Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55 years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8 weeks) and one month later (16 weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8 weeks, however, the difference was not sustained at 16 weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16 weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.

Multimodal analysis of the COVID-19-associated mucormycosis outbreak in Delhi, India indicates the convergence of clinical and environmental risk factors.

BACKGROUND: The aetiology of the major outbreak of COVID-19-associated mucormycosis (CAM) in India in spring 2021 remains incompletely understood. Herein, we provide a multifaceted and multi-institutional analysis of clinical, pathogen-related, environmental and healthcare-related factors during CAM outbreak in the metropolitan New Delhi area. METHODS: We reviewed medical records of all patients diagnosed with biopsy-proven CAM (n = 50) at 7 hospitals in the New Delhi, and NCR area in April-June 2021. Two multivariate logistic regression models were used to compare clinical characteristics of CAM cases with COVID-19-hospitalised contemporary patients as controls (n = 69). Additionally, meteorological parameters and mould spore concentrations in outdoor air were analysed. Selected hospital fomites were cultured. Mucorales isolates from CAM patients were analysed by ITS sequencing and whole-genome sequencing (WGS). RESULTS: Independent risk factors for CAM identified by multivariate analysis were previously or newly diagnosed diabetes mellitus, active cancer and severe COVID-19 infection. Supplemental oxygen, remdesivir therapy and ICU admission for COVID-19 were associated with reduced CAM risk. The CAM incidence peak was preceded by an uptick in environmental spore concentrations in the preceding 3-4 weeks that correlated with increasing temperature, high evaporation and decreasing relative humidity. Rhizopus was the most common genus isolated, but we also identified two cases of the uncommon Mucorales, Lichtheimia ornata. WGS found no clonal population of patient isolates. No Mucorales were cultured from hospital fomites. CONCLUSIONS: An intersection of host and environmental factors contributed to the emergence of CAM. Surrogates of access to advanced COVID-19 treatment were associated with lower CAM risk.

Small airway disease and its predictors in patients with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a connective tissue disease, characterized by symmetric peripheral polyarthritis. Extra-articular disease occurs in approximately 50% of the patients with lung being a common site. The presence of functional or morphological abnormalities in small airways has recently been noted in patients with RA but its exact prevalence and clinical significance is still a subject of debate. This study was aimed to determine the prevalence of small airway disease (SAD) in patients with RA and the factors influencing it. METHODS: Fifty consecutive patients with RA were included in this cross-sectional observational study. All patients were subjected to pulmonary function tests (PFT) including Spirometry and Forced Oscillation technique (FOT). Those with features of SAD on PFT were subjected to High-Resolution Computed Tomography (HRCT) of the chest. RESULTS: Spirometry was suggestive of SAD in 17 patients, with 34% prevalence and FOT was abnormal in 9 patients, with 18% prevalence in the study population. Of 17 patients with SAD on spirometry, 8 (47.05%) patients showed mosaic attenuation, a sign of SAD on the HRCT chest. On univariate analysis, age, Disease Activity Score (DAS-28), joint erosions on X-ray, RF and anti-CCP were found to be associated with SAD. CONCLUSION: SAD was present in one-third of the patients with RA, even in those with short duration of disease, low to moderate disease activity and no respiratory symptoms. It is thus inferred that the complete workup of RA patients should include pulmonary function assessment.

Cyanide-Free Cyanation of sp2 and sp-Carbon Atoms by an Oxazole-Based Masked CN Source Using Flow Microreactors.

This work reports a cyanide-free continuous-flow process for cyanation of sp2 and sp carbons to synthesize aryl, vinyl and acetylenic nitriles from (5-methyl-2-phenyloxazol-4-yl) boronic acid [OxBA] reagent as a sole source of carbon-bound masked -CN source. Non-toxic and stable OxBA reagent is generated by lithiation-borylation of bromo-oxazole, and the consecutive Suzuki-Miyaura cross-coupling with aryl, vinyl, or acetylenic halides and demasking [4+2]/retro-[4+2] sequence were successfully accomplished to give the desired cyano compounds with reasonably good yields in a four-step flow manner. A unique feature of this cyanation protocol in flow enables to cyanate a variety of sp2 and sp carbons to produce a broad spectrum of aryl acetonitrile. It is envisaged that the OxBA based cyanation would replace existing unstable and toxic approaches as well as non-toxic cyanation using two different sources of "C" and "N" to incorporate the -CN group.

