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AZD1222 (ChAdOx1 nCoV-19) is a replication-deficient adenoviral vectored coronavirus disease-19 (COVID-19) vaccine that is manufactured as SII-ChAdOx1 nCoV-19 by the Serum Institute of India Pvt Ltd following technology transfer from Oxford University/AstraZeneca. The non-inferiority of SII-ChAdOx1 nCoV-19 with AZD1222 was previously demonstrated in an observer-blind, phase 2/3 immuno-bridging study (trial registration: CTRI/2020/08/027170). In this analysis of immunogenicity and safety data 6 months post first vaccination (Day 180), 1,601 participants were randomized 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (immunogenicity/reactogenicity cohort n = 401) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort n = 1,200). Immunogenicity was measured by anti-severe acute respiratory syndrome coronavirus 2 spike (anti-S) binding immunoglobulin G and neutralizing antibody (nAb) titers. A decline in anti-S titers was observed in both vaccine groups, albeit with a greater decline in SII-ChAdOx1 nCoV-19 vaccinees (geometric mean titer [GMT] ratio [95% confidence interval (CI) of SII-ChAdOx1 nCoV-19 to AZD1222]: 0.60 [0.41-0.87]). Consistent similar decreases in nAb titers were observed between vaccine groups (GMT ratio [95% CI]: 0.88 [0.44-1.73]). No cases of severe COVID-19 were reported following vaccination, while one case was observed in the placebo group. No causally related serious adverse events were reported through 180 days. No thromboembolic or autoimmune adverse events of special interest were reported. Collectively, these data illustrate that SII-ChAdOx1 nCoV-19 maintained a high level of immunogenicity 6 months post-vaccination. SII-ChAdOx1 nCoV-19 was safe and well tolerated.
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COVID-19 , ChAdOx1 nCoV-19 , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , Estudios de Seguimiento , COVID-19/prevención & control , Inmunoglobulina G , Inmunogenicidad Vacunal , Anticuerpos AntiviralesRESUMEN
OBJECTIVE: To determine the clinical manifestations, risk factors, treatment modalities and maternal outcomes in pregnant women with lab-confirmed COVID-19 and compare it with COVID-19 negative pregnant women in same age group. DESIGN: Multicentric case-control study. DATA SOURCES: Ambispective primary data collection through paper-based forms from 20 tertiary care centres across India between April and November 2020. STUDY POPULATION: All pregnant women reporting to the centres with a lab-confirmed COVID-19 positive result matched with controls. DATA QUALITY: Dedicated research officers extracted hospital records, using modified WHO Case Record Forms (CRF) and verified for completeness and accuracy. STATISTICAL ANALYSIS: Data converted to excel files and statistical analyses done using STATA 16 (StataCorp, TX, USA). Odds ratios (ORs) with 95% confidence intervals (CI) estimated using unconditional logistic regression. RESULTS: A total of 76,264 women delivered across 20 centres during the study period. Data of 3723 COVID positive pregnant women and 3744 age-matched controls was analyzed. Of the positive cases 56·9% were asymptomatic. Antenatal complications like preeclampsia and abruptio placentae were seen more among the cases. Induction and caesarean delivery rates were also higher among Covid positive women. Pre-existing maternal co-morbidities increased need for supportive care. There were 34 maternal deaths out of the 3723(0.9%) positive mothers, while covid negative deaths reported from all the centres were 449 of 72,541 (0·6%). CONCLUSION: Covid-19 infection predisposed to adverse maternal outcomes in a large cohort of Covid positive pregnant women as compared to the negative controls.
