Structural studies of intrinsically disordered MLL-fusion protein AF9 in complex with peptidomimetic inhibitors.

AF9 (MLLT3) and its paralog ENL(MLLT1) are members of the YEATS family of proteins with important role in transcriptional and epigenetic regulatory complexes. These proteins are two common MLL fusion partners in MLL-rearranged leukemias. The oncofusion proteins MLL-AF9/ENL recruit multiple binding partners, including the histone methyltransferase DOT1L, leading to aberrant transcriptional activation and enhancing the expression of a characteristic set of genes that drive leukemogenesis. The interaction between AF9 and DOT1L is mediated by an intrinsically disordered C-terminal ANC1 homology domain (AHD) in AF9, which undergoes folding upon binding of DOT1L and other partner proteins. We have recently reported peptidomimetics that disrupt the recruitment of DOT1L by AF9 and ENL, providing a proof-of-concept for targeting AHD and assessing its druggability. Intrinsically disordered proteins, such as AF9 AHD, are difficult to study and characterize experimentally on a structural level. In this study, we present a successful protein engineering strategy to facilitate structural investigation of the intrinsically disordered AF9 AHD domain in complex with peptidomimetic inhibitors by using maltose binding protein (MBP) as a crystallization chaperone connected with linkers of varying flexibility and length. The strategic incorporation of disulfide bonds provided diffraction-quality crystals of the two disulfide-bridged MBP-AF9 AHD fusion proteins in complex with the peptidomimetics. These successfully determined first series of 2.1-2.6 Å crystal complex structures provide high-resolution insights into the interactions between AHD and its inhibitors, shedding light on the role of AHD in recruiting various binding partner proteins. We show that the overall complex structures closely resemble the reported NMR structure of AF9 AHD/DOT1L with notable difference in the conformation of the ß-hairpin region, stabilized through conserved hydrogen bonds network. These first series of AF9 AHD/peptidomimetics complex structures are providing insights of the protein-inhibitor interactions and will facilitate further development of novel inhibitors targeting the AF9/ENL AHD domain.

ß-Cell Insulin Resistance Plays a Causal Role in Fat-Induced ß-Cell Dysfunction In Vitro and In Vivo.

In the classical insulin target tissues of liver, muscle, and adipose tissue, chronically elevated levels of free fatty acids (FFA) impair insulin signaling. Insulin signaling molecules are also present in ß-cells where they play a role in ß-cell function. Therefore, inhibition of the insulin/insulin-like growth factor 1 pathway may be involved in fat-induced ß-cell dysfunction. To address the role of ß-cell insulin resistance in FFA-induced ß-cell dysfunction we co-infused bisperoxovanadate (BPV) with oleate or olive oil for 48 hours in rats. BPV, a tyrosine phosphatase inhibitor, acts as an insulin mimetic and is devoid of any antioxidant effect that could prevent ß-cell dysfunction, unlike most insulin sensitizers. Following fat infusion, rats either underwent hyperglycemic clamps for assessment of ß-cell function in vivo or islets were isolated for ex vivo assessment of glucose-stimulated insulin secretion (GSIS). We also incubated islets with oleate or palmitate and BPV for in vitro assessment of GSIS and Akt (protein kinase B) phosphorylation. Next, mice with ß-cell specific deletion of PTEN (phosphatase and tensin homolog; negative regulator of insulin signaling) and littermate controls were infused with oleate for 48 hours, followed by hyperglycemic clamps or ex vivo evaluation of GSIS. In rat experiments, BPV protected against fat-induced impairment of ß-cell function in vivo, ex vivo, and in vitro. In mice, ß-cell specific deletion of PTEN protected against oleate-induced ß-cell dysfunction in vivo and ex vivo. These data support the hypothesis that ß-cell insulin resistance plays a causal role in FFA-induced ß-cell dysfunction.

Self-micellizing solid dispersion of thymoquinone with enhanced biopharmaceutical and nephroprotective effects.

