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1.
Mol Pharm ; 21(3): 1285-1299, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38345400

RESUMO

Understanding and predicting protein aggregation represents one of the major challenges in accelerating the pharmaceutical development of protein therapeutics. In addition to maintaining the solution pH, buffers influence both monoclonal antibody (mAb) aggregation in solution and the aggregation mechanisms since the latter depend on the protein charge. Molecular-level insight is necessary to understand the relationship between the buffer-mAb interaction and mAb aggregation. Here, we use all-atom molecular dynamics simulations to investigate the interaction of phosphate (Phos) and citrate (Cit) buffer ions with the Fab and Fc domains of mAb COE3. We demonstrate that Phos and Cit ions feature binding mechanisms, with the protein that are very different from those reported previously for histidine (His). These differences are reflected in distinctive ion-protein binding modes and adsorption/desorption kinetics of the buffer molecules from the mAb surface and result in dissimilar effects of these buffer species on mAb aggregation. While His shows significant affinity toward hydrophobic amino acids on the protein surface, Phos and Cit ions preferentially bind to charged amino acids. We also show that Phos and Cit anions provide bridging contacts between basic amino acids in neighboring proteins. The implications of such contacts and their connection to mAb aggregation in therapeutic formulations are discussed.


Assuntos
Anticorpos Monoclonais , Agregados Proteicos , Anticorpos Monoclonais/química , Soluções Tampão , Concentração de Íons de Hidrogênio , Íons , Aminoácidos
2.
Mol Pharm ; 21(2): 704-717, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38194618

RESUMO

Monoclonal antibodies (mAbs) are active components of therapeutic formulations that interact with the water-vapor interface during manufacturing, storage, and administration. Surface adsorption has been demonstrated to mediate antibody aggregation, which leads to a loss of therapeutic efficacy. Controlling mAb adsorption at interfaces requires a deep understanding of the microscopic processes that lead to adsorption and identification of the protein regions that drive mAb surface activity. Here, we report all-atom molecular dynamics (MD) simulations of the adsorption behavior of a full IgG1-type antibody at the water/vapor interface. We demonstrate that small local changes in the protein structure play a crucial role in promoting adsorption. Also, interfacial adsorption triggers structural changes in the antibody, potentially contributing to the further enhancement of surface activity. Moreover, we identify key amino acid sequences that determine the adsorption of antibodies at the water-air interface and outline strategies to control the surface activity of these important therapeutic proteins.


Assuntos
Anticorpos Monoclonais , Vapor , Anticorpos Monoclonais/química , Adsorção , Água/química , Composição de Medicamentos
3.
Mol Pharm ; 19(9): 3288-3303, 2022 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-35946408

RESUMO

Histidine, a widely used buffer in monoclonal antibody (mAb) formulations, is known to reduce antibody aggregation. While experimental studies suggest a nonelectrostatic, nonstructural (relating to secondary structure preservation) origin of the phenomenon, the underlying microscopic mechanism behind the histidine action is still unknown. Understanding this mechanism will help evaluate and predict the stabilizing effect of this buffer under different experimental conditions and for different mAbs. We have used all-atom molecular dynamics simulations and contact-based free energy calculations to investigate molecular-level interactions between the histidine buffer and mAbs, which lead to the observed stability of therapeutic formulations in the presence of histidine. We reformulate the Spatial Aggregation Propensity index by including the buffer-protein interactions. The buffer adsorption on the protein surface leads to lower exposure of the hydrophobic regions to water. Our analysis indicates that the mechanism behind the stabilizing action of histidine is connected to the shielding of the solvent-exposed hydrophobic regions on the protein surface by the buffer molecules.