Evaluation of point of care serum cryptococcal antigen by lateral flow immunoassay for diagnosis of cryptococcosis and cryptococcal meningitis in HIV-positive patients.

BACKGROUND: Cryptococcal meningitis (CM) is the initial acquired immunodeficiency syndrome (AIDS) defining illness in 2% of patients with CD4 levels <100/µL and a leading cause of mortality in AIDS in the developing world. It is the most common opportunistic infection of the central nervous system in AIDS in various Indian studies. Detection of serum cryptococcal antigen (SCRAG) is the most widely used diagnostic method for cryptococcosis. The presence of cerebrospinal fluid cryptococcal antigen (CSF CRAG) is diagnostic of CM. CRAG can be determined by latex agglutination (LAT), enzyme-linked immunosorbent assay and now, by lateral flow (LFA)immunoassay. LFA is a point of care test that rapidly detects CRAG. AIMS AND OBJECTIVES: This study compares LAT and LFA for the detection of serum CRAG and diagnosing CM. MATERIALS AND METHODS: Two hundred and ten patients of HIV/AIDS were submitted to SCRAG LFA by dipstick. A sample was also sent to laboratory for SCRAG by LAT. CSF examination was done for those who were positive for SCRAG LFA and those who had symptoms suggestive of meningitis. SCRAG by LFA was compared with SCRAG by LAT, CSF CRAG by LAT and LFA, CSF cryptococcal culture and CSF India ink examination for Cryptococcus. RESULTS: Fifteen patients were found positive for SCRAG by LFA dipstick. All of them were also positive for SCRAG by LAT. Twelve of them had C. D4 count below below 100 cells/mm3. CSF CRAG was positive in all 12 SCRAG positive who were submitted to CSF examination. CONCLUSION: We found that serum detection of CRAG by LFA dipstick is as sensitive as CRAG detection in serum by LAT and CSF CRAG detection by LFA and LAT. It is thus a rapid test for diagnosing CM in HIV patients with low CD4 counts.

Diagnostic value of galactomannan antigen test in serum and bronchoalveolar lavage fluid sample from suspected patients of invasive pulmonary aspergillosis.

Invasive pulmonary aspergillosis (IPA) is mainly caused by Aspergillus fumigatus and other Aspergillus species. Galactomannan (GM) is a polysaccharide antigen that exists primarily in the cell walls of Aspergillus species. GM may be released into the blood and other body fluids even in the early stages of Aspergillus invasion; therefore, detection of the GM antigen level can be useful in making an early diagnosis of IPA.

Liposomal amphotericin B-induced reversible ototoxicity in a patient with disseminated histoplasmosis.

Amphotericin B (AmB) is a polyene antifungal agent used widely for systemic fungal infections. Infusion-related side effects, nephrotoxicity, and dyselectrolytemia are well-known adverse effects with the use of this drug. Liposomal preparation of AmB has less adverse events. However, ototoxicity due to AmB is scarcely mentioned in the literature. We report a case of disseminated histoplasmosis who was treated with liposomal amphotericin B (LAmB) and developed hearing loss during the treatment, which recovered after discontinuing the drug. This is a rare adverse effect of LAmB and reported only once from India, to the best of our knowledge.

Outcome of limb reconstruction system in tibial infected non-union and open tibial diaphysial fracture with bone loss.

