A mathematical framework for analysing particle flow in a network with multiple pools.

In many real-world systems, the entry rate of particles into a lane is affected by the occupancy of nearby pools. For instance, in biological networks, the concentration of molecules on the side of a membrane affects the entry of particles through the membrane. To understand the behaviour of such networks, we develop a network model of ribosome flow models (RFMs) having multiple pools where each RFM captures the dynamics of particle flow in a lane and competes for the finite resources present at the nearby pool. We study a ribosome flow model network with two pools (RFMNTP) and show that the network always admits a steady state. We then analyse the behaviour of the RFMNTP with respect to modifying the transition rate through a theoretical framework. Simulations of the RFMNTP demonstrate a counterintuitive result. For example, increasing any of the transition rates in the presence of a slow site in an RFM can increase the output rate of some RFMs and decrease the output rate of the other RFMs simultaneously. This suggests that the role of local sharing of particles incorporated is non-trivial. Finally, we illustrate how these results can provide insights into studying a network with multiple pools.

Competition for resources in an exclusion model with biased lane-changing mechanism.

The motivation for the proposed work is drawn from the attachment-detachment observed in biological and physical transport processes that entail finite resources. We investigate the influence of limited particle availability on particle dynamics within two parallel totally asymmetric simple exclusion lanes, with one lane incorporating only particle detachment and the other considering particle attachment. We establish a theoretical framework by employing vertical mean-field theory in conjunction with singular perturbation technique. The analytical findings are supported by numerical and stochastic validation using a finite-difference scheme and the Gillespie algorithm. By utilizing these approaches, we scrutinize various stationary properties, including particle densities, phase boundaries, and particle currents for both lanes. Our analysis reveals that the complexity of the phase diagram exhibits a nonmonotonic trend in the number of stationary phases as the particle count increases. Each phase diagram is constructed with respect to the intrinsic boundary parameters, illustrating both bulk and surface transitions occurring within the lanes. The interplay between finite resources and coupling mechanisms gives rise to two phases involving upward shock in one of the lanes, while two phases exhibit synchronized downward shock in both lanes. Finally, we delve into shock dynamics to comprehend critical phase transitions occurring in the system.

Our Experience of Comparison of Hearing Outcomes in Patients Undergoing Type-1 Tympanoplasty with Different Graft Materials.

The present study was undertaken to compare the results of various autogenous tissues: temporalis fascia, sliced tragal cartilage and fascia lata as graft materials for type I tympanoplasty in terms of hearing improvement in safe type of chronic suppurative otitis media. A total of 75 cases with central perforation were considered in the study. Of the 75 cases, temporalis fascia graft was used in 25 cases (Group-A), fascia lata graft in 25 cases (Group-B), and sliced tragal cartilage graft in 25 cases (Group-C). The results were evaluated in the form of hearing improvement with respect to the graft materials. A significant association was observed between the groups, that is, temporalis fascia (Group-A), fascia lata (Group-B), and sliced tragal cartilage (Group-C) in terms of improvement in AB gap (P = 0.047). Improvement in AB gap was statistically significant between groups B and A, but not between the other groups. In the present study, fascia lata showed better graft uptake as compared to temporalis fascia and sliced tragal cartilage. The hearing assessment at post-operative 3rd month showed statistically significant hearing improvement with fascia lata when compared to temporalis fascia.

Totally asymmetric simple exclusion process with local resetting in a resource-constrained environment.

Inspired by the process of mRNA translation, in which the stochastic degradation of mRNA-ribosome machinery is modeled by the resetting dynamics, we study an open totally asymmetric simple exclusion process with local resetting at the entry site in a resource-constrained environment. The effect of constrained resources on the stationary properties of the system has been comprehended in the form of the filling factor. The mean-field approximations are utilized to obtain stationary state features, such as density profiles and phase diagrams. The phase diagram possesses pure phases as well as coexisting phases, including a low-density-high-density phase separation, which did not manifest under periodic boundary conditions despite the system being closed there as well. The role of the resetting rate has been investigated on the stationary properties of the system, depending on how the filling factor scales with the system size. In contrast to the resetting model for infinite resources, two distinct phase transitions are observed for the smaller values of the filling factor leading to a change in the topology of the phase diagram. The impact of the resetting rate along with the finite-size effect has also been examined on the shock dynamics. All the mean-field results are found in remarkable agreement with the Monte Carlo simulations.

