Immunogenicity of SARS-CoV-2 vaccines BBV152 (COVAXIN®) and ChAdOx1 nCoV-19 (COVISHIELD™) in seronegative and seropositive individuals in India: a multicentre, nonrandomised observational study.

Background: There are limited global data on head-to-head comparisons of vaccine platforms assessing both humoral and cellular immune responses, stratified by pre-vaccination serostatus. The COVID-19 vaccination drive for the Indian population in the age group 18-45 years began in April 2021 when seropositivity rates in the general population were rising due to the delta wave of COVID-19 pandemic during April-May 2021. Methods: Between June 30, 2021, and Jan 28, 2022, we enrolled 691 participants in the age group 18-45 years across four clinical sites in India. In this non-randomised and laboratory blinded study, participants received either two doses of Covaxin® (4 weeks apart) or two doses of Covishield™ (12 weeks apart) as per the national vaccination policy. The primary outcome was the seroconversion rate and the geometric mean titre (GMT) of antibodies against the SARS-CoV-2 spike and nucleocapsid proteins post two doses. The secondary outcome was the frequency of cellular immune responses pre- and post-vaccination. Findings: When compared to pre-vaccination baseline, both vaccines elicited statistically significant seroconversion and binding antibody levels in both seronegative and seropositive individuals. In the per-protocol cohort, Covishield™ elicited higher antibody responses than Covaxin® as measured by seroconversion rate (98.3% vs 74.4%, p < 0.0001 in seronegative individuals; 91.7% vs 66.9%, p < 0.0001 in seropositive individuals) as well as by anti-spike antibody levels against the ancestral strain (GMT 1272.1 vs 75.4 binding antibody units/ml [BAU/ml], p < 0.0001 in seronegative individuals; 2089.07 vs 585.7 BAU/ml, p < 0.0001 in seropositive individuals). As participants at all clinical sites were not recruited at the same time, site-specific immunogenicity was impacted by the timing of vaccination relative to the delta and omicron waves. Surrogate neutralising antibody responses against variants-of-concern including delta and omicron was higher in Covishield™ recipients than in Covaxin® recipients; and in seropositive than in seronegative individuals after both vaccination and asymptomatic infection (omicron variant). T cell responses are reported from only one of the four site cohorts where the vaccination schedule preceded the omicron wave. In seronegative individuals, Covishield™ elicited both CD4+ and CD8+ spike-specific cytokine-producing T cells whereas Covaxin® elicited mainly CD4+ spike-specific T cells. Neither vaccine showed significant post-vaccination expansion of spike-specific T cells in seropositive individuals. Interpretation: Covishield™ elicited immune responses of higher magnitude and breadth than Covaxin® in both seronegative individuals and seropositive individuals, across cohorts representing the pre-vaccination immune history of most of the vaccinated Indian population. Funding: Corporate social responsibility (CSR) funding from Hindustan Unilever Limited (HUL) and Unilever India Pvt. Ltd. (UIPL).

Niacinamide enhances cathelicidin mediated SARS-CoV-2 membrane disruption.

The continual emergence of SARS-CoV-2 variants threatens to compromise the effectiveness of worldwide vaccination programs, and highlights the need for complementary strategies for a sustainable containment plan. An effective approach is to mobilize the body's own antimicrobial peptides (AMPs), to combat SARS-CoV-2 infection and propagation. We have found that human cathelicidin (LL37), an AMP found at epithelial barriers as well as in various bodily fluids, has the capacity to neutralise multiple strains of SARS-CoV-2. Biophysical and computational studies indicate that LL37's mechanism of action is through the disruption of the viral membrane. This antiviral activity of LL37 is enhanced by the hydrotropic action of niacinamide, which may increase the bioavailability of the AMP. Interestingly, we observed an inverse correlation between LL37 levels and disease severity of COVID-19 positive patients, suggesting enhancement of AMP response as a potential therapeutic avenue to mitigate disease severity. The combination of niacinamide and LL37 is a potent antiviral formulation that targets viral membranes of various variants and can be an effective strategy to overcome vaccine escape.