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Desprendimiento Prematuro de la Placenta , COVID-19 , Embarazo , Humanos , Femenino , COVID-19/epidemiología , Estudios de Casos y Controles , India/epidemiología , MadresRESUMEN
BACKGROUND: This phase 2/3 immunobridging study evaluated the safety and immunogenicity of the ChAdOx1 nCoV-19 Coronavirus Vaccine (Recombinant) (SII-ChAdOx1 nCoV-19), manufactured in India at the Serum Institute of India Pvt Ltd (SIIPL), following technology transfer from the AstraZeneca. METHODS: This participant-blind, observer-blind study randomised participants 3:1 to SII-ChAdOx1 nCoV-19 or AZD1222 (ChAdOx1 nCoV-19) (immunogenicity/reactogenicity cohort) and 3:1 to SII-ChAdOx1 nCoV-19 or placebo (safety cohort). The study participants were enrolled from 14 hospitals across India between August 25 and October 31, 2020. Two doses of study products were given 4 weeks apart. The primary objectives were to demonstrate non-inferiority of SII-ChAdOx1 nCoV-19 to AZD1222 in terms of geometric mean titre (GMT) ratio of anti-SARS-CoV-2 spike IgG antibodies 28 days after the second dose (defined as lower limit of 95% CI >0·67) and to determine the incidence of serious adverse events (SAEs) causally related to SII-ChAdOx1 nCoV-19. The anti-spike IgG response was assessed using a multiplexed electrochemiluminescence-based immunoassay. Safety follow-up continued until 6 months after first dose. Trial registration: CTRI/2020/08/027170. FINDINGS: 1601 participants were enrolled: 401 to the immunogenicity/reactogenicity cohort and 1200 to the safety cohort. After two doses, seroconversion rates for anti-spike IgG antibodies were more than 98·0% in both the groups. SII-ChAdOx1 nCoV-19 was non-inferior to AZD1222 (GMT ratio 0·98; 95% CI 0·78-1·23). SAEs were reported in ≤ 2·0% participants across the three groups; none were causally related. A total of 34 SARS-CoV-2 infections were reported; of which 6 occurred more than 2 weeks after the second dose; none were severe. INTERPRETATION: SII-ChAdOx1 nCoV-19 has a non-inferior immune response compared to AZD1222 and an acceptable safety/reactogenicity profile. Pharmacovigilance should be maintained to detect any safety signals. FUNDING: SIIPL funded the contract research organisation and laboratory costs, while the site costs were funded by the Indian Council of Medical Research. The study vaccines were supplied by SIIPL and AstraZeneca.
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The WHO-UNICEF nurturing care framework (NCF) for early childhood development provides a roadmap for action, focusing on pregnancy and the first three years of life. It emphasizes the need to invest in capacity building and empowerment of service providers, families and communities to create a conducive environment that promotes child development. We describe our experience of implementing nurturing care interventions, beginning with a pilot project in Maharashtra covering a population of 10000 to and scaling it up to a model called Aarambh (the beginning), catering to a population of 1,500,000. Opportunities available within the existing services across multiple sectors were used; Integrated Child Development Services (ICDS) scheme, the health sector, and others. It utilized multiple approaches for promoting NCF within families; home visits by frontline workers (FLWs), mothers' meetings, growth monitoring and promotion sessions, and community-based events as key opportunities. Joint training for FLWs, establishing supervisors of FLWs as their trainers, and an interactive training curriculum were critical elements identified for the success of the model. An environment of appreciation for the FLWs and their supervisors helped build their confidence and helped them own the interventions.
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Creación de Capacidad , Desarrollo Infantil , Niño , Preescolar , Femenino , Humanos , India , Madres , Proyectos Piloto , EmbarazoRESUMEN
Aims: The present study was carried out for comparative evaluation of case-based learning (CBL) aided with WhatsApp and didactic lectures (DL) while teaching a pathology topic to second-year medical students. In addition, the acceptability of WhatsApp as an aid to CBL was assessed. Material and Methods: After obtaining informed consent, 70 second-year Bachelor of Medicine and Bachelor of Surgery (MBBS) students were exposed to six sessions of CBL aided by case scenarios for one set of topics of anemia posted on WhatsApp groups. This was followed by six sessions of DL for separate set of topics in anemia. The multiple-choice questions (MCQ) test scores obtained pre and postintervention, of CBL and DL sessions, were compared to paired t-test (within the groups) and Student's t-test (between the groups). Categorical data were analyzed using Chi-square (χ2) test. Student's self-administered questionnaires and focus group discussions (FGDs) were used to collect student perceptions and analyzed quantitatively, as well as qualitatively. Results: The mean MCQ scores obtained postintervention in CBL topics were significantly higher compared to DL (22.78 ± 2.99 vs 17.78 ± 3.35; P < 0.001). Students perceived that CBL enhanced their curiosity; hence, the acquired knowledge through various resources was retained better. It enhanced their analytical skills and interest in learning pathology. In FGDs, the students appreciated the use of WhatsApp as an aid to CBL for its ease of sharing scenario-related additional information and prior discussions among themselves in chat groups at their convenience. Conclusion: CBL aided by WhatsApp helped students acquire knowledge, discuss and learn actively, score more, and retain better than DL. Using WhatsApp as a platform helped them to interact at their ease and seek guidance from their mentors without resistance and hesitation.