The present study was designed to develop a self-micellizing solid dispersion (SMSD) containing Thymoquinone (TQM), a phytonutrient obtained from Nigella sativa seeds, aiming to improve its biopharmaceutical and nephroprotective functions. The apparent solubility of TQM in polymer solutions was used to choose an appropriate amphiphilic polymer that could be used to make an SMSD system. Based on the apparent solubility, Soluplus® was selected as an appropriate carrier, and mixing with TQM, SMSD-TQM with different loadings of TQM (5-15%) was made by solvent evaporation and freeze-drying techniques, respectively, and the formulations were optimized. The optimized SMSD-TQM was evaluated in terms of particle size distribution, morphology, release characteristics, pharmacokinetic behavior, and nephroprotective effects in a rat model of acute kidney injury. SMSD-TQM significantly improved the dissolution characteristics (97.8%) of TQM in water within 60 min. Oral administration of SMSD-TQM in rats exhibited a 4.9-fold higher systemic exposure than crystalline TQM. In a cisplatin-induced (6 mg/kg, i.p.) acute kidney-damaged rat model, oral SMSD-TQM (10 mg/kg) improved the nephroprotective effects of TQM based on the results of kidney biomarkers and histological abnormalities. These findings suggest that SMSD-TQM might be efficacious in enhancing the nephroprotective effect of TQM by overcoming biopharmaceutical limitations.

The genomic history and global migration of a windborne pest.

Many insect pests, including the brown planthopper (BPH), undergo windborne migration that is challenging to observe and track. It remains controversial about their migration patterns and largely unknown regarding the underlying genetic basis. By analyzing 360 whole genomes from around the globe, we clarify the genetic sources of worldwide BPHs and illuminate a landscape of BPH migration showing that East Asian populations perform closed-circuit journeys between Indochina and the Far East, while populations of Malay Archipelago and South Asia undergo one-way migration to Indochina. We further find round-trip migration accelerates population differentiation, with highly diverged regions enriching in a gene desert chromosome that is simultaneously the speciation hotspot between BPH and related species. This study not only shows the power of applying genomic approaches to demystify the migration in windborne migrants but also enhances our understanding of how seasonal movements affect speciation and evolution in insects.

Elucidating the role of EPPK1 in lung adenocarcinoma development.

BACKGROUND: We recently found that epiplakin 1 (EPPK1) alterations were present in 12% of lung adenocarcinoma (LUAD) cases and were associated with a poor prognosis in early-stage LUAD when combined with other molecular alterations. This study aimed to identify a probable crucial role for EPPK1 in cancer development. METHODS: EPPK1 mRNA and protein expression was analyzed with clinical variables. Normal bronchial epithelial cell lines were exposed to cigarette smoke for 16 weeks to determine whether EPPK1 protein expression was altered after exposure. Further, we used CRISPR-Cas9 to knock out (KO) EPPK1 in LUAD cell lines and observed how the cancer cells were altered functionally and genetically. RESULTS: EPPK1 protein expression was associated with smoking and poor prognosis in early-stage LUAD. Moreover, a consequential mesenchymal-to-epithelial transition was observed, subsequently resulting in diminished cell proliferation and invasion after EPPK1 KO. RNA sequencing revealed that EPPK1 KO induced downregulation of 11 oncogenes, 75 anti-apoptosis, and 22 angiogenesis genes while upregulating 8 tumor suppressors and 12 anti-cell growth genes. We also observed the downregulation of MYC and upregulation of p53 expression at both protein and RNA levels following EPPK1 KO. Gene ontology enrichment analysis of molecular functions highlighted the correlation of EPPK1 with the regulation of mesenchymal cell proliferation, mesenchymal differentiation, angiogenesis, and cell growth after EPPK1 KO. CONCLUSIONS: Our data suggest that EPPK1 is linked to smoking, epithelial to mesenchymal transition, and the regulation of cancer progression, indicating its potential as a therapeutic target for LUAD.

