Maternal and fetal outcomes in pregnant females with rheumatic heart disease

BackgroundCardiac diseases are seen in 1–3% of pregnancies. In developing countries rheumatic heart disease (RHD) contributes a major cause of cardiac disorders.ObjectiveTo study the maternal and fetal outcome in women with valvular heart disease or prosthetic heart valve replacement secondary to RHD in a tertiary care center.MethodThe consecutive pregnant women with RHD attending our institute from May 2018 to August 2019 were included. A maternal adverse outcome was defined as cardiac death, new onset arrhythmia, heart failure, thromboembolic event, hospitalization for other cardiac reasons or cardiac intervention, aortic dissection, infective endocarditis and acute coronary syndrome. Fetal adverse outcome defined as fetal death, preterm birth, and low birth weight.ResultTotal 80 patients were included in this study, native RHD in 60(75%) and 20(25%) had mechanical prosthetic valve replacement. Maternal adverse event occurred in 34(42.5%), comprising of death in 1(1.2%), new onset AF 2(2.5%), 20(25%) underwent balloon mitral valvotomy, 3(3.7%) underwent mitral valve replacement, heart failure hospitalization in 7(8.7%). 1(1.2%) patient developed mitral valve infective endocarditis. Preterm delivery occurred in 19(23.7%), 7(8.7%) abortions and 1(1.2%) intrauterine death. Fetuses with low birth weight were 43(53.7%). Pregnancy with live birth occurred in 57(95%) women with valvular heart disease but no prosthesis and 16(80%) women with prosthetic valve disease.ConclusionWomen with rheumatic heart disease carry a high risk both for mother and fetus. Early diagnosis, close follow-up during pregnancy, early recognition of deterioration in symptoms and timely cardiac intervention can lead to good maternal or fetal outcome.     

Risk factors for death during treatment in pulmonary tuberculosis patients in South India: A cohort study

ObjectiveIdentifying the risk factors for deaths during tuberculosis (TB) treatment is important for achieving the vision of India's National Strategic Plan of ‘Zero Deaths’ by 2025. We aimed to determine the proportion of deaths during TB treatment and its risk factors among smear positive pulmonary TB patients aged more than 15 years.Study designWe performed a cohort study using data collected for RePORT India Consortium (Regional Prospective Observational Research in Tuberculosis).SettingRevised TB Control Program (RNTCP) in three districts of South India.ParticipantsThe cohort consisted of newly diagnosed drug sensitive patients enrolled under the Revised National TB Control Program during 2014–2018 in three districts of southern India. Information on death was collected at homes by trained project staff.Primary outcome measuresWe calculated ‘all-cause mortality’ during TB treatment and expressed this as a proportion with 95% confidence interval (CI). Risk factors for death were assessed by calculating unadjusted and adjusted relative risks with 95% CI.ResultsThe mean (SD) age was of the 1167 participants was 45 (14.5) years and 79% of them were males. Five participants (0.4%) were HIV infected. Among the males, 560 (61%) were tobacco users and 688 (75%) reported consuming alcohol. There were 47 deaths (4%; 95% CI 3.0–5.3) of which 28 deaths (60%) occurred during first two months of treatment. In a bi-variable analysis, age of more than 60 years (RR 2.27; 95%CI: 1.24–4.15), male gender (RR 3.98; 95% CI: 1.25–12.70), alcohol use in last 12 months (RR 2.03; 95%CI: 1.07–3.87), tobacco use (RR 1.87; 95%CI: 1.05–3.36) and severe anaemia (RR 3.53: 95%CI: 1.34–9.30) were associated with a higher risk of death. In adjusted analysis, participants with severe anaemia (<7gm/dl) had 2.4 times higher risk of death compared to their counterparts.ConclusionThough deaths during TB treatment was not very high, early recognition of risk groups and targeted interventions are required to achieve zero TB deaths.     

Strain induced valley degeneracy: a route to the enhancement of thermoelectric properties of monolayer WS2

Two-dimensional transition metal dichalcogenides show great potential as promising thermoelectric materials due to their lower dimensionality, the unique density of states and quantum confinement of carriers. Here the effects of mechanical strain on the thermoelectric performances of monolayer WS₂ have been investigated using density functional theory associated with semiclassical Boltzmann transport theory. The variation of the Seebeck coefficient and band gap with applied strain has followed the same type of trend. For n-type material the relaxation time scaled power factor (S²σ/τ) increases by the application of compressive strain whereas for p-type material it increases with the application of tensile strain due to valley degeneracy. A 77% increase in the power factor has been observed for the n-type material by the application of uniaxial compressive strain. A decrease in lattice thermal conductivity with the increase in temperature causes an almost 40% increase in ZT product under applied uniaxial compressive strain. From the study, it is observed that uniaxial compressive strain is more effective among all types of strain to enhance the thermoelectric performance of monolayer WS₂. Such strain induced enhancement of thermoelectric properties in monolayer WS₂ could open a new window for the fabrication of high-quality thermoelectric devices.