Tailoring the Photophysical Properties of a Homoleptic Iron(II) Tetra N-Heterocyclic Carbene Complex by Attaching an Imidazolium Group to the (C∧N∧C) Pincer Ligand─A Comparative Study.

We here report the synthesis of the homoleptic iron(II) N-heterocyclic carbene (NHC) complex [Fe(miHpbmi)2](PF6)4 (miHpbmi = 4-((3-methyl-1H-imidazolium-1-yl)pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) and its electrochemical and photophysical properties. The introduction of the π-electron-withdrawing 3-methyl-1H-imidazol-3-ium-1-yl group into the NHC ligand framework resulted in stabilization of the metal-to-ligand charge transfer (MLCT) state and destabilization of the metal-centered (MC) states. This resulted in an improved excited-state lifetime of 16 ps compared to the 9 ps for the unsubstituted parent compound [Fe(pbmi)2](PF6)2 (pbmi = (pyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)) as well as a stronger MLCT absorption band extending more toward the red spectral region. However, compared to the carboxylic acid derivative [Fe(cpbmi)2](PF6)2 (cpbmi = 1,1'-(4-carboxypyridine-2,6-diyl)bis(3-methylimidazol-2-ylidene)), the excited-state lifetime of [Fe(miHpbmi)2](PF6)4 is the same, but both the extinction and the red shift are more pronounced for the former. Hence, this makes [Fe(miHpbmi)2](PF6)4 a promising pH-insensitive analogue of [Fe(cpbmi)2](PF6)2. Finally, the excited-state dynamics of the title compound [Fe(miHpbmi)2](PF6)4 was investigated in solvents with different viscosities, however, showing very little dependency of the depopulation of the excited states on the properties of the solvent used.

How Rigidity and Conjugation of Bidentate Ligands Affect the Geometry and Photophysics of Iron N-Heterocyclic Complexes: A Comparative Study.

Two iron complexes featuring the bidentate, nonconjugated N-heterocyclic carbene (NHC) 1,1'-methylenebis(3-methylimidazol-2-ylidene) (mbmi) ligand, where the two NHC moieties are separated by a methylene bridge, have been synthesized to exploit the combined influence of geometric and electronic effects on the ground- and excited-state properties of homoleptic FeIII-hexa-NHC [Fe(mbmi)3](PF6)3 and heteroleptic FeII-tetra-NHC [Fe(mbmi)2(bpy)](PF6)2 (bpy = 2,2'-bipyridine) complexes. They are compared to the reported FeIII-hexa-NHC [Fe(btz)3](PF6)3 and FeII-tetra-NHC [Fe(btz)2(bpy)](PF6)2 complexes containing the conjugated, bidentate mesoionic NHC ligand 3,3'-dimethyl-1,1'-bis(p-tolyl)-4,4'-bis(1,2,3-triazol-5-ylidene) (btz). The observed geometries of [Fe(mbmi)3](PF6)3 and [Fe(mbmi)2(bpy)](PF6)2 are evaluated through L-Fe-L bond angles and ligand planarity and compared to those of [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. The FeII/FeIII redox couples of [Fe(mbmi)3](PF6)3 (-0.38 V) and [Fe(mbmi)2(bpy)](PF6)2 (-0.057 V, both vs Fc+/0) are less reducing than [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. The two complexes show intense absorption bands in the visible region: [Fe(mbmi)3](PF6)3 at 502 nm (ligand-to-metal charge transfer, 2LMCT) and [Fe(mbmi)2(bpy)](PF6)2 at 410 and 616 nm (metal-to-ligand charge transfer, 3MLCT). Lifetimes of 57.3 ps (2LMCT) for [Fe(mbmi)3](PF6)3 and 7.6 ps (3MLCT) for [Fe(mbmi)2(bpy)](PF6)2 were probed and are somewhat shorter than those for [Fe(btz)3](PF6)3 and [Fe(btz)2(bpy)](PF6)2. [Fe(mbmi)3](PF6)3 exhibits photoluminescence at 686 nm (2LMCT) in acetonitrile at room temperature with a quantum yield of (1.2 ± 0.1) × 10-4, compared to (3 ± 0.5) × 10-4 for [Fe(btz)3](PF6)3.

Characterization of a Myeloid Differentiation Factor 2-Derived Peptide that Facilitates THP-1 Macrophage-Mediated Phagocytosis of Gram-Negative Bacteria.