INTRODUCTION: Incidence of open fractures of the long bones is increasing due to the increase in road traffic accidents (RTA) which leads to an increased incidence of complex non-unions of long bones. Patients are usually operated many times for fracture fixation (and healing) or to eradicate infection, which causes soft tissue scarring and devitalization of any surviving bone. OBJECTIVE: In this study, we assess the outcome of the Limb reconstruction system in tibial infected non-union and open tibial diaphyseal fracture with bone loss. METHOD: It is a prospective study conducted on 15 patients and patients included in this study having compound fractures of shaft tibia with bone loss classified by Gustilo-Anderson open fracture classification. With the defect in the distal tibia, proximal corticotomy 1.5 cm distal to the last screw in the proximal clamp and proximal to distal transports were done and vice versa. All patients were evaluated with the ASAMI scoring system into bone results and functional results. RESULTS: In the majority of patients, the injury was caused by road traffic accidents 80% of cases. Out of 15 cases, 2 belong to the upper 3rd, 9 cases belong to the middle 3rd and 4 cases belong to the lower 3rd of shaft tibia. The union time ranges from 4 to 11 months but the maximum union was achieved in 7-9 months in 8 (53.33%). Pin tract infection was reported in two (13.33%) patients who became better with regular dressing. Ankle stiffness was present in one case (6.67%), most probably due to improper physiotherapy.According to ASAMI Criteria excellent radiological results were present in 11 (73.33%) cases, good results were found in 4 (26.67) cases and excellent functional results were observed in 7 cases (46.67%) and good results were found in 8 (53.33%) cases. Infection was cured in all patients and did not recur till the last follow-up. CONCLUSIONS: Advantages of rail fixator include less invasive surgery, early weight-bearing, less infection, less blood loss, prevention of diffuse osteoporosis and atrophy, preservation of limb function, no need for bone grafting, correction of deformity during the process of healing, thus no need for a second surgery. Non-union, bone defect, and deformity can be corrected simultaneously. Hence, we recommend the use of this system (rail fixator) especially for infected non-union of long bones and compound fractures with bone loss.

Evaluation and comparison of molecular and conventional diagnostic modalities for detecting pulmonary tuberculosis in bronchoalveolar lavage fluid.

CONTEXT: In cases of sputum smear-negative and sputum-scarce (SSN/SC) pulmonary tuberculosis (PTB), bronchoalveolar lavage (BAL) fluid may be helpful in establishing diagnosis. No specific recommendations for BAL samples have yet been formulated due to limited literature. AIMS: 1. To find a sensitive and specific protocol for same-day diagnosis of PTB using BAL in SSN/SC clinically suspected patients. 2. To evaluate the need to routinely perform MGIT for all BAL samples. SETTINGS AND DESIGN: Prospective observational study design in a tertiary care hospital in New Delhi. METHODS AND MATERIAL: Fibreoptic bronchoscopy was performed and BAL collected from 175 clinically suspected SSN/SC PTB patients. BAL samples were subjected to: ZN Stain, Xpert MTB/RIF CBNAAT, BACTEC MGIT 960 liquid culture and M. tuberculosis complex DNA Real time PCR. The results of the various diagnostic tests were analysed using a) MGIT as gold standard and b) a composite reference standard (CRS) for a final diagnosis of PTB. STATISTICAL ANALYSIS USED: Microsoft Excel 2016 and SPSS version 21.0 were used. Sensitivity, specificity and predictive values were calculated and compared using McNemar test. A p value of <0.05 was considered statistically significant. RESULTS: 34 Cases had a final diagnosis of TB as per the CRS. Using CRS, MGIT had a sensitivity of 50.0% (32.4%-67.6%). There was no statistically significant difference between sensitivities of CBNAAT and PCR; both were more sensitive than ZN stain. Sensitivity and specificity of CBNAAT was 79.4% (62.1%-91.3%) and 100.0% (97.4%-100.0%) respectively. The preferred protocol for the hospital is CBNAAT and ZN stain. There was no statistically significant difference in sensitivity by adding PCR or MGIT to this protocol. CONCLUSIONS: We found it a good strategy to perform CBNAAT and ZN stain on BAL fluid for accurate and same-day PTB diagnosis. CBNAAT is useful for ruling PTB in even when BAL cultures are negative. It is prudent to continue to routinely perform MGIT for all BAL samples.

Flow parallel synthesizer for multiplex synthesis of aryl diazonium libraries via efficient parameter screening.

The development of miniaturized flow platforms would enable efficient and selective synthesis of drug and lead molecules by rapidly exploring synthetic methodologies and screening for optimal conditions, progress in which could be transformative for the field. In spite of tremendous advances made in continuous flow technology, these reported flow platforms are not devised to conduct many different reactions simultaneously. Herein, we report a metal-based flow parallel synthesizer that enables multiplex synthesis of libraries of compounds and efficient screening of parameters. This miniaturized synthesizer, equipped with a unique built-in flow distributor and n number of microreactors, can execute multiple types of reactions in parallel under diverse conditions, including photochemistry. Diazonium-based reactions are explored as a test case by distributing the reagent to 16 (n = 16) capillaries to which various building blocks are supplied for the chemistry library synthesis at the optimal conditions obtained by multiplex screening of 96 different reaction variables in reaction time, concentration, and product type. The proficiency of the flow parallel synthesizer is showcased by multiplex formation of various C-C, C-N, C-X, and C-S bonds, leading to optimization of 24 different aryl diazonium chemistries.