Strain induced valley degeneracy results enhancement of thermoelectric properties of monolayer WS₂. Electron valleys and hole valleys become degenerate by applying compressive and tensile strain, respectively.     

T‐bet modulates the antibody response and immune protection during murine malaria

CD4⁺ T‐cell subtypes govern the synthesis of different Ab isotypes and other immune functions. The influence of CD4⁺ T‐cell differentiation programs on isotype switching and other aspects of host immunological networks during malaria infection are currently poorly understood. Here, we used Tbx21^?/? mice deficient for T‐bet, a regulator of Th1 CD4⁺ T‐cell differentiation, to examine the effect of Th1 CD4⁺ T cells on the immune protection to nonlethal murine malaria Plasmodium yoelii 17XNL. We found that Tbx21^?/? mice exhibited significantly lower parasite burden that correlated with elevated levels of IgG1, indicating that T‐bet‐dependent Ab isotype switching may be responsible for lower parasite burden. Absence of T‐bet was also associated with a transient but significant loss of T cells during the infection, suggesting that T‐bet may suppress malaria‐induced apoptosis or induce proliferation of T cells. However, Tbx21^?/? mice produced greater numbers of Foxp3⁺CD25⁺ regulatory CD4⁺ T cells, which may contribute to the early contraction of T cells. Lastly, Tbx21^?/? mice exhibited unimpaired production of IFN‐γ by a diverse repertoire of immune cell subsets and a selective expansion of IFN‐γ‐producing T cells. These observations may have implications in malaria vaccine design.     

Potassium 2-methoxy-4-vinylphenolate: a novel hit exhibiting quorum-sensing inhibition in Pseudomonas aeruginosa via LasIR/RhlIR circuitry

The emergence of multidrug-resistant (MDR) bacterial strains in the last decade is astonishingly alarming. Many of the widely used antibiotics have failed to exhibit clinical efficacy against such strains. Eventually we will exhaust all the resources in our antibiotic armamentarium. As a need of the hour, novel strategies are desperately required not only to curb, but also to reverse, the development of resistance in these pathogens, thereby maintaining their sensitivity towards current antibiotics. Intervention of bacterial virulence, rather than killing them, by inhibiting specific pathways/targets has emerged as a novel approach to tackle the drug resistance problem. The bacterial virulence is regulated via quorum-sensing, a cell–cell communication process precisely controlled by autoinducer molecules such as acyl homoserine lactone (AHL). The present study aimed at identifying promising quorum-sensing inhibitors in Pseudomonas aeruginosa, an opportunistic human pathogen especially associated with nosocomial infections, yielding four potential hits. Out of these, potassium 2-methoxy-4-vinylphenolate was the most potent quorum-sensing inhibitor targeting P. aeruginosa LasIR/RhlIR circuitry. It also inhibited biofilm formation, various virulence factors like LasA protease, LasB elastase and pyocyanin, and motility of bacteria like swarming and twitching.

Effect of potassium 2-methoxy-4-vinylphenolate on quorum sensing in Pseudomonas aeruginosa.     

Bite Force Evaluation of Conventional Plating System Versus Locking Plating System for Mandibular Fracture

Aims and Objectives

To compare and evaluate the variation in recorded bite forces in patients with mandibular fractures undergoing open reduction and rigid internal fixation using standard 2.0 versus 2.0 mm locking miniplates.

Materials and Methods

A prospective randomized study was conducted for the treatment of mandibular fractures. Twenty adult patients with 31 mandibular fractures requiring an open reduction and internal fixation were included in the study. The sample was divided into two groups depending upon whether the patients received 2.0 mm non-locking (standard) or 2.0 mm locking miniplates for rigid fixation respectively. Bite force was evaluated at 1st, 3rd and 6th week after the open reduction and rigid fixation using miniplates.

Results

A statistically significant difference was not found in the clinical parameters such as pain, swelling, infection, paresthesia, hardware failure, and mobility between the fracture segments. The results showed that amongst locking vs non-locking miniplates, the former showed a greater bite force enhancement when compared to baseline values(post-trauma).A comparison between 2nd day post-operative vs 6th week post-operative values showed a significant increase in bite force in Group 1 (non-locking) (p < 0.05) whereas the values Were highly significant (p < 0.001) in Group 2 (locking Plate).

Conclusion

The findings were suggestive that the efficacy of locking miniplates plate in mandibular fracture was superior in terms of bearing the masticatory loads during osteosynthesis of the fracture. However, the clinical results were almost similar to those seen with non-locking miniplate osteosynthesis.     