Successful treatment of recurrent visceral leishmaniasis relapse in an immunocompetent adult female with functional hypopituitarism in Bangladesh.

BACKGROUND: Currently available treatment options are mostly effective in achieving long-term cure in visceral leishmaniasis (VL) patients. However, there have been reports of recurrence of this illness in both immunosuppressed and immunocompetent patients. CASE PRESENTATION: We report the first case of recurrent VL relapse in a 19-year-old immunocompetent female with functional hypopituitarism (hypogonadotropic hypogonadism with central hypothyroidism) from Bangladesh, who has been treated three times previously with optimal dosage and duration- liposomal amphotericin B (LAmB) alone and in combination with miltefosine. We treated the patient successfully with a modified treatment regimen of 10 mg/kg body weight LAmB for two consecutive days along with oral miltefosine for seven days as loading dose. For secondary prophylaxis, the patient received 3 mg/kg body weight LAmB along with oral miltefosine for seven days monthly for five doses followed by hormonal replacement. The patient remained relapse free after 12 months of her treatment completion. CONCLUSION: In the absence of protective vaccines against Leishmania species and standard treatment regimen, this modified treatment regimen could help the management of recurrent relapse cases.

Xpert MTB/RIF Ultra for the rapid diagnosis of extrapulmonary tuberculosis in a clinical setting of high tuberculosis prevalence country and interpretation of 'trace' results.

To evaluate the diagnostic performance of Xpert MTB/RIF Ultra (Ultra) for the diagnosis of extrapulmonary tuberculosis (EPTB) from different types of extrapulmonary specimens in comparison with culture and composite microbiological reference standard (CRS). A total of 240 specimens were prospectively collected from presumptive EPTB patients between July 2021-January 2022 and tested by Ultra, Xpert, culture and acid-fast bacilli (AFB) smear microscopy. Out of 240 specimens, 35.8 %, 20.8 %, 11.3 %, and 7.1 % were detected as Mycobacterium tuberculosis complex by Ultra, Xpert, culture and AFB microscopy, respectively. An additional 15.0 % cases were detected by Ultra compared to Xpert MTB/RIF (Xpert) assay. A total of 28 (11.7 %) cases were identified as 'trace' category by Ultra with indeterminate rifampicin resistance result; of which 36.4 % were clinically confirmed as EPTB. Compared to culture, the sensitivity and specificity of Ultra and Xpert were 100 % and 72.3 %; 92.6 % and 88.3 %, respectively. In comparison with CRS, these were respectively: 98.9 % and 100 %; 57.5 % and 100 %. For individual category of specimens, sensitivity of Ultra was 100 % with varying specificity. We found that Ultra was highly sensitive for the rapid diagnosis of EPTB and has extensive potential over current diagnostics in high TB burden countries, but 'trace' results should be interpreted with caution.

Bronchogenic cyst at unusual location.

Bronchogenic cyst results from abnormal bronchial budding. Thin-stalked mobile bronchogenic cysts are rare and sometimes radiologically mimic mass lesion, making preoperative diagnosis difficult. We present a 12-year-old boy with a preoperative diagnosis of intraparenchymal cystic lung lesion misled by radiology. We performed a mini-thoracotomy revealing a thin stalked mobile elongated cyst that arose from the right inferior pulmonary ligament, confirmed as a bronchogenic cyst in histopathology.

Validation of a Proteomic Signature of Lung Cancer Risk from Bronchial Specimens of Risk-Stratified Individuals.

