Emerging phosphodiesterase inhibitors for treatment of neurodegenerative diseases.

Neurodegenerative diseases (NDs) cause progressive loss of neuron structure and ultimately lead to neuronal cell death. Since the available drugs show only limited symptomatic relief, NDs are currently considered as incurable. This review will illustrate the principal roles of the signaling systems of cyclic adenosine and guanosine 3',5'-monophosphates (cAMP and cGMP) in the neuronal functions, and summarize expression/activity changes of the associated enzymes in the ND patients, including cyclases, protein kinases, and phosphodiesterases (PDEs). As the sole enzymes hydrolyzing cAMP and cGMP, PDEs are logical targets for modification of neurodegeneration. We will focus on PDE inhibitors and their potentials as disease-modifying therapeutics for the treatment of Alzheimer's disease, Parkinson's disease, and Huntington's disease. For the overlapped but distinct contributions of cAMP and cGMP to NDs, we hypothesize that dual PDE inhibitors, which simultaneously regulate both cAMP and cGMP signaling pathways, may have complementary and synergistic effects on modifying neurodegeneration and thus represent a new direction on the discovery of ND drugs.

Evolution of anaesthesia technique for endolaryngeal surgery through and post-COVID-19 pandemic: An experience from a tertiary referral centre for airway surgery.

Background and Aims: Anaesthesia for endolaryngeal surgery is specialised to provide almost a tubeless surgical field. During the coronavirus disease-19 pandemic, when most of the surgeries were staggered, we being in a tertiary referral centre for airway surgery had to modify our existing techniques and observed an evolution in the anaesthesia management which we could continue even in the postpandemic period. Hence, we conducted this retrospective study to analyse the reliability of our locally developed apnoeic high-flow oxygenation technique (AHFO) for endolaryngeal procedures. Methods: We conducted this single-centric retrospective study from January 2020 to August 2021 to observe the choice of airway management techniques in endolaryngeal surgery and assess the feasibility and safety of AHFO. We also intend to propose an algorithm for airway management. We calculated the percentages of all necessary parameters to denote the trend in change of practices roughly classifying the study period as prepandemic, pandemic and postpandemic. Results: A total of 413 patients were analysed in our study. The changing trend over preference of AHFO from prepandemic (72%) and dominance of AHFO (92.5%) in the postpandemic period are the most significant observations of our study with 17% patients needing conversion to tube in-tube out technique due to desaturation which is comparable to 14% in prepandemic period. Conclusion: The tubeless field provided by AHFO replaced the conventional airway management techniques. Our study demonstrates the safety and feasibility of AHFO for endolaryngeal surgeries. We also propose an algorithm for anaesthetists involved in laryngology unit.

Targeted next generation sequencing directly from sputum for comprehensive genetic information on drug resistant Mycobacterium tuberculosis.

BACKGROUND: Timely drug resistance detection is essential to global tuberculosis management. Unfortunately, rapid molecular tests assess resistance to only a few drugs, with culture required for comprehensive susceptibility test results. METHODS: We evaluated targeted next generation sequencing (tNGS) for tuberculosis on 40 uncultured sputum samples. Resistance profiles from tNGS were compared with profiles from Xpert MTB/RIF, line probe assay (LPA), pyrosequencing (PSQ), and phenotypic testing. Concordance, sensitivity, specificity, and overall test agreement were compared across assays. RESULTS: tNGS provided results for 39 of 40 samples (97.5%) with faster turnaround than phenotypic testing (median 3 vs. 21 days, p = 0.0068). Most samples were isoniazid and rifampin resistant (N = 31, 79.5%), 21 (53.8%) were fluoroquinolone resistant, and 3 (7.7%) were also resistant to Kanamycin. Half were of the Beijing lineage (N = 20, 51.3%). tNGS from uncultured sputum identified all resistance to isoniazid, rifampin, fluoroquinolones, and second-line injectable drugs that was identified by other methods. Agreement between tNGS and existing assays was excellent for isoniazid, rifampin, and SLDs, very good for levofloxacin, and good for moxifloxacin. CONCLUSION: tNGS can rapidly identify tuberculosis, lineage, and drug resistance with faster turnaround than phenotypic testing. tNGS is a potential alternative to phenotypic testing in high-burden settings.

Interpreting very low Mycobacterium tuberculosis detected on Xpert Mycobacterium tuberculosis/rifampicin.

The development and rollout of the Xpert® Mycobacterium tuberculosis/rifampicin assay for the GeneXpert platform is considered an important breakthrough in the fight against tuberculosis. Xpert though robust is known to have issues that occur with very low load of tuberculosis detection, wherein it is recommended to confirm resistance if resistance is not suspected using another genotypic test.

Utility of pyrosequencing for rapid detection of tubercular meningitis (TBM) and associated susceptibility directly from CSF specimens.

Tubercular meningitis (TBM) is a serious form of tuberculosis (TB). The diagnosis of TBM & susceptibility/resistance is difficult as TB MGIT culture lacks sensitivity & timeliness. Timely and accurate diagnosis of the TBM is the need of the hour for initiation of appropriate therapy. We have exploited pyrosequencing to detect TB and associated Multi/extensively drug resistant (MDR/ XDR-TB) directly from Cerebrospinal Fluid (CSF) specimens.

Pyrosequencing to resolve discrepant Xpert MTB/RIF and Mycobacterial Growth Indicator Tube 960.

Delayed diagnosis of drug resistance has been a major obstacle to proper management and control of drug-resistant tuberculosis (TB). Expanded access to rapid molecular diagnostics such as Xpert MTB/RIF has been helpful, but has generated confusion about how to interpret genotype-phenotype discordance. Optimal management is not clearly defined for patients with rifampin resistance by Xpert MTB/RIF but rifampin susceptibility by phenotypic testing. To resolve this discrepancy, we performed pyrosequencing of discordant isolates identified at a reference laboratory over a 6-month period. We present here strategies to address genotype-phenotype discordance using sequencing.