Strategies to target SARS-CoV-2 entry and infection using dual mechanisms of inhibition by acidification inhibitors.

Many viruses utilize the host endo-lysosomal network for infection. Tracing the endocytic itinerary of SARS-CoV-2 can provide insights into viral trafficking and aid in designing new therapeutic strategies. Here, we demonstrate that the receptor binding domain (RBD) of SARS-CoV-2 spike protein is internalized via the pH-dependent CLIC/GEEC (CG) endocytic pathway in human gastric-adenocarcinoma (AGS) cells expressing undetectable levels of ACE2. Ectopic expression of ACE2 (AGS-ACE2) results in RBD traffic via both CG and clathrin-mediated endocytosis. Endosomal acidification inhibitors like BafilomycinA1 and NH4Cl, which inhibit the CG pathway, reduce the uptake of RBD and impede Spike-pseudoviral infection in both AGS and AGS-ACE2 cells. The inhibition by BafilomycinA1 was found to be distinct from Chloroquine which neither affects RBD uptake nor alters endosomal pH, yet attenuates Spike-pseudovirus entry. By screening a subset of FDA-approved inhibitors for functionality similar to BafilomycinA1, we identified Niclosamide as a SARS-CoV-2 entry inhibitor. Further validation using a clinical isolate of SARS-CoV-2 in AGS-ACE2 and Vero cells confirmed its antiviral effect. We propose that Niclosamide, and other drugs which neutralize endosomal pH as well as inhibit the endocytic uptake, could provide broader applicability in subverting infection of viruses entering host cells via a pH-dependent endocytic pathway.

Assessing trait contribution and mapping novel QTL for salinity tolerance using the Bangladeshi rice landrace Capsule.

BACKGROUND: Salinity is one of the most widespread abiotic stresses affecting rice productivity worldwide. The purpose of this study was to establish the relative importance of different traits associated with salinity tolerance in rice and to identify new quantitative trait loci (QTL) conferring tolerance to salinity at seedling stage. A total of 231 F2:3 plants derived from a cross between a sensitive variety BRRI dhan29 (BR29 hereafter) and Capsule, a salt tolerant Bangladeshi indica landrace, were evaluated under salt stress in a phytotron. RESULTS: Out of the 231 F2 plants, 47 highly tolerant and 47 most sensitive lines were selected, representing the two extreme tails of the phenotypic distribution. These 94 plants were genotyped for 105 simple sequence repeat (SSR) and insertion/deletion (InDel) markers. A genetic linkage map spanning approximately 1442.9 cM of the 12 linkage groups with an average marker distance of 13.7 cM was constructed. QTL were identified on the long arm of chromosome 1 for Na+ concentration, K+ concentration, Na+-K+ ratio and survival; chromosome 3 for Na+ concentration, survival and overall phenotypic evaluation using the Standard Evaluation system (SES); and chromosome 5 for SES. A total of 6 pairwise epistatic interactions were also detected between QTL-linked and QTL-unlinked regions. Graphical genotyping indicated an association between the phenotypes of the extreme families and their QTL genotypes. Path coefficient analysis revealed that Na+ concentration, survival, Na+-K+ ratio and the overall phenotypic performance (SES score) are the major traits associated with salinity tolerance of Capsule. CONCLUSIONS: Capsule provides an alternative source of salinity tolerance aside from Pokkali and Nona Bokra, the two Indian salt tolerant landraces traditionally used for breeding salt tolerant rice varieties. Pyramiding the new QTL identified in this study with previously discovered loci, such as Saltol, will facilitate breeding varieties that are highly tolerant of salt stress.

Co-Tetraphenylporphyrin (co-TPP) in TM-TPP (TM = Fe, Co, Ni, Cu, and Zn) series: a new optical material under DFT.