A major challenge in lung cancer prevention and cure hinges on identifying the at-risk population that ultimately develops lung cancer. Previously, we reported proteomic alterations in the cytologically normal bronchial epithelial cells collected from the bronchial brushings of individuals at risk for lung cancer. The purpose of this study is to validate, in an independent cohort, a selected list of 55 candidate proteins associated with risk for lung cancer with sensitive targeted proteomics using selected reaction monitoring (SRM). Bronchial brushings collected from individuals at low and high risk for developing lung cancer as well as patients with lung cancer, from both a subset of the original cohort (batch 1: n = 10 per group) and an independent cohort of 149 individuals (batch 2: low risk (n = 32), high risk (n = 34), and lung cancer (n = 83)), were analyzed using multiplexed SRM assays. ALDH3A1 and AKR1B10 were found to be consistently overexpressed in the high-risk group in both batch 1 and batch 2 brushing specimens as well as in the biopsies of batch 1. Validation of highly discriminatory proteins and metabolic enzymes by SRM in a larger independent cohort supported their use to identify patients at high risk for developing lung cancer.

Phyllanthus emblica (Amla) methanolic extract regulates multiple checkpoints in 15-lipoxygenase mediated inflammopathies: Computational simulation and in vitro evidence.

Amla (Phyllanthus emblica) has long been used in traditional folk medicine to prevent and cure a variety of inflammatory diseases. In this study, the antioxidant activity (DPPH scavenging and reducing power), anti-inflammatory activity (RBC Membrane Stabilization and 15-LOX inhibition), and anticoagulation activity (Serin protease inhibition and Prothrombin Time assays) of the methanolic extract of amla were conducted. Amla exhibited a substantial amount of phenolic content (TPC: 663.53 mg GAE/g) and flavonoid content (TFC: 418.89 mg GAE/g). A strong DPPH scavenging effect was observed with an IC50 of 311.31 µg/ml as compared to standard ascorbic acid with an IC50 of 130.53 µg/ml. In reducing power assay, the EC50 value of the extract was found to be 196.20 µg/ml compared to standard ascorbic acid (EC50 = 33.83 µg/ml). The IC50 value of the RBC membrane stabilization and 15-LOX assays was observed as 101.08 µg/ml (IC50 of 58.62 µg/ml for standard aspirin) and 195.98 µg/ml (IC50 of 19.62 µg/ml for standard quercetin), respectively. The extract also strongly inhibited serine protease (trypsin) activity with an IC50 of 505.81 µg/ml (IC50 of 295.44 µg/ml for standard quercetin). The blood coagulation time (PTT) was found to be 11.91 min for amla extract and 24.11 min for standard Warfarin. Thus, the findings of an in vitro study revealed that the methanolic extract of amla contains significant antioxidant, anti-inflammatory, and anticoagulation activity. Furthermore, in silico docking and simulation of reported phytochemicals of amla with human 15-LOXA and 15-LOXB were carried out to validate the anti-inflammatory activity of amla. In this analysis, epicatechin and catechin showed greater molecular interaction and were considerably stable throughout the 100 ns simulation with 15-lipoxygenase A (15-LOXA) and 15-lipoxygenase B (15-LOXB) respectively.

Irrational use of antibiotics and factors associated with antibiotic resistance: Findings from a cross-sectional study in Bangladesh.

Background and aims: Irrational antibiotic (AB) usage poses a serious concern to third-world countries because of poor surveillance, lack of information, and patients' propensity for self-medication. Additionally, the unpredictability of the coronavirus disease 2019 (COVID-19) pandemic promoted the abuse of ABs, which accelerated the prevalence of antibiotic resistance (ABR). The primary aim of this study was to assess the pattern of AB usage and irrational use of ABs-related potential factors associated with ABR among the students and teachers of a leading public university of Bangladesh. Methods: A cross-sectional web-based survey was conducted among the students and teachers (n = 783) of the selected university, from January 1 to February 28, 2022. Descriptive statistics, χ 2 test, and logistic regression analysis were employed to analyze the collected data. Results: The regression analysis supported that male participants had a 34% lower experience of acquiring ABR than female respondents (adjusted odds ratio [AOR] = 0.66, 95% confidence interval [CI] = 0.448, 0.973; p = 0.036). The 1st/2nd-year level students had more than two times higher experience with ABR than the master's or higher-class students (AOR = 2.149, 95% CI = 1.047, 4.412; p = 0.037). The participants who took ABs for 4-6 days showed more than two times ABR experience than those who took ABs for above 10 days (AOR = 2.016, 95% CI = 1.016, 4.003; p = 0.045). Respondents who finished their AB medication (dose completion) had a 57% less chance of acquiring ABR than the participants who did not complete their dose. Conclusion: This study found that irrational use of ABs is more prevalent among the youth and female participants. At this stage, there is an urgent need for comprehensive statutory AB control rules, as well as measures for appropriate information, education, and surveillance throughout different groups of Bangladesh.