Mutational analysis of Kaposica reveals that bridging of MG2 and CUB domains of target protein is crucial for the cofactor activity of RCA proteins

The complement system has evolved to annul pathogens, but its improper regulation is linked with diseases. Efficient regulation of the system is primarily provided by a family of proteins termed regulators of complement activation (RCA). The knowledge of precise structural determinants of RCA proteins critical for imparting the regulatory activities and the molecular events underlying the regulatory processes, nonetheless, is still limited. Here, we have dissected the structural requirements of RCA proteins that are crucial for one of their two regulatory activities, the cofactor activity (CFA), by using the Kaposi’s sarcoma-associated herpesvirus RCA homolog Kaposica as a model protein. We have scanned the entire Kaposica molecule by sequential mutagenesis using swapping and site-directed mutagenesis, which identified residues critical for its interaction with C3b and factor I. Mapping of these residues onto the modeled structure of C3b–Kaposica–factor I complex supported the mutagenesis data. Furthermore, the model suggested that the C3b-interacting residues bridge the CUB (complement C1r-C1s, Uegf, Bmp1) and MG2 (macroglobulin-2) domains of C3b. Thus, it seems that stabilization of the CUB domain with respect to the core of the C3b molecule is central for its CFA. Identification of CFA-critical regions in Kaposica guided experiments in which the equivalent regions of membrane cofactor protein were swapped into decay-accelerating factor. This strategy allowed CFA to be introduced into decay-accelerating factor, suggesting that viral and human regulators use a common mechanism for CFA.The complement system is the central component of innate immunity that controls invading pathogens directly by lysis or inactivation and indirectly by recruiting and boosting the pathogen-specific adaptive immunity (1, 2). Although the system efficiently targets the invaders, it is equally deleterious to the host cells, and therefore, an effective regulation is needed to control complement activation on the cell surface. This regulation is primarily achieved by a family of proteins termed regulators of complement activation (RCA), which are located on the cell surface, such as decay acceleration factor (DAF; CD55), membrane cofactor protein (MCP; CD46), and complement receptor 1 (CR1; CD35), and in solution, like factor H (FH) and C4b-binding protein (3). The RCA proteins are formed by 4–59 complement control protein (CCP) modules that are separated by small linkers and regulate complement by inactivating C3 convertases by two distinct mechanisms dubbed as “cofactor activity” (CFA) and “decay-accelerating activity,” which work in concert to achieve the robust regulation. It is, therefore, not inexplicable that mutations and polymorphisms in RCA proteins are linked to various diseases, like age-related macular degeneration, atypical hemolytic uremic syndrome, and dense deposit disease (4–6).Complement regulation owing to CFA refers to serving of RCA protein as a cofactor during serine protease factor I-mediated inactivation of C3b and C4b (the subunits of C3 convertases). To examine the structural requirements for the CFA of RCA proteins, initial studies focused on the identification of minimum CCP modules required for this activity and identified three CCPs as the smallest structural unit essential for this activity (3, 7, 8). Later, mutagenesis studies primarily performed on CR1 and MCP identified residues within the CCPs and concluded that functional sites are located in each of the three functionally critical CCPs (9, 10). A major advance in understanding the molecular mechanism of CFA came only recently because of the availability of structural and biochemical data (11–14). In particular, structure of FH(1–4) in complex with C3b identified the contact regions of FH(1–4) and their footprints on C3b (13). Also, the structure of factor I revealed allosteric regulation in factor I and identified the putative factor I interaction sites on the regulator and C3b (14). Although the aforementioned studies elucidated that interaction of three to four modules of a regulator with the target proteins C3b or C4b forms a docking platform for factor I, resulting in binding and reorientation of factor I for cleavages in the CUB (complement C1r-C1s, Uegf, Bmp1) domains of C3b/C4b, there are questions that still remain unanswered. (i) Among the contact regions for C3b/C4b found in each of the functional domains of a regulator (13), which region(s) is most critical for imparting CFA and why? (ii) Which residues of a regulator participate in the interaction with factor I? (iii) Do different regulators use a common molecular mechanism to inactivate C3b and C4b?Among the human pathogens, RCA proteins are known to be encoded by pox (e.g., variola) and herpes viruses [e.g., Kaposi''s sarcoma-associated herpesvirus (KSHV)]. Also, intriguingly, these mimics also regulate C3 convertases through their decay-accelerating activity and CFA (15). Thus, these viral proteins can serve as useful tools to understand the functioning of RCA proteins. Extensive mutagenesis studies in these viral regulators have led to the understanding that CCP modules 2 and 3 are critical for imparting CFA and that the factor I binding site resides in these domains (16–19). However, the underlying molecular mechanisms of complement regulation by viral RCA are still enigmatic.In this study, we, therefore, have used Kaposica, the complement regulator of Kaposi’s sarcoma-associated herpesvirus, as a model protein to further probe the molecular mechanism underlying CFA. By performing extensive mutagenesis and biochemical characterization of Kaposica mutants and combining these data with the earlier structural data (13, 14), we propose that, apart from providing a docking surface for factor I, bridging of the MG2 (macroglobulin-2) and CUB domains of C3b/C4b by Kaposica is critical for imparting CFA. Furthermore, based on the DAF-MCP chimera data, we propose that such bridging is also vital for CFA of the human RCA proteins.