A detailed investigation of the structure, electronic, spectroscopic, and optical properties of a series of transition metal-doped tetraphenylporphyrins (TM-TPP; TM = Fe, Co, Ni, Cu and Zn) is performed under density functional framework. The structure and stability of tetraphenylporphyrin (TPP) and TM-TPPs are understood with HOMO-LUMO gap, chemical hardness, and binding energies of the transition metals to the compound. Optical properties of TPP and TM-TPP series are assessed with relevant optical absorption spectra. A couple of visible active compounds, viz. Co-TPP and Ni-TPP, are reported for the first time for future opto-electronic applications. To gain insight on the possible synthesis of these compounds, we have analyzed frontier molecular orbitals (FMOs) as well as infra-red spectra. Graphical abstract Optical absorption spectra of TPP and TM-TPPs, and infrared spectra of TPP merged with Co-TPP.

Exploring novel genetic sources of salinity tolerance in rice through molecular and physiological characterization.

BACKGROUND AND AIMS: Agricultural productivity is increasingly being affected by the build-up of salinity in soils and water worldwide. The genetic base of salt-tolerant rice donors being used in breeding is relatively narrow and needs broadening to breed varieties with wider adaptation to salt-affected areas. This study evaluated a large set of rice accessions of diverse origins to identify and characterize novel sources of salt tolerance. METHODS: Diversity analysis was performed on 107 germplasm accessions using a genome-wide set of 376 single-nucleotide polymorphism (SNP) markers, along with characterization of allelic diversity at the major quantitative trait locus Saltol Sixty-nine accessions were further evaluated for physiological traits likely associated with responses to salt stress during the seedling stage. KEY RESULTS: Three major clusters corresponding to the indica, aus and aromatic subgroups were identified. The largest group was indica, with the salt-tolerant Pokkali accessions in one sub-cluster, while a set of Bangladeshi landraces, including Akundi, Ashfal, Capsule, Chikirampatnai and Kutipatnai, were in a different sub-cluster. A distinct aus group close to indica contained the salt-tolerant landrace Kalarata, while a separate aromatic group closer to japonica rice contained a number of traditional, but salt-sensitive Bangladeshi landraces. These accessions have different alleles at the Saltol locus. Seven landraces - Akundi, Ashfal, Capsule, Chikirampatnai, Jatai Balam, Kalarata and Kutipatnai - accumulated less Na and relatively more K, maintaining a lower Na/K ratio in leaves. They effectively limit sodium transport to the shoot. CONCLUSIONS: New salt-tolerant landraces were identified that are genetically and physiologically distinct from known donors. These landraces can be used to develop better salt-tolerant varieties and could provide new sources of quantitative trait loci/alleles for salt tolerance for use in molecular breeding. The diversity observed within this set and in other donors suggests multiple mechanisms that can be combined for higher salt tolerance.

Combining ability of pod yield and related traits of groundnut (Arachis hypogaea L.) under salinity stress.

A study was performed using 6 × 6 F1 diallel population without reciprocals to assess the mode of inheritance of pod yield and related traits in groundnut with imposed salinity stress. Heterosis was found for pod number and yield. Data on general and specific combining ability (gca and sca) indicated additive and nonadditive gene actions. The gca: sca ratios were much less than unity suggesting predominant role of nonadditive gene effects. Cultivars "Binachinabadam-2" and "Dacca-1" and mutant M6/25/64-82 had the highest, second highest, and third highest pod number, as well as gca values, respectively. These two cultivars and another mutant M6/15/70-19 also had the highest, second highest, and third highest pod yield, as well as gca values, respectively. Therefore, "Dacca-1", "Binachinabadam-2", M6/25/64-82, and M6/15/70-19 could be used as source of salinity tolerance. Cross combinations showing high sca effects arising from parents with high and low gca values for any trait indicate the influence of nonadditive genes on their expression. Parents of these crosses can be used for biparental mating or reciprocal recurrent selection for developing high yielding varieties. Crosses with high sca effects having both parents with good gca effects could be exploited by pedigree breeding to get transgressive segregants.