PLAAT1 deficiency alleviates high-fat diet-induced hepatic lipid accumulation in mice.

The phospholipase A and acyltransferase (PLAAT) family is composed of three isoforms in mice (PLAAT1, 3, and 5), all of which function as phospholipid-metabolizing enzymes exhibiting phospholipase A1 /A2 and acyltransferase activities. Plaat3-deficient (Plaat3-/- ) mice were previously reported to show lean phenotype and remarkable hepatic fat accumulation under high-fat diet (HFD) feeding, while Plaat1-/- mice have not been analyzed. In the present study, we generated Plaat1-/- mice and investigated the effects of PLAAT1 deficiency on HFD-induced obesity, hepatic lipid accumulation, and insulin resistance. After HFD treatment, PLAAT1 deficiency caused a lower body weight gain compared to wild-type mice. Plaat1-/- mice also showed reduced liver weight with negligible hepatic lipid accumulation. In accordance with these findings, PLAAT1 deficiency improved HFD-induced hepatic dysfunction and lipid metabolism disorders. Lipidomics analysis in the liver revealed that in Plaat1-/- mice, the levels of various glycerophospholipids tended to increase, while all classes of lysophospholipids examined tended to decrease, suggesting that PLAAT1 functions as phospholipase A1 /A2 in the liver. Interestingly, the HFD treatment of wild-type mice significantly increased the mRNA level of PLAAT1 in the liver. Furthermore, the deficiency did not appear to elevate the risk of insulin resistance in contrast to PLAAT3 deficiency. These results suggested that the suppression of PLAAT1 improves HFD-induced overweight and concomitant hepatic lipid accumulation.

Unusual cause of mediastinal tumor: A case of calcified pericardial cyst.

Pericardial cysts are rare benign intrathoracic lesions, and calcified pericardial cysts are even more uncommon. Most pericardial cysts are asymptomatic, but patients may present with chest pain, dyspnea and any complications of pericardial effusion. We present a case of a left-sided calcified pericardial cyst, highlighting its rarity and symptoms in relation to its location.

The impact of deontological and teleological variables on the intention to visit green hotel: The moderating role of trust.

Green hotels have grown in popularity due to customers' increased awareness of environmental issues. This study aims to construct and evaluate a model that combines the theory of Planned Behavior (TPB) and the theory of ethics to explain green hotel visitors' intentions and behavior. The study also considers the role of trust & subjective norms as a moderator. The framework of the study was evaluated using a quantitative method. Most of the respondents to the study, which was carried out in Noakhali, Bangladesh, were students at Noakhali Science and Technology University and their family members. The data was collected from 414 respondents and analyzed using the structural equation modeling (SEM) technique. The data collection took around two weeks, starting from December 3, 2021. According to the study's findings, the deontological (Moral obligation and justice) and teleological variables (perceived benefit and perceived risk) significantly influence green hotel visitors' intentions and actual behavior. Moreover, trust noticeably influences the relationship between subjective norm (SN) and Intention, and subjective norm affects the connection between attitude and intention. Therefore, hotel management can utilize this research to examine and understand visitors' intention and actual behavior to visit green hotels, which will assist them in attracting guests by portraying their services as eco-friendly. Furthermore, the findings may help hotel management formulate competitive marketing strategies, design effective promotional tools, and help generate an eco-conscious customer base.