Myeloid differentiation factor 2 (MD2), the TLR4 coreceptor, has been shown to possess opsonic activity and has been implicated in phagocytosis and intracellular killing of Gram-negative bacteria. However, any MD2 protein segment involved in phagocytosis of Gram-negative bacteria is not yet known. A short synthetic MD2 segment, MD54 (amino acid regions 54 to 69), was shown to interact with a Gram-negative bacterial outer membrane component, LPS, earlier. Furthermore, the MD54 peptide induced aggregation of LPS and facilitated its internalization in THP-1 cells. Currently, it has been investigated if MD2-derived MD54 possesses any opsonic property and role in phagocytosis of Gram-negative bacteria. Remarkably, we observed that MD54 facilitated agglutination of Gram-negative bacteria, Escherichia coli (ATCC 25922) and Pseudomonas aeruginosa (ATCC BAA-427), but not of Gram-positive bacteria, Bacillus subtilis (ATCC 6633) and Staphylococcus aureus (ATCC 25923). The MD54-opsonized Gram-negative bacteria internalized within PMA-treated THP-1 cells and were killed over a longer incubation period. However, both internalization and intracellular killing of the MD54-opsonized Gram-negative bacteria within THP-1 phagocytes were appreciably inhibited in the presence of a phagocytosis inhibitor, cytochalasin D. Furthermore, MD54 facilitated the clearance of Gram-negative bacteria E. coli (ATCC 25922) and P. aeruginosa (ATCC BAA-427) from the infected BALB/c mice whereas an MD54 analog, MMD54, was inactive. Overall, for the first time, the results revealed that a short MD2-derived peptide can specifically agglutinate Gram-negative bacteria, act as an opsonin for these bacteria, and facilitate their phagocytosis by THP-1 phagocytes. The results suggest that the MD54 segment could have a crucial role in MD2-mediated host-pathogen interaction involving the Gram-negative bacteria.

Outcome of Osteosynthesis of Late-Presenting Proximal Humerus Non-union: A Case Series.

Introduction: It can be challenging to treat proximal humeral non-union (PHN). The challenge gets compounded when they are presented either late or after previous surgery. The challenges are far greater due to small proximal fragments, scalloping of the head, medial bone defect, osteoporosis, soft tissue contractures, and problems related to the previous implants. Material and Methods: In this retro-prospective study (2007-2020), we report on six cases of PHN which were presented to us more than 5 years after the original injury and managed using an intra-medullary autologous fibular strut graft (FSG) along with fixation with a proximal humeral locking plate and cancellous bone grafting. We quantified shoulder function based on constant score and disabilities of the arm, shoulder and hand (DASH) score. Results: The mean age of patients is found to be 54.3 years (range, 22-74 years) with females dominating our study. The mean pre-operative constant score is 26.33 which improved to 71.83 in the post-operative period. The mean DASH score is 77.98 preoperatively, which improved to 19.5 postoperatively. The paired sample t-test compared the difference in mean of the pre-operative and post-operative scores, which shows significant improvement in outcome. Conclusion: Even in very late PHN in poor-quality bone, the additional use of intramedullary strut grafts provides structural support to the fixation and further enhances the ability to withstand the load-start early motion and have a satisfactory functional outcome. Keywords: Non-union, proximal humerus non-union, proximal humerus fracture, proximal humerus internal locking system, locking plate, autogenous fibular strut graft.

Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism.

Insulin resistance (IR) is the key pathophysiological cause of type 2 diabetes, and inflammation has been implicated in it. The death domain (DD) of the adaptor protein, MyD88 plays a crucial role in the transduction of TLR4-associated inflammatory signal. Herein, we have identified a 10-residue peptide (M10), from the DD of MyD88 which seems to be involved in Myddosome formation. We hypothesized that M10 could inhibit MyD88-dependent TLR4-signaling and might have effects on inflammation-associated IR. Intriguingly, 10-mer M10 showed oligomeric nature and reversible self-assembly property indicating the peptide's ability to recognize its own amino acid sequence. M10 inhibited LPS-induced nuclear translocation of NF-κB in L6 myotubes and also reduced LPS-induced IL-6 and TNF-α production in peritoneal macrophages of BALB/c mice. Remarkably, M10 inhibited IL-6 and TNF-α secretion in diabetic, db/db mice. Notably, M10 abrogated IR in insulin-resistant L6 myotubes, which was associated with an increase in glucose uptake and a decrease in Ser307-phosphorylation of IRS1, TNF-α-induced JNK activation and nuclear translocation of NF-κB in these cells. Alternate day dosing with M10 (10 and 20 mg/kg) for 30 days in db/db mice significantly lowered blood glucose and improved glucose intolerance after loading, 3.0 g/kg glucose orally. Furthermore, M10 increased insulin and adiponectin secretion in db/db mice. M10-induced glucose uptake in L6 myotubes involved the activation of PI3K/AKT/GLUT4 pathways. A scrambled M10-analog was mostly inactive. Overall, the results show the identification of a 10-mer peptide from the DD of MyD88 with anti-inflammatory and anti-diabetic properties, suggesting that targeting of TLR4-inflammatory pathway, could lead to the discovery of molecules against IR and diabetes.