Evaluating the functional net value of pharmacologic agents in treating irritable bowel syndrome.

BACKGROUND: The recent FDA provisional endpoint incorporates a one-tailed measure of improvement for IBS based on the underlying motility complaint. However, motility exists along a spectrum. Patients may experience diarrhoea resulting from therapy for their constipation-predominant IBS (IBS-C) or constipation during treatment for diarrhoea-predominant IBS (IBS-D), but still meet a unidirectional motility-based FDA endpoint. AIM: To weigh the reported efficacy of existing therapies based on patient-reported outcomes with negative intestinal side effects in controlled clinical trial data. METHODS: We analysed the difference between 'attributable risk' of efficacy based on number needed to treat (NNT) in the literature and percentage of adverse events (AE) of opposite intestinal complaints in placebo-controlled trials identified through a literature search of IBS trials. This calculation was coined 'functional net value' (FNV) or net benefit of the given drug. RESULTS: For treating IBS-C, lubiprostone caused diarrhoea in excess of placebo in 3.9% of patients, leading to a FNV of 3.9 percentage units. Linaclotide caused diarrhoea in 15.3% resulting in negative FNV (-1.0 percentage unit). For IBS-D, alosetron and tricyclic anti-depressants caused constipation among a respective 16.9% and 13.0% resulting in a FNV of -3.6 and -0.5 percentage units. Among all therapies, only rifaximin did not cause the adverse event opposite the underlying motility complaint and the drug only had benefit, not detriment. CONCLUSIONS: Functional net value (FNV) offers a method of evaluating the net benefit of a drug in IBS. Most IBS treatments have a negative effect on IBS that exceeds the benefits.

Preventive strategies to fight complications during percutaneous multitrack balloon valvotomy "refining the technique".

BACKGROUND: Percutaneous mitral valvuloplasty (PMV) is still the treatment of choice in selected cases of mitral stenosis (MS). Multitrack balloon (MTB) catheter is one of the techniques used for PMV with optimal results. We describe a novel refinement of appropriate balloon sizing and wire placement to reduce mitral regurgitation (MR) and Left ventricular (LV) apical perforation, respectively. METHODS: Ninety four consecutive patients with moderate to severe rheumatic mitral stenosis (MS) were selected for PMV with MTB catheter. Balloon sizing was done by effective balloon dilatation area (EBDA), using standard geometric formula. 0.35" PMV wire was placed in aortic arch /ascending aorta (AA) to avoid LV apical perforation. RESULTS: Mild MR was present in 28(29.8%). Post-procedure MR was present in 50(53.2%). Out of 50 MR cases 44(88%) had mild and 6(12.0%) had moderate MR. No patient had severe MR. With placement of wire in AA and arch of aorta none of the patients developed complication of LV apical perforation. CONCLUSION: EDBA as balloon sizing for multitrack system can be used to reduce severity of mitral regurgitation. Placement of PMV guide wire in Aortic arch/AA ascending aorta can eliminate/substantially reduce dreadful complication of LV perforation.

Adverse events appear to unblind clinical trials in irritable bowel syndrome.

BACKGROUND: Clinical trial design is challenging in irritable bowel syndrome (IBS) due in part to a high placebo effect. We postulated that the mere presence of an adverse event (AE) may unmask patients in clinical trials who are assigned to the active agent, and this may lead to higher reported efficacy. METHODS: We evaluated therapies receiving at least a Grade 1B from the American College of Gastroenterology Task Force for IBS or which passed recent phase III clinical trials. Therapies with AE data derived from less than 50 patients in each study arm were excluded. Statistically significant excess AE were identified, risk difference was calculated for each AE, and incidence of AE in the treatment arm was reported. We examined the relationship of attributable drug benefit, defined as the reciprocal of number-needed-to-treat found in literature, with various measures of AE incidence. KEY RESULTS: Attributable drug benefit correlated significantly with average AE risk difference, calculated as treatment arm AE incidence minus placebo arm AE incidence (R(2) = 0.70, p = 0.039), and also with highest treatment arm AE incidence (R(2) = 0.70, p = 0.038) for each therapy. There were also trends toward correlation with average treatment arm AE incidence (R(2) = 0.54, p = 0.096) and highest AE risk difference (R(2) = 0.63, p = 0.059) for each therapy. CONCLUSIONS & INFERENCES: Our study suggests that higher AE incidence on active therapy is associated with more beneficial patient-reported outcomes in IBS clinical trials. This raises the issue of spontaneous unblinding.