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Competencia Clínica , Instrucción por Computador/métodos , Educación de Pregrado en Medicina/métodos , Aprendizaje , Aplicaciones Móviles , Patología/educación , Teléfono Inteligente , Red Social , Estudiantes de Medicina/psicología , Adulto , Femenino , Humanos , Masculino , Aplicaciones Móviles/estadística & datos numéricos , Sistemas en Línea , EnseñanzaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Mesenchymal stem cells (MSCs) are multipotent stem cells possessing regenerative potential. Symphytum officinale (SO) is a medicinal plant and in homoeopathic literature, believed to accelerate bone healing. AIM OF THE STUDY: This study aimed to determine if homoeopathic doses of SO could augment osteogenesis in MSCs as they differentiate into osteoblasts in vitro. MATERIALS AND METHODS: Bone marrow samples were obtained from patients who underwent bone grafting procedures (nâ¯=â¯15). MSCs were isolated, expanded and characterized by flow cytometry (CD90, CD105). Cytotoxicity of SO was evaluated by MTT assay. Osteogenic differentiation was induced in MSCs with ß-glycerophosphate, ascorbic acid and dexamethasone over 2 weeks. Different homoeopathic doses of SO (MT, 3C, 6C, 12C and 30C) were added to the basic differentiation medium (BDM) and efficiency of MSCs differentiating into osteoblasts were measured by evaluating expression of Osteocalcin using flow cytometry, and alkaline phosphatase activity using ELISA. Gene expression analyses for osteoblast markers (Runx-2, Osteopontin and Osteocalcin) were evaluated in differentiated osteoblasts using qPCR. RESULTS: Flow cytometry (CD90, CD105) detected MSCs isolated from bone marrow (93-98%). MTT assay showed that the selected doses of SO did not induce any cytotoxicity in MSCs (24â¯hours). The efficiency of osteogenic differentiation (2 weeks) for different doses of Symphytum officinale was determined by flow cytometry (nâ¯=â¯10) for osteoblast marker, Osteocalcin, and most doses of Symphytum officinale enhanced osteogenesis. Interestingly, gene expression analysis for Runx-2 (nâ¯=â¯10), Osteopontin (nâ¯=â¯10), Osteocalcin (nâ¯=â¯10) and alkaline phosphatase activity (nâ¯=â¯8) also showed increased osteogenesis with the addition of Symphytum officinale to BDM, specially mother tincture. CONCLUSIONS: Our findings suggest that homoeopathic dose (specially mother tincture) of Symphytum officinale has the potential to enhance osteogenesis.
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Conservadores de la Densidad Ósea/farmacología , Diferenciación Celular/efectos de los fármacos , Consuelda , Homeopatía , Células Madre Mesenquimatosas/efectos de los fármacos , Osteoblastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Extractos Vegetales/farmacología , Fosfatasa Alcalina/metabolismo , Conservadores de la Densidad Ósea/aislamiento & purificación , Diferenciación Celular/genética , Línea Celular , Consuelda/química , Subunidad alfa 1 del Factor de Unión al Sitio Principal/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica , Humanos , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteocalcina/genética , Osteocalcina/metabolismo , Osteogénesis/genética , Osteopontina/genética , Osteopontina/metabolismo , Fenotipo , Extractos Vegetales/aislamiento & purificaciónAsunto(s)
Salud/historia , Población Rural , Factores Socioeconómicos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , IndiaRESUMEN
BACKGROUND: A lyophilized bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, Rotasiil®) was licensed in 2016. A liquid formulation of this vaccine (LBRV-PV, Rotasiil - Liquid) was subsequently developed and was tested for non-inferiority to Rotasiil® and for lot-to-lot consistency. METHODS: This Phase II/III, open label, randomized study was conducted at seven sites across India from November 2017 to June 2018. Participants were randomized into four arms; Lots A, B, and C of LBRV-PV and Rotasiil® in 1:1:1:1 ratio. Three doses of study vaccines were given at 6, 10, and 14â¯weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. Non-inferiority of LBRV-PV to Rotasiil was proven if the lower limit two-sided 95% confidence interval (CI) of geometric mean concentration (GMC) ratio was at least 0.5. Lot-to-lot consistency was proven if 95% CI of the GMC ratios of three lots were between 0.5 and 2. Solicited reactions were collected by using diary cards. RESULTS: Of the 1500 randomized infants, 1436 infants completed the study. The IgA GMC ratio of LBRV-PV to Rotasiil® was 1.19 (95% CI 0.96, 1.48). The corresponding IgA seropositivity rates were 60.41% (57.41, 63.35) and 52.75% (47.48, 57.97). The IgA GMC ratios among the three LBRV-PV lots were: Lot A versus Lot B: 1.34 (1.03, 1.75); Lot A versus Lot C: 1.22 (0.93, 1.60); and Lot B versus Lot C: 0.91 (0.69, 1.19). The 95% CIs for the GMC ratios were between 0.69 and 1.75. The incidence of solicited reactions was comparable across the four arms. Only one serious adverse event of gastroenteritis event in the Rotasiil® group was causally related. CONCLUSION: The immunological non-inferiority of LBRV-PV against Rotasiil® as well as lot-to-lot consistency of LBRV-PV was demonstrated. LBRV-PV had safety profile similar to Rotasiil®. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov [NCT03474055] and Clinical Trial Registry of India [CTRI/2017/10/010104].
