinetics assays, the above-mentioned antibiotics were combined with thioridazine and verapamil to evaluate their potentiating capacity. All five antibiotics led to a fold change of ≥2 Log2 in expression of one or more genes encoding transporter systems. This effect was most pronounced for the ribosome-targeting antibiotics amikacin, clarithromycin, and tigecycline. Time-kill kinetics assays demonstrated synergy between amikacin, tigecycline, clofazimine, cefoxitin, and both thioridazine and verapamil. Antibiotic stressors induce expression of efflux pump encoding genes in M. abscessus, especially antibiotics that target the ribosome. Putative efflux inhibitors thioridazine and verapamil show synergy with various guideline-recommended antibiotics, making them interesting candidates for the improvement of M. abscessus treatment.