High-Frequency Direct Detection of Triazole Resistance in Aspergillus fumigatus from Patients with Chronic Pulmonary Fungal Diseases in India.

Aspergillosis due to azole-resistant Aspergillus fumigatus is a worldwide problem with major therapeutic implications. In patients with invasive aspergillosis, a low yield of fungal cultures results in underestimation of azole resistance. To detect azole resistance in A. fumigatus, we applied the AsperGenius® Resistance multiplex real-time polymerase chain reaction (PCR) assay to detect TR34/L98H, and TR46/T289A/Y121F mutations and the AsperGenius® G54/M220 RUO PCR assay to detect G54/M220 mutations directly in bronchoalveolar lavage (BAL) samples of 160 patients with chronic respiratory diseases in Delhi, India. Only 23% of samples were culture-positive compared to 83% positivity by A. fumigatus species PCR highlighting concerns about the low yield of cultures. Notably, 25% of BAL samples (33/160 patients) had azole resistance-associated mutation by direct detection using PCR assay. Detection of resistance-associated mutations was found mainly in 59% and 43% patients with chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA), respectively. Overall, a G54 mutation, conferring itraconazole resistance, was the predominant finding in 87.5% and 67% of patients with CPA and ABPA, respectively. In culture-negative, PCR-positive samples, we detected azole-resistant mutations in 34% of BAL samples. Azole resistance in chronic Aspergillus diseases remains undiagnosed, warranting standardization of respiratory culture and inclusion of rapid techniques to detect resistance markers directly in respiratory samples.

Genotypic diversity in clinical and environmental isolates of Cryptococcus neoformans from India using multilocus microsatellite and multilocus sequence typing.

BACKGROUND: Cryptococcus neoformans is the leading cause of cryptococcal meningitis in HIV/AIDS patients. As infections in humans are predominantly caused by the inhalation of basidiospores from environmental sources, therefore, analysing the population structure of both clinical and environmental populations of C neoformans can increase our understanding of the molecular epidemiology of cryptococcosis. OBJECTIVE: To investigate the genotypic diversity and antifungal susceptibility profile of a large collection of C neoformans isolates (n = 523) from clinical and environmental sources in India between 2001 and 2014. MATERIALS AND METHODS: Cryptococcus neoformans isolates were genotyped by AFLP, microsatellite typing (MLMT) and MLST. In vitro antifungal susceptibility for standard antifungals was undertaken using CLSI M27-A3. RESULTS: All isolates were C neoformans, AFLP1/VNI and exhibited mating-type MATα. MLMT revealed that the majority of isolates belonged to microsatellite cluster (MC) MC3 (49%), followed by MC1 (35%), and the remaining isolates fell in 11 other MC types. Interestingly, two-thirds of clinical isolates were genotype MC3 and only 17% of them were MC1, whereas majority of environmental strains were MC1 (54%) followed by MC3 (16%). Overall, MLST assigned 5 sequence types (STs) among all isolates and ST93 was the most common (n = 76.7%), which was equally distributed in both HIV-positive and HIV-negative patients. Geometric mean MICs revealed that isolates in MC1 were significantly less (P < .05) susceptible to amphotericin B, 5-flucytosine, itraconazole, posaconazole and isavuconazole than isolates in MC3. CONCLUSIONS: The study shows a good correlation between MLMT and MLST genotyping methods. Further, environmental isolates were genetically more diverse than clinical isolates.

Harnessing Nucleophilicity of Allenol Ester with p-Quinone Methides via Gold Catalysis: Application to the Synthesis of Diarylmethine-Substituted Enones.