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Gastroenteritis/prevención & control , Inmunogenicidad Vacunal , Virus Reordenados/inmunología , Infecciones por Rotavirus/prevención & control , Vacunas contra Rotavirus/inmunología , Rotavirus/inmunología , Factores de Edad , Animales , Anticuerpos Antivirales/inmunología , Bovinos , Femenino , Humanos , India , Lactante , Masculino , Evaluación de Resultado en la Atención de Salud , Vacunas contra Rotavirus/administración & dosificación , Vacunas contra Rotavirus/efectos adversos , Vacunas contra Rotavirus/normas , VacunaciónRESUMEN
OBJECTIVE: To review the Mid-upper arm circumference (MUAC) cut-off currently being used to identify Severe Acute Malnutrition (SAM) as currently defined using Weight-for-Height. METHODS: Cross-sectional study conducted in 24 villages of a Primary Health Centre in Wardha district of Maharashtra among 2650 children between the ages of 6 to 59 months. RESULTS: For identifying SAM, sensitivity of MUAC was 23.5% and specificity was 99.7% for cut-off <11.5 cm. Using Youden index, best Mid-upper arm circumference cut-off point to identify SAM was <13 cm with sensitivity of 74.5% and specificity of 92.7%. Using Receiver operating characteristics curve, best MUAC cut-off point was 12.8 cm with 74.5% sensitivity and 92.7% specificity. Area under curve was 0.88 (95%CI: 0.85-0.91). CONCLUSION: The current MUAC cut-off of <11.5 cm for detecting SAM needs to be increased to ensure that children, who need referral for management of malnutrition, are not missed.
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Antropometría/métodos , Brazo/anatomía & histología , Desnutrición Aguda Severa/diagnóstico , Preescolar , Femenino , Humanos , India , Lactante , Masculino , Curva ROC , Población RuralRESUMEN
BACKGROUND: Necrotising enterocolitis (NEC) is one of the most common life-threatening emergencies of the gastrointestinal tract in preterm neonates. The present study aimed to determine the efficacy of oropharyngeal colostrum with respect to reducing NEC in preterm neonates. METHODS: A literature search was conducted for various randomised control trials by searching the Cochrane Central Register of Controlled Trials, PubMed, EMBASE and ongoing clinical trials. Randomised or quasi-randomised trials comparing oropharyngeal colostrum versus placebo in neonates (birthweight ≤ 1500 g or gestational age ≤ 32 weeks) were included in the review. The methodological quality of each trial was independently reviewed by the authors. For categorical and continuous variables, typical estimates for relative risk and typical estimates for weighted mean difference were calculated, respectively. A random effect model was assumed for meta-analysis. RESULTS: In total, four eligible trials were included in the review. Oropharyngeal colostrum therapy was not associated with a statistically significant reduction in the incidence of NEC stage ≥2 [typical relative risk (RR) = 0.64; 95% confidence interval (CI) = 0.27-1.49], mortality from any cause (typical RR = 0.86; 95% CI = 0.15-4.80) and time to reach full feed [typical weighted mean difference (WMD) = -3.26; 95% CI = -8.87 to 2.35]. Duration of hospital stay was significantly less in the control group (typical WMD = 9.77; 95% CI = 3.96-15.59). CONCLUSIONS: The current evidence is insufficient for recommending oropharyngeal colostrum as a routine clinical practice in the prevention of NEC. We emphasise the need for large randomised controlled trials with an adequate sample size and validated clinical outcomes in preterm neonates.