Assuntos
Histidina , Simulação de Dinâmica Molecular , Anticorpos Monoclonais/química , Composição de Medicamentos , Histidina/química , Interações Hidrofóbicas e Hidrofílicas
4.
BMC Public Health ; 22(1): 376, 2022 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-35193546

RESUMO

BACKGROUND: The aim of the present study was to recalibrate the effectiveness of Indian Diabetes Risk Score (IDRS) and Community-Based Assessment Checklist (CBAC) by opportunistic screening of Diabetes Mellitus (DM) and Hypertension (HT) among the people attending health centres, and estimating the risk of fatal and non-fatal Cardio-Vascular Diseases (CVDs) among them using WHO/ISH charts. METHODS: All the people aged ≥ 30 years attending the health centers were screened for DM and HT. Weight, height, waist circumference, and hip circumferences were measured, and BMI and Waist-Hip Ratio (WHR) were calculated. Risk categorization of all participants was done using IDRS, CBAC, and WHO/ISH risk prediction charts. Individuals diagnosed with DM or HT were started on treatment. The data was recorded using Epicollect5 and was analyzed using SPSS v.23 and MedCalc v.19.8. ROC curves were plotted for DM and HT with the IDRS, CBAC score, and anthropometric parameters. Sensitivity (SN), specificity (SP), Positive Predictive Value (PPV), Negative Predictive Value (NPV), Accuracy and Youden's index were calculated for different cut-offs of IDRS and CBAC scores. RESULTS: A total of 942 participants were included for the screening, out of them, 9.2% (95% CI: 7.45-11.31) were diagnosed with DM for the first time. Hypertension was detected among 25.7% (95% CI: 22.9-28.5) of the participants. A total of 447 (47.3%) participants were found with IDRS score ≥ 60, and 276 (29.3%) with CBAC score > 4. As much as 26.1% were at moderate to higher risk (≥ 10%) of developing CVDs. Area Under the Curve (AUC) for IDRS in predicting DM was 0.64 (0.58-0.70), with 67.1% SN and 55.2% SP (Youden's Index 0.22). While the AUC for CBAC was 0.59 (0.53-0.65). For hypertension both the AUCs were 0.66 (0.62-0.71) and 0.63 (0.59-0.67), respectively. CONCLUSIONS: IDRS was found to have the maximum AUC and sensitivity thereby demonstrating its usefulness as compared to other tools for screening of both diabetes and hypertension. It thus has the potential to expose the hidden NCD iceberg. Hence, we propose IDRS as a useful tool in screening of Diabetes and Hypertension in rural India.


Assuntos
Diabetes Mellitus Tipo 2 , Hipertensão , Doenças não Transmissíveis , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hipertensão/epidemiologia , Índia/epidemiologia , Fatores de Risco , População Rural , Circunferência da Cintura
5.
Monaldi Arch Chest Dis ; 93(4)2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36524853

RESUMO

Awake self-proning is being used widely as respiratory support in COVID-19 hypoxemia, in resource-limited settings. We aimed to investigate the effectiveness of early awake self-proning in preventing mortality and the need for intubation in adults with moderate COVID-19 hypoxemia. In this randomized clinical trial with inten-tion-to-treat analysis, we enrolled eligible adults with COVID-19 hypoxemia (SpO2 <94%), requiring supplemental oxygen via nasal prongs or facemask from a tertiary-care setting in Jodhpur, India between June 15 to December 24, 2020. Awake proning comprised of 4-hour cycles with prone position maintained 2 h per cycle. The control group did not maintain any specific position. All participants received standard care. The primary outcomes were 30-day mortal-ity and requirement for mechanical ventilation. Of 502 participants included, mean (SD) age was 59.7 (12.7) years with 124 women (24.6%); 257 were randomized to awake-proning, 245 to control group and all 502 were included for follow-up mortality analysis. Mortality at follow-up was 16.3% in the awake-prone and 15.1% in the control group [OR:1.10 (0.68-1.78), p=0.703). The requirement of mechanical ventilation was 10% in both groups (p=0.974). Survival time (in days) was not significantly different between the groups [Log-rank test, HR: 1.08 (95% CI, 0.70-1.68), p=0.726]. Likewise, time to intubation was comparable (Log-rank test, HR: 0.93 (95% CI, 0.56-1.70), p=0.974). Hence, awake self-proning did not improve survival or requirement of mechanical-ventilation in non-intubated patients with mild to moderate COVID-19 hypox-emia. Trial Registration: Clinical trial registry of India, ID: CTRI/2020/06/025804.   The trial is accessible from WHO's International Clinical Trials Registry Platform (ICTRP) at https://trialsearch.who.int ***************************************************************   *Appendix Authors list  Deepak Kumar1, Gopal Krishna Bohra1, Nishant Kumar Chauhan2, Nikhil Kothari3, Vijaya Lakshmi Nag4 Sanjeev Misra5  1Department of Internal Medicine; 2Department of Pulmonary Medicine; 3Department of Anaesthesiology and Critical Care; 4Department of Microbiology; 5Department of Surgical Oncology, All India Institute of Medical Sciences, Jodhpur, India.