Leukemia-associated aberrant immunophenotype: A flow cytometry-based experience of 110 cases from a tertiary care center in Northern India.

Background: Leukemic cells express a characteristic set of "cluster of differentiation" (CD) markers, which forms the basis of the current WHO classification. Leukemia-associated aberrant immunophenotype (LAIP) refers to expression of unusual CD markers by leukemic cells, which are not normally expressed by their respective lineage. The incidence of LAIP varies considerably, and its clinical implications, prognostic relevance, and sensitivity to therapy are still debatable. This study was conducted to identify the immunophenotypic aberrancies in newly diagnosed leukemias in our Institute. Method: This was an observational study, which included newly diagnosed leukemias on flow cytometry. Aberrant immunophenotypic expressions were recorded whenever present and were correlated with prognostic factors like age, gender, and total leucocyte count (TLC). Results: The study included 110 newly diagnosed cases of leukemias (85 acute and 25 chronic) over 1.5 years. Immunophenotypic aberrancies were detected in 40.4% of the cases. The highest incidence of aberrations was detected in acute myeloid leukemia (60.7%). LAIPs were detected in 50% of T-acute lymphoblastic leukemia and 25% cases of in B-cell acute lymphoblastic leukemia (B-ALL). Aberrant CD33 and CD56 expression in B-ALL correlated with poor prognostic factors like higher age and higher TLC, respectively. Immunophenotypic aberrancies were present in 28% cases of chronic lymphocytic leukemia. Conclusion: The results of this study have generated valuable baseline data on the incidence of LAIPs in this region. This information is vital because establishing LAIPs at the time of diagnosis is crucial for disease monitoring. Some LAIPs are associated with underlying cytogenetic abnormalities and hence impact the management and prognosis.

Ferrous and ferric complexes with cyclometalating N-heterocyclic carbene ligands: a case of dual emission revisited.

Iron N-heterocyclic carbene (FeNHC) complexes with long-lived charge transfer states are emerging as a promising class of photoactive materials. We have synthesized [FeII(ImP)2] (ImP = bis(2,6-bis(3-methylimidazol-2-ylidene-1-yl)phenylene)) that combines carbene ligands with cyclometalation for additionally improved ligand field strength. The 9 ps lifetime of its 3MLCT (metal-to-ligand charge transfer) state however reveals no benefit from cyclometalation compared to Fe(ii) complexes with NHC/pyridine or pure NHC ligand sets. In acetonitrile solution, the Fe(ii) complex forms a photoproduct that features emission characteristics (450 nm, 5.1 ns) that were previously attributed to a higher (2MLCT) state of its Fe(iii) analogue [FeIII(ImP)2]+, which led to a claim of dual (MLCT and LMCT) emission. Revisiting the photophysics of [FeIII(ImP)2]+, we confirmed however that higher (2MLCT) states of [FeIII(ImP)2]+ are short-lived (<10 ps) and therefore, in contrast to the previous interpretation, cannot give rise to emission on the nanosecond timescale. Accordingly, pristine [FeIII(ImP)2]+ prepared by us only shows red emission from its lower 2LMCT state (740 nm, 240 ps). The long-lived, higher energy emission previously reported for [FeIII(ImP)2]+ is instead attributed to an impurity, most probably a photoproduct of the Fe(ii) precursor. The previously reported emission quenching on the nanosecond time scale hence does not support any excited state reactivity of [FeIII(ImP)2]+ itself.