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Calostro/inmunología , Enterocolitis Necrotizante/prevención & control , Inmunoterapia/métodos , Recién Nacido de muy Bajo Peso/inmunología , Enterocolitis Necrotizante/epidemiología , Femenino , Humanos , Incidencia , Recién Nacido , Tiempo de Internación , Masculino , Orofaringe/inmunología , Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del TratamientoRESUMEN
Lymphatic filariasis (LF) affects 73 countries, causes morbidity and impedes socioeconomic development. We had found no difference in safety and micro (Mf) and macro filarial action of single-dose diethylcarbamazine (DEC) and DEC + albendazole (ABZ) in an F01 study done in India (year 2000). There was a programmatic need to evaluate safety and efficacy of multiple annual treatments (F02). Subjects (155) from the F01 study, meeting inclusion-exclusion criteria, were enrolled in F02 and treated with further two annual doses of DEC or DEC + ABZ. Efficacy was evaluated for Mf positivity by peripheral smear (PS) and nucleopore (NP) filter, circulating filarial antigen (CFA) and filarial dance sign (FDS) positivity and Mf count at yearly follow-up. Safety was assessed for 5 days after drug administration. Total of 139 subjects evaluated for efficacy (69 DEC and 70 DEC + ABZ group). Mf positivity prevalence declined progressively by 95% (PS), 66% (NP), and 95% (PS) and 86% (NP); CFA positivity prevalence declined by 15% and 9%; FDS by 100% each; Mf count declined by 75.5 and 76.9% with three annual treatment of DEC and DEC + ABZ, respectively. Addition of ABZ did not show any advantage over DEC given as three annual rounds for LF. DEC and DEC + ABZ were well tolerated. There was no correlation between result of CFA and FDS, (both claimed to be indicative of adult worm). Analysis of published studies and our data indicate that macrofilaricidal effect of DEC/DEC + ABZ may be seen in children and not adults, with three or more annual dosing.
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Albendazol/uso terapéutico , Dietilcarbamazina/uso terapéutico , Filariasis Linfática/tratamiento farmacológico , Filaricidas/uso terapéutico , Wuchereria bancrofti , Adulto , Albendazol/administración & dosificación , Albendazol/efectos adversos , Animales , Antígenos Helmínticos/sangre , Dietilcarbamazina/administración & dosificación , Dietilcarbamazina/efectos adversos , Método Doble Ciego , Esquema de Medicación , Quimioterapia Combinada , Filariasis Linfática/epidemiología , Femenino , Filaricidas/administración & dosificación , Filaricidas/efectos adversos , Humanos , India/epidemiología , Estudios Longitudinales , Masculino , Prevalencia , Wuchereria bancrofti/inmunologíaRESUMEN
BACKGROUND: New permanent contraceptive methods are in development, including nonsurgical permanent contraception (NSPC). OBJECTIVE: In the present study, perceptions of NSPC in India among married women, married men, mothers-in-law, providers, and health advocates in Eastern Maharashtra (Wardha district) and New Delhi were examined. METHODS: We conducted semi-structured interviews with 40 married women and 20 mothers-in-law; surveys with 150 married men; and focus group discussions with obstetrics/gynecology providers and advocates. Transcripts were coded and analyzed using a grounded theory approach, where emerging themes are analyzed during the data collection period. RESULTS: The majority of female respondents expressed support of permanent contraception and interest in NSPC, stating the importance of avoiding surgery and minimizing recovery time. They expressed concerns about safety and efficacy; many felt that a confirmation test would be necessary regardless of the failure rate. Most male respondents were supportive of female permanent contraception (PC) and preferred NSPC to a surgical method, as long as it was safe and effective. Providers were interested in NSPC yet had specific concerns about safety, efficacy, cost, uptake, and government pressure. They also had concerns that a nonsurgical approach could undermine the inherent seriousness of choosing PC. Advocates were interested in NSPC but had concerns about safety and potential misuse in the Indian context. CONCLUSION: Although perceptions of NSPC were varied, all study populations indicated interest in NSPC. Concerns about safety, efficacy, appropriate patient counseling, and ethics emerged from the present study and should be considered as NSPC methods continue to be developed.