Diagnostic Performance of Different Laboratory Methods for the Detection of Extrapulmonary Tuberculosis.

Accurate and appropriate extrapulmonary tuberculosis (EPTB) diagnosis remains challenging due to its paucibacillary nature, requirement of invasive collection procedures, and lack of sensitive tests. This study investigated the diagnostic performance of different methods for the diagnosis of EPTB. A total of 1340 EPTB specimens were collected from presumptive EPTB patients from four different hospitals between November 2015 and March 2017. The collected specimens were tested with AFB microscopy, culture, Xpert MTB/RIF assay (Xpert), and MTBDRplus assay. Among the 1340 EPTB specimens, 49 (3.66%), 141 (10.52%), 166 (12.39%), and 154 (11.49%) were positive in AFB microscopy, culture, Xpert MTB/RIF, and MTBDRplus assay, respectively. A total of 194 (14.9%) cases were found positive in at least one of these methods. Using culture as a reference standard, the sensitivity and specificity of AFB microscopy, Xpert MTB/RIF, and MTBDRplus assay were: 27.0%/99.1%, 83.7%/96.0%, and 79.4%/96.5%, respectively. Compared to the composite reference standard, the sensitivity of culture, AFB microscopy, Xpert MTB/RIF, and MTBDRplus assay was 72.7%, 25.3%, 85.6%, and 79.4%, respectively, with a specificity of 100% for all the methods. The Xpert MTB/RIF assay showed the highest sensitivity compared to other methods. Considering the short turnaround time and promising findings, Xpert MTB/RIF assay should be integrated into national TB guidelines as a routine diagnostic test.

A prospective study of arthroscopic primary ACL reconstruction with ipsilateral peroneus longus tendon graft: Experience of 439 cases.

Anterior cruciate ligament (ACL) tears are frequent ligamentous injuries that necessitate reconstruction in many cases. The patellar tendon and the hamstring tendon are the most frequently utilized autografts for reconstruction. However, both have certain disadvantages. We hypothesized that the peroneus longus tendon would be an acceptable graft for arthroscopic ACL reconstruction. The aim of this study is to determine whether a peroneus Longus tendon transplant is a functionally viable option for arthroscopic ACL reconstruction without compromising donor ankle activity. In this prospective study 439 individuals aged between 18 to 45 years, who underwent ACL reconstruction using ipsilateral Peroneus longus tendon autograft were observed. The injury to the ACL was initially assessed by physical examinations and further confirmed by magnetic resonance imaging (MRI). The outcome was assessed at 6, 12, and 24 months after the surgery using Modified Cincinnati, International Knee Documentation Committee (IKDC), and Tegner-Lysholm scores. The donor ankle stability was evaluated using foot and ankle disability index (FADI) and AOFAS scores, as well as hop tests. Significant (P < .001) improvement in the result of the IKDC score, Modified Cincinnati, and Tegner-Lysholm score was observed at the final follow-up. The Lachman test was mildly (1+) positive only in 7.70% of cases, the anterior drawer became negative in all cases, and the pivot shift test was negative in 97.43% of cases at 24 months after the surgery. FADI and AOFAS scores for donor's ankle functional assessment were impressive, as were single hop test, triple hop test, and cross over hop test results at 2 years. None of the patients had any neurovascular deficit. However, 6 cases of superficial wound infection were observed, 4 at the port site and 2 at the donor site. All resolved after appropriate oral antibiotic therapy. The peroneus longus tendon can be considered a safe, effective, and promising graft of choice for arthroscopic primary single-bundle ACL reconstruction because it has a good functional outcome and impressive donor ankle function after surgery.

Slightly acidic electrolyzed water as a novel thawing media combined with ultrasound for improving thawed mutton quality, nutrients and microstructure.