Influence of 24-Week Yoga Intervention on Cardiovascular Risk Factors and Inflammatory Markers in Type 2 Diabetes.

Background and Aims: Persistent hyperglycemia, dyslipidemia, inflammation, and oxidative stress are important in cardiovascular risk in type-2 diabetes mellitus (DM). To evaluate the effect of 24-week yoga intervention on anthropometry and biochemical markers in DM patients, we performed a study. Methods: A hospital-based prospective randomized study in 104 participants with DM divided into control (n = 52) and intervention (n = 52) groups was performed. Patients in the intervention group performed 40 min of multifaceted individualized yoga exercises 5 days/week for 24 weeks. Anthropometric measurements and biochemical analysis were performed at baseline and after 24 weeks in both groups. Descriptive statistics are reported. Results: Baseline characteristics were similar in both groups. At 24 weeks, participants in the intervention versus controls had lower body mass index (25.6 ± 2.9 vs. 28.0 ± 3.2 kg/m2), waist-hip ratio (0.94 ± 0.06 vs. 0.99 ± 0.05), systolic blood pressure (121.2 ± 11.7 vs. 139.3 ± 19.1 mmHg), fasting glucose (142.7 ± 45.3 vs. 175.7 ± 45.4 mg/dL), glycated hemoglobin (7.2 ± 1.8 vs. 9.4 ± 1.9%), low-density lipoprotein cholesterol (167.5 ± 38.1 vs. 192.2 ± 51.4 mg/dL), nonhigh-density lipoprotein cholesterol (136.8 ± 35.3 vs. 158.6 ± 47.2 mg/dL), interleukin-6 (32.0 ± 21.5 vs. 43.5 ± 34.3 pg/mL), and high-sensitivity C-reactive protein (5.1 ± 3.7 vs. 9.5 ± 15.6 mg/L) (P ≤ 0.05). In the intervention group, higher levels of high-density lipoprotein cholesterol (49.2 ± 15.0 vs. 40.4 ± 7.2 mg/dL) and serum total antioxidants (1.9 ± 0.4 vs. 1.4 ± 0.4 mmol/L) were observed (P < 0.001). Conclusion: A short-term yoga intervention led to reduced glycemia, dyslipidemia, and inflammatory markers and increased antioxidant status in patients with type-2 DM.

Ocular involvement-An unusual initial presentation of chronic myeloid leukemia: A case report.

Chronic myeloid leukemia (CML) patients frequently exhibit systemic symptoms such as fatigue, abdominal discomfort, weight loss, and fever but rarely can have atypical initial presentation in the form of ophthalmic manifestations, which can precede the diagnosis of the primary malignancy. We describe a case of a 29-year-old male who presented in our ophthalmology out-patient department (OPD) with complaints of painless, diminution of vision, which was sudden in onset in right eye (RE) and loss of vision in left eye (LE) for four and seven days, respectively. There had been a history of loss of weight and appetite for the past 2 months. The visual acuity (VA) recorded was finger counting two meters in RE and perception of light in LE with an inaccurate projection of rays in both eyes (BE). The anterior segment evaluation of both eyes (BE) was normal. Fundus revealed multiple elevated yellow subretinal lesions with exudative detachment in the RE and no view in the LE. Ultrasound-Brightness (USG B) scan in the LE revealed multiple hyperreflective echoes likely vitreous hemorrhage. Optical coherence tomography (OCT) showed subretinal hyperreflectivity with surrounding edema in RE suggestive of leukemic infiltrates. On further systemic investigations, chronic myeloid leukemia-chronic phase (CML-CP) was detected; hence, the diagnosis of RE exudative retinal detachment (RD) and LE vitreous hemorrhage with CML-CP was made. Ophthalmic involvement is more often seen in acute than chronic leukemia, which makes the diagnosis challenging. We describe a unique case of a young patient with CML-CP who initially presented with ocular involvement preceding systemic diagnosis. This case report illustrates the importance of a primary care physician or an ophthalmologist in the early diagnosis and prompt management of hematological malignancy, as ophthalmic manifestations may be a rare initial presenting feature in CML-CP. These conditions require urgent referral to a hematologist by a primary care physician in the view of early commencement of therapy.

Thalassemia and Hemoglobinopathy Screening in Women Attending Antenatal Clinic at a Tertiary Care Center in Uttarakhand, India: A Re-look at the Laboratory Parameters Mandating High-Performance Liquid Chromatography Workup.