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Actitud del Personal de Salud , Anticoncepción/métodos , Anticoncepción/psicología , Conocimientos, Actitudes y Práctica en Salud , Adulto , Femenino , Grupos Focales , Teoría Fundamentada , Humanos , India , Entrevistas como Asunto , MasculinoRESUMEN
AIM: To evaluate the imaging characteristics of biliary complications following liver transplantation on magnetic resonance cholangiopancreatography (MRCP) and its diagnostic accuracy in comparison with direct cholangiography. MATERIAL AND METHODS: In this prospective study, 34 patients being evaluated for possible biliary complications after living-donor liver transplantation (LDLT) with abnormal MRCP findings were followed up for information regarding direct cholangiography either endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) within 7 days of MRCP. Twenty-nine patients underwent ERCP and five patients underwent PTC. RESULTS: Compared to findings at direct cholangiography, MRCP presented 96.9% sensitivity, 96.9% positive predictive value, and 94.1% accuracy for the detection of biliary complications. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for detection of anastomotic strictures, biliary leak, and biliary stone or sludge on MRCP was found to be 100%, 84.6%, 91.3%, 100% and 94.1%; 72.7%, 95.7%, 88.9%, 88% and 88.2%; 80%, 100%, 100%, 96.7% and 97.1%, respectively. CONCLUSION: MRCP is a reliable non-invasive technique to evaluate the biliary complications following LDLT. MRCP should be the imaging method of choice for diagnosis in this setting and direct cholangiography should be reserved for cases that need therapeutic interventions.
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Enfermedades de las Vías Biliares/diagnóstico por imagen , Colangiografía , Pancreatocolangiografía por Resonancia Magnética , Trasplante de Hígado , Complicaciones Posoperatorias/diagnóstico por imagen , Adulto , Anciano , Femenino , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Activity of both c-Jun and cyclin D1 is deemed critical for melanoma cell proliferation. This functionality is corroborated by frequently elevated expression and activity of these proteins in human melanomas. Correspondingly, alleviating c-Jun and cyclin D1 function is vital to the success of antimelanoma therapeutics. OBJECTIVES: To understand the role of the c-Jun N-terminal kinase (JNK) signalling pathway in melanoma cell proliferation and survival. METHODS: The effect of JNK inhibitors SP600125 and JNK-IN-8 on the proliferation and survival of genetically highly representative human melanoma cell lines was studied in assays of proliferation and apoptosis. Changes in c-Jun and cyclin D1 protein and mRNA levels in response to JNK and mitogen-activated protein kinase kinase (MEK) inhibition were investigated through immunoblotting and quantitative reverse-transcription polymerase chain reaction. The effects of JNK and MEK inhibitors on cell-cycle distribution were assessed by flow cytometry. RESULTS: We demonstrate the requirement of JNK signalling in melanoma cell proliferation and survival. While JNK inhibition suppressed the expression and activity of c-Jun, it failed to suppress cyclin D1 levels. Consistently with its inability to downregulate cyclin D1, JNK inhibition failed to induce G1 arrest. In contrast, the blockade of MEK-extracellular signal-regulated kinase (ERK) signalling, although unable to suppress c-Jun activity and expression, paradoxically abated cyclin D1 levels and triggered G1 arrest. This previously unreported dual disconnect between JNK-cyclin D1 and ERK-c-Jun levels was confirmed by concomitant JNK and BRAF inhibition, which suppressed both c-Jun and cyclin D1 levels and exhibited a heightened antiproliferative response. CONCLUSIONS: Dual disjunction between JNK-cyclin D1 and ERK-c-Jun signalling forms the basis for further investigation of combined JNK and MAPK signalling blockade as a more effective therapeutic approach in human melanoma.