The effects of ultrasound-assisted slightly acidic electrolyzed water thawing (UET), air thawing (AT), water thawing (WT) and microwave thawing (MT) on the quality, nutrients and microstructure were investigated. The UET treatment did not affect the lightness (L*) but reduced the redness (a*) and yellowness (b*) of the mutton. The UET treatment could better maintain the textural properties. The UET group had a higher immobilized water and lower free water, which was closer to the state of the control group. The UET treatment not only effectively inhibited the lipid oxidation but also reduced the loss of nutrients, especially minerals. The microstructure of the UET group was smoother and more complete, and the muscle fibers did not show significant breakage. In conclusion, UET treatment could better maintain the quality, nutrients and microstructure of thawed mutton. Therefore, UET could be regarded as a potential thawing method for application in the processing of meat products.

Pharmacokinetic-Pharmacodynamic Determinants of Clinical Outcomes for Rifampin-Resistant Tuberculosis: A Multisite Prospective Cohort Study.

BACKGROUND: Rifampin-resistant and/or multidrug-resistant tuberculosis (RR/MDR-TB) treatment requires multiple drugs, and outcomes remain suboptimal. Some drugs are associated with improved outcome. It is unknown whether particular pharmacokinetic-pharmacodynamic relationships predict outcome. METHODS: Adults with pulmonary RR/MDR-TB in Tanzania, Bangladesh, and the Russian Federation receiving local regimens were enrolled from June 2016 to July 2018. Serum was collected after 2, 4, and 8 weeks for each drug's area under the concentration-time curve over 24 hours (AUC0-24). Quantitative susceptibility of the M. tuberculosis isolate was measured by minimum inhibitory concentrations (MICs). Individual drug AUC0-24/MIC targets were assessed by adjusted odds ratios (ORs) for favorable treatment outcome, and hazard ratios (HRs) for time to sputum culture conversion. K-means clustering algorithm separated the cohort of the most common multidrug regimen into 4 clusters by AUC0-24/MIC exposures. RESULTS: Among 290 patients, 62 (21%) experienced treatment failure, including 30 deaths. Moxifloxacin AUC0-24/MIC target of 58 was associated with favorable treatment outcome (OR, 3.75; 95% confidence interval, 1.21-11.56; P = .022); levofloxacin AUC0-24/MIC of 118.3, clofazimine AUC0-24/MIC of 50.5, and pyrazinamide AUC0-24 of 379 mg × h/L were associated with faster culture conversion (HR >1.0, P < .05). Other individual drug exposures were not predictive. Clustering by AUC0-24/MIC revealed that those with the lowest multidrug exposures had the slowest culture conversion. CONCLUSIONS: Amidst multidrug regimens for RR/MDR-TB, serum pharmacokinetics and M. tuberculosis MICs were variable, yet defined parameters to certain drugs-fluoroquinolones, pyrazinamide, clofazimine-were predictive and should be optimized to improve clinical outcome. CLINICAL TRIALS REGISTRATION: NCT03559582.

Trends and prospects of geothermal energy as an alternative source of power: A comprehensive review.

The world has capitalized on numerous renewable energy resources by developing its energy infrastructure mainly around solar, biomass, and hydro energy. However, geothermal energy has not yet been developed at a significant scale, despite reports from 62 wells showing evidence of geothermal gradients ranging from 20.8 °C/km to 48.7 °C/km in various areas of the world. Recent studies suggest that Bangladesh also has a huge potential for geothermal energy. This review extensively reports on exploiting the range of geothermal temperature in various direct and indirect energy application sectors including but not limited to the agriculture and industrial sector of Bangladesh. Additionally, the authors have analyzed and proposed adaptable measures to harness the abundance of geothermal energy. Furthermore, a comparative and possible solution has been discussed extensively for implementing a geothermal powerplant by analyzing techno-economic costs, policies, and systems of other countries in the world. Further, this review also shows the prospect of geothermal energy for Bangladesh as a case study.