Assuntos
COVID-19 , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Hipóxia/terapia , Respiração Artificial , SARS-CoV-2 , Vigília , Masculino , Idoso
6.
Epidemiol Infect ; 149: e132, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34011421

RESUMO

The coronavirus disease 2019 (COVID-19) vaccine was launched in India on 16 January 2021, prioritising health care workers which included medical students. We aimed to assess vaccine hesitancy and factors related to it among medical students in India. An online questionnaire was filled by 1068 medical students across 22 states and union territories of India from 2 February to 7 March 2021. Vaccine hesitancy was found among 10.6%. Concern regarding vaccine safety and efficacy, lack of awareness regarding their eligibility for vaccination and lack of trust in government agencies predicted COVID-19 vaccine hesitancy among medical students. On the other hand, the presence of risk perception regarding themselves being affected with COVID-19 reduced vaccine hesitancy as well as hesitancy in participating in COVID-19 vaccine trials. Vaccine-hesitant students were more likely to derive information from social media and less likely from teachers at their medical colleges. Choosing between the two available vaccines (Covishield and Covaxin) was considered important by medical students both for themselves and for their future patients. Covishield was preferred to Covaxin by students. Majority of those willing to take the COVID-19 vaccine felt that it was important for them to resume their clinical posting, face-to-face classes and get their personal life back on track. Around three-fourths medical students viewed that COVID-19 vaccine should be made mandatory for both health care workers and international travellers. Prior adult vaccination did not have an effect on COVID-19 vaccine hesitancy. Targeted awareness campaigns, regulatory oversight of vaccine trials and public release of safety and efficacy data and trust building activities could further reduce COVID-19 vaccine hesitancy among medical students.


Assuntos
Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Tomada de Decisões , Estudantes de Medicina/psicologia , COVID-19/epidemiologia , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Índia/epidemiologia , Fatores de Risco , SARS-CoV-2/imunologia , Inquéritos e Questionários , Vacinação/psicologia , Vacinação/estatística & dados numéricos
7.
Soft Matter ; 16(3): 634-641, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31840704

RESUMO

Several analytical calculations and computer simulations propose that cylindrical monodispersive rods having an aspect ratio (ratio of length to diameter) greater than 4 can exhibit liquid crystal (LC) ordering. But, recent experiments demonstrated the signature of LC ordering in systems of 4- to 20-base pair (bp) long nucleic acids (NAs) that do not satisfy the shape anisotropy criterion. Mechanisms of end-to-end adhesion and stacking have been proposed to explain this phenomenon. In this study, using all-atom molecular dynamics (MD) simulation, we explicitly verify the end-to-end stacking of double-stranded RNA (dsRNA) and demonstrate the LC ordering at the microscopic level. Using umbrella sampling (US) calculation, we quantify the potential of mean force (PMF) between two dsRNAs for various reaction coordinates (RCs) and compare our results with previously reported PMFs for double-stranded DNA (dsDNA). The PMF profiles demonstrate the anisotropic nature of inter-NA interaction. We find that, like dsDNA, dsRNA also prefers to stack on top of each other while repelling sideways, leading to the formation of supra-molecular-columns that undergo LC ordering at high NA volume fraction (φ). We also demonstrate and quantify the nematic ordering of the RNAs using several hundred nanosecond-long MD simulations that remain almost invariant for different initial configurations and under different external physiological conditions.