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Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Melanoma/mortalidad , Neoplasias Cutáneas/mortalidad , Antracenos/farmacología , Proliferación Celular , Ciclina D1/metabolismo , Humanos , Melanoma/patología , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/fisiología , Neoplasias Cutáneas/patología , Células Tumorales CultivadasRESUMEN
MITF (microphthalmia-associated transcription factor) is a frequently amplified lineage-specific oncogene in human melanoma, whose role in intrinsic drug resistance has not been systematically investigated. Utilizing chemical inhibitors for major signaling pathways/cellular processes, we witness MITF as an elicitor of intrinsic drug resistance. To search kinase(s) targets able to bypass MITF-conferred drug resistance, we employed a multi-kinase inhibitor-directed chemical proteomics-based differential affinity screen in human melanocytes carrying ectopic MITF overexpression. A subsequent methodical interrogation informed mitotic Ser/Thr kinase Aurora Kinase A (AURKA) as a crucial regulator of melanoma cell proliferation and migration, independent of the underlying molecular alterations, including TP53 functional status and MITF levels. Crucially, assessing the efficacy of investigational AURKA inhibitor MLN8237, we pre-emptively witness the procurement of a molecular program consistent with acquired drug resistance. This involved induction of multiple MAPK (mitogen-activated protein kinase) signaling pathway components and their downstream proliferation effectors (Cyclin D1 and c-JUN) and apoptotic regulators (MITF and Bcl-2). A concomitant AURKA/BRAF and AURKA/MEK targeting overcame MAPK signaling activation-associated resistance signature in BRAF- and NRAS-mutated melanomas, respectively, and elicited heightened anti-proliferative activity and apoptotic cell death. These findings reveal a previously unreported MAPK signaling-mediated mechanism of immediate resistance to AURKA inhibitors. These findings could bear significant implications for the application and the success of anti-AURKA approaches that have already entered phase-II clinical trials for human melanoma.
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Apoptosis , Aurora Quinasa A/metabolismo , Resistencia a Antineoplásicos , Melanoma/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Transducción de Señal , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Azepinas/farmacología , Línea Celular Tumoral , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/patología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Factor de Transcripción Asociado a Microftalmía/genética , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Pirimidinas/farmacología , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
PURPOSE: Glomus tumours are benign, vascular neoplasms arising from glomus body and are often found near the fingertips. Complete surgical excision of the tumour must be ensured to avoid its recurrence. Several surgical approaches for its excision have been described in the literature; however, most of the approaches are associated with nail deformity in the post-operative period or fail to offer a complete exposure of the tumour. We wish to share our experience with our described nail-preserving modified lateral subperiosteal approach, where on account of the distal curve over the pulp tip, we achieve a large flap yielding an excellent exposure of the tumour mass. METHODS: We retrospectively evaluated 30 patients with subungual glomus tumour who were operated using this approach at a mean follow-up of 35.33 months. All patients were assessed for relief in the pre-operative symptoms, nail deformity, recurrence or any other complications. RESULTS: All wounds healed well without any possible wound complications such as wound dehiscence, suture margin necrosis or infection. At the end of the follow-up, all patients were relieved of the pre-operative symptoms. There was no evidence of deformity of nail or fingertip. No patient had recurrence. All the operated fingers were functionally normal. CONCLUSIONS: Nail-preserving modified lateral subperiosteal approach does not damage the nail bed or interosseous supports to the distal phalanx. It is a very simple, less time-consuming approach for the resection of subungual tumours, and we would like to recommend it to our fellow orthopaedic surgeons.
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Tumor Glómico/cirugía , Enfermedades de la Uña/cirugía , Uñas , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: Fracture union is a complex biological process, which depends upon several systemic and local factors. Disturbance of any of these factors may lead to nonunion of the fracture. These nonunions have a huge impact on quality of life as well as socioeconomical aspects. The platelets on activation release a number of growth factors and differentiation factors, which play important role in fracture healing. This study aimed to look for efficacy of platelet-rich plasma in the treatment of established fracture nonunions of long bones. METHODS: A total of 94 patients with established nonunion of long bone (35 tibia, 30 femur, 11 humerus, 4 radius, 12 ulna, 2 with both radius and ulna) were included in this study. We injected 15-20 ml of autologous platelet-rich plasma (>2,000,000 platelets/µl) under image intensifier at each nonunion site. The fracture union was evaluated clinically and radiologically regularly at monthly interval till 4 months. RESULTS: Eighty-two patients had their fracture united at the end of 4 months. Thirty-four patients showed bridging trabeculae on X-rays at the end of 2 months, while 41 patients showed bridging trabeculae at the end of third month. Twelve patients did not show any attempt of union at 4 months and were labeled as failure of treatment. There were no complications. CONCLUSION: Platelet-rich plasma is a safe and effective treatment for the treatment of nonunions. More studies are needed to look into molecular mechanism of this fracture healing acceleration by platelet-rich plasma.