INTRODUCTION: Thalassemia and hemoglobinopathies are the most common inherited hematological disorders. Of these, ß thalassemia is the commonest disorder reported in India, followed by certain hemoglobinopathies encountered in different regions of the country. The data pertaining to the incidence of these disorders in the Uttarakhand region of India are sparse. AIM AND OBJECTIVES: To ascertain the prevalence and spectrum of thalassemia/hemoglobinopathies amongst antenatal women in Uttarakhand. The study also aimed to analyze the ability of red cell indices in differentiating beta thalassemia trait (BTT) from mild iron deficiency anemia (IDA). MATERIAL AND METHODS: A total of 460 pregnant women in the first trimester of pregnancy were screened by cation exchange high-performance liquid chromatography. Retention time and proportions of normal/abnormal hemoglobin peaks were documented in all cases. Hemoglobin A2 (HbA2) values of ≥4% were taken as a cut-off for diagnosing BTT. Blood samples were also collected for complete blood counts, reticulocyte counts, and serum ferritin. The ability of the various discriminatory indices to differentiate between IDA and BTT was also assessed. RESULTS: The prevalence of BTT and hemoglobin D-Punjab trait amongst pregnant women was found to be 2.6% and 0.2%, respectively. RBC count, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) were found to be moderately strong predictors of BTT, with an area under the curve of 0.860, 0.857, and 0.842, respectively, which were comparable to the discriminatory indices found to be most useful in this study. CONCLUSION: In view of the 2.6% prevalence of BTT in antenatal women in this region of Uttarakhand, a routine screening will be helpful in detecting carriers early in the antenatal period. Careful interpretation of red cell indices is crucial to the distinction between BTT and IDA. Discriminatory indices are reasonably accurate in differentiating BTT from mild iron deficiency, but for practical purposes, MCV and MCH provide equivalent information to identify cases that require further workup.

Metabolic non-communicable disease health report of India: the ICMR-INDIAB national cross-sectional study (ICMR-INDIAB-17).

BACKGROUND: Non-communicable disease (NCD) rates are rapidly increasing in India with wide regional variations. We aimed to quantify the prevalence of metabolic NCDs in India and analyse interstate and inter-regional variations. METHODS: The Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study, a cross-sectional population-based survey, assessed a representative sample of individuals aged 20 years and older drawn from urban and rural areas of 31 states, union territories, and the National Capital Territory of India. We conducted the survey in multiple phases with a stratified multistage sampling design, using three-level stratification based on geography, population size, and socioeconomic status of each state. Diabetes and prediabetes were diagnosed using the WHO criteria, hypertension using the Eighth Joint National Committee guidelines, obesity (generalised and abdominal) using the WHO Asia Pacific guidelines, and dyslipidaemia using the National Cholesterol Education Program-Adult Treatment Panel III guidelines. FINDINGS: A total of 113 043 individuals (79 506 from rural areas and 33 537 from urban areas) participated in the ICMR-INDIAB study between Oct 18, 2008 and Dec 17, 2020. The overall weighted prevalence of diabetes was 11·4% (95% CI 10·2-12·5; 10 151 of 107 119 individuals), prediabetes 15·3% (13·9-16·6; 15 496 of 107 119 individuals), hypertension 35·5% (33·8-37·3; 35 172 of 111 439 individuals), generalised obesity 28·6% (26·9-30·3; 29 861 of 110 368 individuals), abdominal obesity 39·5% (37·7-41·4; 40 121 of 108 665 individuals), and dyslipidaemia 81·2% (77·9-84·5; 14 895 of 18 492 of 25 647). All metabolic NCDs except prediabetes were more frequent in urban than rural areas. In many states with a lower human development index, the ratio of diabetes to prediabetes was less than 1. INTERPRETATION: The prevalence of diabetes and other metabolic NCDs in India is considerably higher than previously estimated. While the diabetes epidemic is stabilising in the more developed states of the country, it is still increasing in most other states. Thus, there are serious implications for the nation, warranting urgent state-specific policies and interventions to arrest the rapidly rising epidemic of metabolic NCDs in India. FUNDING: Indian Council of Medical Research and Department of Health Research, Ministry of Health and Family Welfare, Government of India.

Allosteric Determinants in High Temperature Requirement A Enzymes Are Conserved and Regulate the Population of Active Conformations.