Assuntos
Cristais Líquidos/química , Simulação de Dinâmica Molecular , Ácidos Nucleicos/química , Anisotropia , Conformação de Ácido Nucleico , Termodinâmica
8.
BMC Infect Dis ; 20(1): 10, 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31906924

RESUMO

BACKGROUND: A visceral leishmaniasis outbreak was reported from a village in a low-endemic district of Bihar, India. METHODS: Outbreak investigation with house-to-house search and rapid test of kala-azar suspects and contacts was carried out. Sandfly collection and cone bio-assay was done as part of entomological study. RESULTS: A spatially and temporally clustered kala-azar outbreak was found at Kosra village in Sheikhpura district with 70 cases reported till December 2018. Delay of more than a year was found between diagnosis and treatment of the index case. The southern hamlet with socio-economically disadvantaged migrant population was several times more affected than rest of the village (attack rate of 19.0% vs 0.5% respectively, ORMH = 39.2, 95% CI 18.2-84.4). The median durations between onset of fever to first contact with any health services, onset to kala-azar diagnosis, diagnosis to treatment were 10 days (IQR 4-18), 30 days (IQR 17-73) and 1 day (IQR 0.5 to 3), respectively, for 50 kala-azar cases assessed till June 2017. Three-fourths of these kala-azar cases had out-of-pocket medical expenditure for their condition. Known risk factors for kala-azar such as illiteracy, poverty, belonging to socially disadvantaged community, migration, residing in kutcha houses, sleeping in rooms with unplastered walls and non-use of mosquito nets were present in majority of these cases. Only half the dwellings of the kala-azar cases were fully sprayed. Fully gravid female P. argentipes collected post indoor residual spraying (IRS) and low sandfly mortality on cone-bioassay indicated poor effectiveness of vector control. CONCLUSIONS: There is need to focus on low-endemic areas of kala-azar. The elimination programme should implement a routine framework for kala-azar outbreak response. Complete case-finding, use of quality-compliant insecticide and coverage of all sprayable surfaces in IRS could help interrupt transmission during outbreaks.


Assuntos
Surtos de Doenças , Leishmaniose Visceral/epidemiologia , Migrantes , Animais , Surtos de Doenças/prevenção & controle , Feminino , Humanos , Incidência , Índia/epidemiologia , Controle de Insetos/estatística & dados numéricos , Inseticidas/administração & dosagem , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/terapia , Leishmaniose Visceral/transmissão , Psychodidae/fisiologia , Fatores de Risco
9.
J Vector Borne Dis ; 57(3): 240-248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-34472508

RESUMO

BACKGROUND & OBJECTIVES: Indoor residual spraying (IRS) is part of a key strategy for elimination of visceral leishmaniasis (kala-azar). IRS for kala-azar elimination in India uses 125 g 5% alpha-Cypermethrin wettable powder which is mixed with 7.5 litres of water and sprayed on walls using hand compression sprayers. Insecticide quantity is measured volumetrically through a container. METHODS: A cross-sectional study design with cluster random sampling was adopted to select 272 IRS squads of 46 blocks across 12 districts in Bihar, India. The quantity of insecticide measured by the container used by each IRS squad was recorded. RESULTS: Mean weight of insecticide measured was found to be 147 g (SD 33.9). One-thirds of squads were measuring less than the nationally recommended quantity of 125 g. Two-fifths of squads were overdosing with use of more than 150 g insecticide powder. Shoving the containers into a heap of insecticide powder resulted in heavier and less consistent measurements as compared to filling the containers from the top. Different types of measuring containers and different manufacturers of insecticide were shown to significantly account for the variation in the quantity of insecticide being measured. INTERPRETATION AND CONCLUSION: Standardization of insecticide measurement by IRS squads is needed, both to prevent under-dosing and overdosing of insecticide residue on walls. Standard operating procedures for calibrating and using uniform measuring containers should be implemented. Further, use of measuring containers may be replaced altogether with manufacturer-packaged amounts of insecticide formulation which could be directly used to prepare one-tank load of insecticide suspension.


Assuntos
Inseticidas , Leishmaniose Visceral , Estudos Transversais , Humanos , Índia/epidemiologia , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/prevenção & controle
10.
J Vector Borne Dis ; 57(2): 161-169, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-34290161