A gold(I)-catalyzed protocol for intermolecular 1,6-conjugate addition of nucleophilic allenol ester generated in situ through [3,3]-sigmatropic rearrangement with p-quinone methides ( p-QMs) has been developed. The gold catalyst plays a dual role by the π-acid-triggered activation of alkynes and at the same time as a Lewis acid for activation of p-QMs toward nucleophilic attack. This method enables rapid access to a wide range of densely functionalized diarylmethine-substituted enones, a Morita-Baylis-Hillman (MBH) product with high selectivity, excellent yields, and broad substrate scope.

Unravelling the Nucleophilicity of Butenolides for 1,6-Conjugate Addition to p-Quinone Methides: A Direct Access to Diversely Substituted Butenolide-Derived Diarylmethanes.

A Lewis acid catalyzed regioselective C-C bond is constructed through ß-addition of deconjugated butenolides with p-quinone methides in a 1,6-conjugate addition manner. Interestingly, Lewis acid catalyzed vinylogous Mukaiyama-Michael reaction of silyloxyfurans with p-QMs proceeds selectively through the α or γ position exclusively. The reaction is mild with broad substrate scope, thus allowing easy access to a wide range of bis-arylated α-/ß-/γ-substituted butenolides.

Human immunodeficiency virus type-1 (HIV-1) evades antibody-dependent phagocytosis.

Fc gamma receptor (FcyR)-mediated antibody functions play a crucial role in preventing HIV infection. One such function, antibody-dependent phagocytosis (ADP), is thought to be involved in controlling other viral infections, but its role in HIV infection is unknown. We measured the ability of HIV-specific polyclonal and monoclonal antibodies (mAbs) to mediate the internalization of HIV-1 virions and HIV-1-decorated cells by phagocytes. To measure ADP of virions, we primarily used a green-fluorescent protein-expressing molecular clone of HIV-1JRFL, an R5, clinical isolate, in combination with polyclonal HIVIG or mAbs known to capture and/or neutralize HIV-1. THP-1 and U937 cells, as well as freshly isolated primary monocytes from healthy individuals, were used as phagocytic effector cells, and uptake of virions was measured by cytometry. We surprisingly found minimal or no ADP of virions with any of the antibodies. However, after coating virions with gp41 or with gp41-derived peptides, gp41- (but not gp120-) specific mAbs efficiently mediated phagocytosis. We estimated that a minimum of a few hundred gp41 molecules were needed for successful phagocytosis, which is similar to the number of envelope spikes on viruses that are readily phagocytosed (e.g. influenza virus). Furthermore, by employing fluorescence correlation spectroscopy, a well-established technique to measure particle sizes and aggregation phenomena, we found a clear association between virus aggregation and ADP. In contrast to virions themselves, virion-decorated cells were targets for ADP or trogocytosis in the presence of HIV-specific antibodies. Our findings indicate that ADP of virions may not play a role in preventing HIV infection, likely due to the paucity of trimers and the consequent inability of virion-bound antibody to cross-link FcyRs on phagocytes. However, ADP or trogocytosis could play a role in clearing HIV-infected cells and cells on the verge of infection.

Transition metal catalysis-a unique road map in the stereoselective synthesis of 1,3-polyols.

The present review summarizes recent diverse reactions employed in the formation of 1,3-polyols providing an overview of the mechanistic pathway and the enantioselectivity obtained, in terms of the properties of transition metals directly involved in the catalytic transformations and their interaction with various ligands.

CSF ADA Determination in Early Diagnosis of Tuberculous Meningitis in HIV-Infected Patients.

Tuberculous and Cryptococcal meningitis are common in HIV patients. A highly specific and sensitive rapid test for diagnosis of Tuberculous meningitis especially in setting of HIV is not available in developing countries where the burden of disease is high. We measured ADA (adenosine deaminase) levels using spectrophotometric method in the CSF of HIV patients with meningitis to differentiate Tuberculous meningitis from meningitis due to other causes. Kruskal-Wallis test was used to compare ADA values between tuberculous meningitis (TBM) and nontuberculous (non-TB) meningitis patients and a receiver-operating characteristic (ROC) analysis curve was drawn from these values. Levels of ADA in the CSF of patients with TBM were significantly higher than those in patients with meningitis due to other causes. CSF ADA level determination with a cut-off value of 6 IU/L was found to be highly specific and fairly sensitive test for the diagnosis of TBM in HIV positive patients.