Comparison of Inoue balloon, metallic commissurotome and multi-track double-balloon valvuloplasty in the treatment of rheumatic mitral stenosis.

UNLABELLED: BACKGROUND Percutaneous mitral valvuloplasty (PMV) is a well known non-surgical technique for treating patients with rheumatic mitral stenosis (MS). There are very few studies that have compared the 3 techniques together for their safety and efficacy. METHODS: To compare the three different techniques for percutaneous mitral valvuloplasty (PMV) using Inoue balloon (IB), metallic commissurotome (PMMC), or multi-track double balloon (MTDB) in patients with MS. RESULTS: A total of 486 patients were subjected to PMV using any of the 3 techniques, IB, PMMC or MTDB. The overall success rate was 97.3% (n = 473); 95.7% for IB, 97.6% for PMMC, and 98.3% for MTDB. Overall, the transmitral gradient decreased from 20.7 +/- 7.2 mmHg to 6.5 +/- 3.7 mmHg (p < 0.001) and mitral valve area (MVA) increased from 0.87 +/- 0.2 cm(2) to 1.9 +/- 0.4 cm(2) (p < 0.001). Left atrial pressure decreased from 29.3 +/- 8.4 mmHg to 16.1 +/- 11.5 mmHg (p < 0.001) and pulmonary arterial pressure decreased from 76.9 +/- 41.8 mmHg to 45.2 +/- 17.6 mmHg (p < 0.001). Thirteen patients (2.7%) required mitral valve replacement (MVR) for severe mitral regurgitation (MR) while one patient (0.2%) developed cardiac tamponade requiring urgent pericardiocentesis followed by surgical repair of the tear and open mitral valvotomy. There was no statistical difference among the 3 techniques used. CONCLUSION: In conclusion, percutaneous mitral valvuloplasty is an effective procedure for MS with any of the three above techniques.

A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.

The neuropsychological performance of 85 women with early stage breast cancer scheduled for chemotherapy, 43 women scheduled for endocrine therapy and/or radiotherapy and 49 healthy control subjects was assessed at baseline (T1), postchemotherapy (or 6 months) (T2) and at 18 months (T3). Repeated measures analysis found no significant interactions or main effect of group after controlling for age and intelligence. Using a calculation to examine performance at an individual level, reliable decline on multiple tasks was seen in 20% of chemotherapy patients, 26% of nonchemotherapy patients and 18% of controls at T2 (18%, 14 and 11%, respectively, at T3). Patients who had experienced a treatment-induced menopause were more likely to show reliable decline on multiple measures at T2 (OR=2.6, 95% confidence interval (CI) 0.823-8.266 P=0.086). Psychological distress, quality of life measures and self-reported cognitive failures did not impact on objective tests of cognitive function, but were significantly associated with each other. The results show that a few women experienced objective measurable change in their concentration and memory following standard adjuvant therapy, but the majority were either unaffected or even improve over time.

Aspects of computer-aided detection (CAD) and volumetry of pulmonary nodules using multislice CT.