RESUMO

BACKGROUND & OBJECTIVES: Detection and treatment of post-kala-azar dermal leishmaniasis (PKDL) cases is considered important for kala-azar elimination. The objective of our study was to find out the proportion of different forms of lesions, interruption of treatment and rate of treatment completion, cure rates of PKDL, risk factors for developing severe forms of PKDL and utilization of services offered by the kala-azar elimination program. METHODS: A cross-sectional survey of PKDL patients registered for treatment at all levels of care during 2015 and 2016 was done. RESULTS: 576 PKDL patients who had started treatment in 2015 and 2016 were studied. Three-fourths of all patients were found to be clinically cured after a year of follow-up. Around 90% lesions were of macular type. Interruption of treatment was observed in one-fourth of PKDL patients. Median duration between kala-azar treatment and development of PKDL was 4.5 years. Around 79% patients had past history of kala-azar treatment. Discontinuation of treatment during earlier kala-azar episode was significantly associated with the development of papular and nodular forms of lesion. 43% of patients had received the incentive of INR 2000 after completion of treatment. Around three-fourths women in the reproductive age group were found not to use any contraceptive method during PKDL treatment. INTERPRETATION & CONCLUSION: PKDL treatment interruption should be reduced through ensuring drug supply and timely retrieval of patients. Directly observed treatment should be implemented and combination regimen should be explored to improve final cure rate. Delivery of financial incentive to PKDL patients and counselling and contraception to women of reproductive age group should be improved.


Assuntos
Antiprotozoários/uso terapêutico , Leishmaniose Cutânea/epidemiologia , Leishmaniose Visceral/complicações , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Criança , Pré-Escolar , Estudos Transversais , Doenças Endêmicas , Feminino , Humanos , Índia/epidemiologia , Lactente , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/etiologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Fosforilcolina/uso terapêutico , Fatores de Risco , Adulto Jovem
11.
Lancet ; 393(10174): 871, 2019 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-30837138
12.
Int J Dermatol ; 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38757673

RESUMO

BACKGROUND: Hyperkeratotic hand and foot dermatitis significantly affects quality of life. Some patients respond suboptimally to topical corticosteroids and have multiple recurrences. OBJECTIVE: Our aim was to compare the efficacy and safety profile of apremilast and topical corticosteroid versus corticosteroid alone in hyperkeratotic hand and foot dermatitis. METHODS: This randomized controlled study involved 77 patients treated for 3 months. Group A (39 patients) received mometasone furoate 0.1% cream with oral apremilast 30 mg twice daily, and Group B (38 patients) received mometasone alone. They were assessed monthly using the Hand Eczema Clinical Severity Index (HECSI) and Visual Analogue Scale (VAS) scores for pruritus. Investigator Global Assessment (IGA) and Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were conducted at the end of 3 months. RESULTS: The HECSI, VAS score, and QOLHEQ showed a significant decrease in both groups from baseline to the third month. Intergroup comparisons of HECSI failed to reach the significance level. When compared, patients receiving apremilast had significantly better improvement in the third month according to the Patient Global Assessment (PGA) and Investigator Global Assessment (IGA). They also had a smaller number of flares. CONCLUSION: Adding apremilast to topical corticosteroid leads to better patient and physician-perceived improvement and reduces the number of flares in hyperkeratotic hand eczema.

13.
Indian J Public Health ; 57(4): 276-9, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24351392

RESUMO

Use of Insecticide-Treated Bednets (ITNs) has been shown to reduce the incidence of mosquito-borne diseases. However, the impact of ITNs depends on its community acceptance. We studied the ITN usage and factors influencing it, following the distribution of one ITN to each family in an urban area of Puducherry. Around 93.6% of the 157 respondents surveyed were aware of mosquito-borne diseases. Coils and vaporizers were used in 91.1% of the families. Around two-fifths (41.3%) of the 116 families who received the ITNs used it regularly with another 5.1% using it irregularly. Majority of the users (85%) reported reduced mosquito bites and pleasant sleep after use. Small size of ITNs was the most common reason for non-use (46.3%). Families not using normal bed nets at the time of distribution of ITNs were unlikely to use ITNs at present (odds ratio = 5.22, P < 0.001). Therefore, ITN size should be increased and distribution in urban settings should accompany behavior change communication.