Asunto(s)
Fracturas Óseas/terapia , Fracturas no Consolidadas/terapia , Satisfacción del Paciente , Plasma Rico en Plaquetas , Calidad de Vida , Femenino , Fracturas del Fémur/terapia , Estudios de Seguimiento , Curación de Fractura , Fracturas Óseas/diagnóstico por imagen , Fracturas no Consolidadas/diagnóstico por imagen , Humanos , Fracturas del Húmero/terapia , Inyecciones Subcutáneas , Masculino , Estudios Prospectivos , Fracturas del Radio/terapia , Fracturas de la Tibia/terapia , Resultado del Tratamiento , Fracturas del Cúbito/terapiaRESUMEN
OBJECTIVES: To assess the effect of the probiotic VSL#3 in prevention of neonatal sepsis in low birthweight (LBW) infants. DESIGN: Randomised, double-blind, placebo-controlled trial. SETTING: Community setting in rural India. PARTICIPANTS: LBW infants aged 3-7â days. INTERVENTIONS: Infants were randomised to receive probiotic (VSL#3, 10 billion colony-forming units (cfu)) or placebo for 30â days, and were followed up for 2â months. MAIN OUTCOME MEASURE: Possible serious bacterial infection (PSBI) as per the Integrated Management of Neonatal Childhood Illnesses algorithm, as diagnosed by fieldworkers/physicians. RESULTS: 668 infants were randomised to VSL#3 and 672 to placebo. By intention-to-treat analysis, the risk of PSBI among infants in the overall population of LBW infants was not statistically significant (RR 0.79 (95% CI 0.56 to 1.03)). Probiotics reduced median days of hospitalisation (6â days vs 3â days in probiotics) (p=0.018) but not the risk of hospitalisation (RR 0.66 (95% CI 0.42 to 1.04). The onset of PSBI in 10% of infants occurred on the 40th day in the probiotics arm versus the 25th day in the control arm (p=0.063). CONCLUSIONS: Daily supplementation of LBW infants with probiotics VSL#3 (10 billion cfu) for 30â days led to a non-significant 21% reduction in risk of neonatal sepsis. A larger study with sufficient power and a more specific primary end point is warranted to confirm the preventive effect of VSL#3 on neonatal sepsis in LBW infants. TRIAL REGISTRATION NUMBER: The study is registered at the Clinical Trial Registry of India (CTRI/2008/091/000049).
Asunto(s)
Infecciones Bacterianas/epidemiología , Heces/microbiología , Recién Nacido de Bajo Peso , Probióticos/administración & dosificación , Sepsis/prevención & control , Método Doble Ciego , Femenino , Humanos , India , Recién Nacido , Estimación de Kaplan-Meier , Masculino , Probióticos/efectos adversos , Probióticos/clasificación , Resultado del TratamientoRESUMEN
Hepatitis B and Haemophilus influenzae type b (Hib) infections are major public health problems in developing countries, including India. Hence, combination vaccines containing DTwP, recombinant hepatitis B and Hib conjugate vaccines have been developed. Here, we report a Phase IV study which assessed safety and reactogenicity of a new DTwP-HepB+Hib vaccine. Three doses of DTwP-HepB+Hib vaccine (Pentavac, Serum Institute of India Ltd) or Tritanrix-HB+Hib (GlaxoSmithKline Beecham) were administered to infants at 6, 10 and 14 weeks of age in 2:1 ratio. The subjects were followed till one month after the third dose for safety assessment. Adverse events were captured in structured diaries and physical examinations were performed on each visit. The study was conducted in 1510 infants. Both vaccines caused injection site local and systemic reactions and the incidence was similar in both the groups. The incidence of local solicited reactions was: tenderness 35.9 %-33.6 %; redness 18.1 %-17.2 %; swelling 23.7 %-22.4 %; induration 12.8 % -13.7 %. The percentage of systemic solicited reactions were: diarrhea 2.2 %-2.2 %; drowsiness 3.3 %-3.4 %; fever 14.0 %-11.2 %; irritability 28.1 %-25.4 %; loss of appetite 6.6 %-5.6 %; persistent crying 17.7 %-15.7 %; vomiting 3.5 %-3.0 %. No serious adverse event was caused by the vaccines. The new DTwP-HepB+Hib combination vaccine showed similar safety profile to that of an imported vaccine in Indian infants.