High temperature requirement A (HtrA) are allosterically regulated enzymes wherein effector binding to the PDZ domain triggers proteolytic activity. Yet, it remains unclear if the inter-residue network governing allostery is conserved across HtrA enzymes. Here, we investigated and identified the inter-residue interaction networks by molecular dynamics simulations on representative HtrA proteases, Escherichia coli DegS and Mycobacterium tuberculosis PepD, in effector-bound and free forms. This information was used to engineer mutations that could potentially perturb allostery and conformational sampling in a different homologue, M. tuberculosis HtrA. Mutations in HtrA perturbed allosteric regulation─a finding consistent with the hypothesis that the inter-residue interaction network is conserved across HtrA enzymes. Electron density from data collected on cryo-protected HtrA crystals revealed that mutations altered the topology of the active site. Ensemble models fitted into electron density calculated from room-temperature diffraction data showed that only a fraction of these models had a catalytically competent active site conformation alongside a functional oxyanion hole thus providing experimental evidence that these mutations influenced conformational sampling. Mutations at analogous positions in the catalytic domain of DegS perturbed the coupling between effector binding and proteolytic activity, thus confirming the role of these residues in the allosteric response. The finding that a perturbation in the conserved inter-residue network alters conformational sampling and the allosteric response suggests that an ensemble allosteric model best describes regulated proteolysis in HtrA enzymes.

Severity and mortality associated with COVID-19 among children hospitalised in tertiary care centres in India: a cohort study.

Background: It is critical to identify high-risk groups among children with COVID-19 from low-income and middle-income countries (LMICs) to facilitate the optimum use of health system resources. The study aims to describe the severity and mortality of different clinical phenotypes of COVID-19 in a large cohort of children admitted to tertiary care hospitals in India. Methods: Children aged 0-19 years with evidence of SARS-CoV-2 infection (real time polymerase chain reaction or rapid antigen test positive) or exposure (anti-SARS-CoV-2 antibody, or history of contact with SARS-CoV-2) were enrolled in the study, between January 2021 and March 2022 across five tertiary hospitals in India. All study participants enrolled prospectively and retrospectively were followed up for three months after discharge. COVID-19 was classified into severe (Multisystem Inflammatory Syndrome in Children (MIS-C), severe acute COVID-19, 'unclassified') or non-severe disease. The mortality rates were estimated in different phenotypes. Findings: Among 2468 eligible children enrolled, 2148 were hospitalised. Signs of illness were present in 1688 (79%) children with 1090 (65%) having severe disease. High mortality was reported in MIS-C (18.6%), severe acute COVID-19 (13.3%) and the unclassified severe COVID-19 disease (12.3%). Mortality remained high (17.5%) when modified MIS-C criteria was used. Non-severe COVID-19 disease had 14.1% mortality when associated with comorbidity. Interpretation: Our findings have important public health implications for low resource settings. The high mortality underscores the need for better preparedness for timely diagnosis and management of COVID-19. Children with associated comorbidity or coinfections are a vulnerable group and need special attention. MIS-C requires context specific diagnostic criteria for low resource settings. It is important to evaluate the clinical, epidemiological and health system-related risk factors associated with severe COVID-19 and mortality in children from LMICs. Funding: Department of Biotechnology, Govt of India and Department of Maternal, Child and Adolescent Health and Aging, WHO, Geneva, Switzerland.

Association between neutrophil lymphocyte ratio and status of symptom control in children and adolescents with bronchial asthma.

Neutrophil lymphocyte ratio (NLR), an easy and readily available biomarker of systemic inflammation, has been less studied so far as a putative marker of asthma control. Our study aimed to assess its feasibility. A total of 90 asthmatic children, aged 5-18 years, diagnosed according to Global Initiative for Asthma (GINA) guidelines, were. Control status of asthma was assessed using the asthma control test (ACT) or childhood ACT and categorized as controlled group-1 (ACT > 19) and uncontrolled group-2 (ACT ≤ 19). The difference between mean values in both groups was analysed, finding a significant difference between children with and without a family history (p = 0.004) and those with and without a need for admission (p = 0.045). Also, a significant association was established between NLR and the type of severity of asthma (p = 0.049), but none between NLR and age, gender, BMI, coexisting allergic rhinitis, or asthma exacerbation. Thus we found no significant association between NLR and symptom control status. However, NLR has the potential to be a putative marker of inflammation, although its relative status to CRP needs further studies.