Assuntos
Mosquiteiros Tratados com Inseticida/estatística & dados numéricos , Animais , Estudos Transversais , Feminino , Humanos , Índia , Insetos Vetores , Masculino , Controle de Mosquitos , Inquéritos e Questionários
14.
ACS Omega ; 8(11): 9729-9747, 2023 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-36969402

RESUMO

Intrinsically disordered proteins (IDPs) and regions (IDRs) form a large part of the eukaryotic proteome. Contrary to the structure-function paradigm, the disordered proteins perform a myriad of functions in vivo. Consequently, they are involved in various disease pathways and are plausible drug targets. Unlike folded proteins, that have a defined structure and well carved out drug-binding pockets that can guide lead molecule selection, the disordered proteins require alternative drug-development methodologies that are based on an acceptable picture of their conformational ensemble. In this review, we discuss various experimental and computational techniques that contribute toward understanding IDP "structure" and describe representative pursuances toward IDP-targeting drug development. We also discuss ideas on developing rational drug design protocols targeting IDPs.

15.
16.
J Clin Orthop Trauma ; 38: 102125, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36866194

RESUMO

Background: We studied ankle arthrodesis with a transfibular approach using sagitally spilitted fibula as a biological plate (onlay grafting) as well as other half of fibula as morcellised local interpositional graft (inlay grafting) to achieve bony union. Material and methods: Retrospective clinico-radiological evaluation of 36 operated cases was done at 3, 6, 12 and 30 months follow-ups. Clinically union was considered once ankle became pain free on full weight bearing. Pain assessment was done by using VAS (visual analogue scale) score and functional evaluation was done by AOFAS (American Orthopaedic Foot & Ankle Society) hind foot score preoperatively and at different follow ups. Radiologically, sagittal plane ankle alignment and fusion status was determined at each follow up. Results: Mean age of patients was 40.36 ± 10.56 years (range 18-55), who were evaluated for mean duration of 33.32 ± 11.25 months (range 24-65). Thirty-three (91.7%) ankles were fused adequately and mean duration to achieve bony union was 5.09 ± 1.3 months (range 4-9 months). Mean post-operative AOFAS score at final follow up was 76.65 ± 4.87 in comparison to 45.76 ± 3.38, preoperatively. VAS score improved significantly from 7.8 (pre-operative) to 2.3 (final follow-up). Non-union in three patients (8.3%) and ankle malalignment in one patient was observed. Conclusion: Transfibular ankle arthrodesis achieves excellent bony unions and functional outcomes in severe ankle arthritis. Biologically incompetent fibula that to be judged individually by the operating surgeon to use it as a graft. Patients having inflammatory arthritis have more dissatisfaction than other aetiologies.

17.
Indian J Pediatr ; 2023 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-38060153

RESUMO

This study aimed to determine the effect of protocolized sedation using the COMFORT-B scale on the duration of mechanical ventilation (DMV). Eighty children with anticipated Duration of mechanical ventilation (DMV) >24 h admitted to the Pediatric intensive care unit (PICU) were randomized into one group that received protocolized sedation (PS) using the COMFORT behavioural (COMFORT-B) scale, and another group that received non-protocolized sedation (NPS). The primary outcome was the impact on the DMV. The DMV was significantly lower in PS (PS: 3.5 [3-7] vs. NPS group: 8.5 [4.25-13.75] d; p = 0.008). The cumulative dose and duration of fentanyl in the PS group was significantly lower (median [IQR]; 120 [62.88-279.12] vs. 320.4 [110.88-851.52] µg/kg; p = 0.007 and 4 [2.25-7.75] vs. 8 [4-17.5] d; p = 0.009, respectively). The authors found a decrease in DMV and sedation related adverse events (SRAE) like ventilator associated pneumonia (VAP), accidental extubation, post-extubation stridor and dose and duration of sedative agents with PS.

18.
Mol Phys ; 121(19-20): e2236248, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38107421

RESUMO

The aggregation of therapeutic proteins in solution has attracted significant interest, driving efforts to understand the relationship between microscopic structural changes and protein-protein interactions determining aggregation processes in solution. Additionally, there is substantial interest in being able to predict aggregation based on protein structure as part of molecular developability assessments. Molecular Dynamics provides theoretical tools to complement experimental studies and to interrogate and identify the microscopic mechanisms determining aggregation. Here we perform all-atom MD simulations to study the structure and inter-protein interaction of the Fab and Fc fragments of the monoclonal antibody (mAb) COE3. We unravel the role of ion-protein interactions in building the ionic double layer and determining effective inter-protein interaction. Further, we demonstrate, using various state-of-the-art force fields (charmm, gromos, amber, opls/aa), that the protein solvation, ionic structure and protein-protein interaction depend significantly on the force field parameters. We perform SANS and Static Light Scattering experiments to assess the accuracy of the different forcefields. Comparison of the simulated and experimental results reveal significant differences in the forcefields' performance, particularly in their ability to predict the protein size in solution and inter-protein interactions quantified through the second virial coefficients. In addition, the performance of the forcefields is correlated with the protein hydration structure.