With the superb spatial resolution of modern multislice CT scanners and their ability to complete a thoracic scan within one breath-hold, software algorithms for computer-aided detection (CAD) of pulmonary nodules are now reaching high sensitivity levels at moderate false positive rates. A number of pilot studies have shown that CAD modules can successfully find overlooked pulmonary nodules and serve as a powerful tool for diagnostic quality assurance. Equally important are tools for fast and accurate three-dimensional volume measurement of detected nodules. These allow monitoring of nodule growth between follow-up examinations for differential diagnosis and response to oncological therapy. Owing to decreasing partial volume effect, nodule volumetry is more accurate with high resolution CT data. Several studies have shown the feasibility and robustness of automated matching of corresponding nodule pairs between follow-up examinations. Fast and automated growth rate monitoring with only few reader interactions also adds to diagnostic quality assurance.

Short- and intermediate-term follow-up results of percutaneous transluminal balloon valvuloplasty in adolescents and young adults with congenital pulmonary valve stenosis.

Percutaneous pulmonary balloon valvuloplasty (PBV) is a well-established treatment alternative to surgery in many cardiology centers. We described our experience with PBV in 25 adolescent and young adult patients with isolated pulmonary valve stenosis (PVS). Among 20 successful PBVs, there was a significant immediate decrease in right ventricular systolic pressure from 116.9 32.4 mmHg to 60.5 18.7 mmHg (p < 0.0001) and a decrease in transpulmonary valve pressure gradient from 93.5 32.8 mmHg to 33.5 9.7 mmHg (p < 0.0001) was noted. The follow-up period was 1-5 years (mean = 3.2 1.2 years), during which patients were periodically assessed by Doppler echocardiogram. During follow-up, the transpulmonary valve pressure gradient further decreased from 33.5 9.7 mmHg to 18.6 3.4 mmHg (p < 0.0001) mainly due to regression of infundibular hypertrophy. Thus, the study showed excellent short-term and intermediate-term results of PBV.

A prospective study of genito-urinary dysfunction after surgery for colorectal cancer.

OBJECTIVE: To establish the incidence of impotence and urinary dysfunction after different forms of pelvic and colorectal surgery. PATIENTS AND METHODS: Over a period of one year, 78 consecutive patients, mean age 66.8 years (range 43-91 years), underwent surgery for colorectal cancer. Genito-urinary function was studied by clinical assessment and a postoperative questionnaire. RESULTS: Pre-operatively all males except one claimed to be potent. Of the 56 patients who had operations on the sigmoid colon and rectum, 12 (21.4%) developed urinary dysfunction; 6 (5 males, 1 female) had increased frequency while 6 (4 females, 2 males) had stress incontinence. Four (12.9%) of the 31 male patients became impotent. Of the control 22 patients who had had operations on the ascending colon, one female developed stress incontinence and none of the male patients developed impotence. CONCLUSION: Although the introduction of autonomic nerve sparing techniques and total mesorectal excision (TME) may have lowered the incidence of genito-urinary dysfunction after rectal surgery, there remains a degree of morbidity compared to procedures where the rectum is not mobilized.

Use of the laryngeal mask airway in thyroid and parathyroid surgery as an aid to the identification and preservation of the recurrent laryngeal nerves.

A prospective study was carried out in patients undergoing thyroid and parathyroid surgery using a laryngeal mask airway (LMA) and electrical nerve stimulation to identify the recurrent laryngeal nerves. A total of 150 consecutive patients undergoing thyroid and parathyroid surgery by a single surgeon were assessed for suitability of anaesthesia via the LMA. Peroperatively, a fibre-optic laryngoscope was passed through the LMA to enable the anaesthetist to visualise the vocal cords while adduction of the cords was elicited by applying a nerve stimulator in the operative field. In all, 144 patients were selected for anaesthesia via the LMA. Fibre-optic laryngoscopy and nerve stimulation were performed in 64 patients (42.7%). The trachea was deviated in 51 (34.0%) and narrowed in 33 (22.0%). The recurrent laryngeal nerves were identified in all patients. There were no cases of vocal cord dysfunction resulting from surgery. The LMA can be safely used for thyroid and parathyroid surgery even in the presence of a deviated or narrowed trachea. It can assist in identification and preservation of the recurrent laryngeal nerve and is, therefore, of benefit to both patient and surgeon.