19.
PLoS One ; 18(3): e0283263, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36972242

RESUMO

BACKGROUND: Indian Diabetic Risk Score (IDRS) and Community Based Assessment Checklist (CBAC) are easy, inexpensive, and non-invasive tools that can be used to screen people for Metabolic Syndrome (Met S). The study aimed to explore the prediction abilities of IDRS and CBAC tools for Met S. METHODS: All the people of age ≥30 years attending the selected rural health centers were screened for Met S. We used the International Diabetes Federation (IDF) criteria to diagnose the Met S. ROC curves were plotted by taking Met S as dependent variables, and IDRS and CBAC scores as independent/prediction variables. Sensitivity (SN), specificity (SP), Positive and Negative Predictive Value (PPV and NPV), Likelihood Ratio for positive and negative tests (LR+ and LR-), Accuracy, and Youden's index were calculated for different IDRS and CBAC scores cut-offs. Data were analyzed using SPSS v.23 and MedCalc v.20.111. RESULTS: A total of 942 participants underwent the screening process. Out of them, 59 (6.4%, 95% CI: 4.90-8.12) were found to have Met S. Area Under the Curve (AUC) for IDRS in predicting Met S was 0.73 (95%CI: 0.67-0.79), with 76.3% (64.0%-85.3%) sensitivity and 54.6% (51.2%-57.8%) specificity at the cut-off of ≥60. For the CBAC score, AUC was 0.73 (95%CI: 0.66-0.79), with 84.7% (73.5%-91.7%) sensitivity and 48.8% (45.5%-52.1%) specificity at the cut-off of ≥4 (Youden's Index, 2.1). The AUCs of both parameters (IDRS and CBAC scores) were statistically significant. There was no significant difference (p = 0.833) in the AUCs of IDRS and CBAC [Difference between AUC = 0.00571]. CONCLUSION: The current study provides scientific evidence that both IDRS and CBAC have almost 73% prediction ability for Met S. Though CBAC holds relatively greater sensitivity (84.7%) than IDRS (76.3%), the difference in prediction abilities is not statistically significant. The prediction abilities of IDRS and CBAC found in this study are inadequate to qualify as Met S screening tools.


Assuntos
Diabetes Mellitus , Síndrome Metabólica , Humanos , Adulto , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Lista de Checagem , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/prevenção & controle , Fatores de Risco , Curva ROC , Medição de Risco
20.
Disaster Med Public Health Prep ; 16(5): 2129-2133, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-34384516

RESUMO

Modeling studies indicate that the closure of schools during the coronavirus disease (COVID-19) pandemic may not be well grounded for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as evidences indicate that children are less affected by this virus, and the clinical attack rates in the 0-19 age group are low. Experts also opine that school closures might have negative effects on the scholastic abilities of children and also an adverse impact on the economy and health care system, considering the responsibilities conferred upon the parents. Also, in a developing country like India, it is difficult for the rural population to afford distance online learning, which brings into importance the reopening of schools in a safe environment to avoid adversities such as increased drop-outs in the upcoming academic year, loss of in-person benefits such as mid-day meal scheme. This study highlights a field experience in relation to readiness assessment of a rural school in the Jodhpur district of Rajasthan, India, for a safe reopening to accept students in a safe and conducive atmosphere, which shall help prevent transmission of the virus in the schools among the children. In this regard, an indigenous readiness checklist has been developed to achieve the purpose, which assesses the readiness in 3 domains: (1) procedural readiness; (2) supplies, sanitation, and infrastructure-related; and (3) education and training.


Assuntos
COVID-19 , Pandemias , Criança , Humanos , Pandemias/prevenção & controle , SARS-CoV-2 , COVID-19/epidemiologia , COVID-19/prevenção & controle , Índia/epidemiologia , Instituições Acadêmicas
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