RESUMEN
Germline mutations of homologous-recombination (HR) genes are among the top contributors to medulloblastomas. A significant portion of human medulloblastomas exhibited genomic signatures of HR defects. We asked whether ablation of Brca2, Palb2, and their related Brca1 and Bccip genes, in the mouse brain can differentially initiate medulloblastomas. We established conditional knockout mouse models of these HR-genes, and a conditional knockdown of Bccip (shBccip-KD). Deletion of any of these genes led to microcephaly and neurological defects, with Brca1- and Bccip- producing the worst. Trp53 co-deletion significantly rescued the microcephaly with Brca1, Palb2, and Brca2 deficiency, but it exhibited limited impact on Bccip- mice. For the first time, inactivation of either Brca1 or Palb2 with Trp53 was found to induce medulloblastomas. Bccip/Trp53 deletions failed, despite that shBccip-CKD was highly penetrative, to induce medulloblastomas. The tumors displayed diverse immunohistochemical features and chromosome copy number variation. While there were widespread upregulations of cell proliferative pathways, most of the tumors expressed biomarkers of the Sonic Hedgehog subgroup. The MBs developed from Brca1-, Palb2-, and Brca2- mice were highly sensitive to a PARP inhibitor, but not the ones from shBccip-CKD mice. Our models recapitulate the spontaneous medulloblastoma development with high penetrance and narrow time-window, providing ideal platforms to test therapeutic agents with the ability to differentiate HR defective and proficient tumors.
RESUMEN
BACKGROUND: The clinical spectrum of Cerebral palsy (CP) can differ in various places depending upon knowledge of the people and resources for prevention, diagnosis and management. Although studied extensively in high-resource countries, adequate data related to CP from resource-constraint settings are lacking. This study aims to describe the profile of children with CP at a tertiary care center in eastern Nepal. METHODS: This was a hospital-based cross-sectional descriptive study done from 2017 to 2018. Children 6 months to 15 years who presented with CP were enrolled and their clinical details recorded and described. RESULTS: Amongst 110 children with CP, 74.54% were male. Majority (76.36%) were 5 years or below with the median age being 3(2.00-4.75) years. Children with spastic quadriplegia (44.44%) and Gross Motor Function Classification System level III (41.81%) were most common. Etiologically, perinatal factors (64.54%) like perinatal asphyxia (35.45%) and prematurity (20.90%) and postnatal infections (25.45%) were common. The common comorbidities were intellectual disability (71.81%) and epilepsy (66.36%). The main treatment modalities were: antiepileptics (59.09%) and centre-based physiotherapy sessions (35.45%). School education was provided in 23.07% with special education in 11.53%. CONCLUSIONS: This study describes the profile of CP at our centre in eastern Nepal. Predominance of perinatal complications and postnatal infections points towards the urgent need to further improve the perinatal and neonatal health care delivery system and practices.
Asunto(s)
Parálisis Cerebral , Parálisis Cerebral/diagnóstico , Parálisis Cerebral/epidemiología , Parálisis Cerebral/etiología , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Recién Nacido , Masculino , Nepal/epidemiología , Embarazo , Cuadriplejía/etiología , Centros de Atención TerciariaRESUMEN
BACKGROUND: Bacterial meningitis is a paediatric emergency with high mortality and morbidity requiring prompt diagnosis and treatment. Clinically, it is often difficult to differentiate between bacterial and non-bacterial meningitis. Several studies have demonstrated the raised values of serum procalcitonin (PCT) in bacterial infections including meningitis but without definite cut-off guidelines. Hence, this study was done to evaluate serum PCT as a marker to differentiate bacterial and non-bacterial meningitis in children and assess its efficacy. METHODS: It was a cross-sectional study done over a period of 5 months (Aug 2016-Dec 2016) in the department of Paediatrics, B P Koirala Institute of Health Sciences (BPKIHS). Fifty children aged 3 months to 15 years with suspected meningitis were enrolled and investigated with relevant investigations like complete blood counts, and cerebrospinal fluid (CSF) analysis along with serum PCT. Patients were classified into bacterial (22) and non-bacterial meningitis (28) according to clinical & CSF findings and data analysed using SPSS software. RESULTS: Serum PCT levels were significantly higher in bacterial meningitis group (median = 2.04 (1.2-3.18) ng/ml) compared with non-bacterial meningitis (median = 0.35 (0.18-0.35) ng/ml); p < 0.001. The sensitivity and specificity of serum PCT in diagnosis of bacterial meningitis at cut-off level of 0.5 ng/ml were 95.45% and 84.61% respectively. Procalcitonin showed maximum area under receiver operating characteristics (ROC) curve 0.991 (0.974-1.00) (p < 0.001) compared to total leukocyte count and CSF cytochemistry. CONCLUSION: Serum PCT has high sensitivity and specificity for early diagnosis of bacterial meningitis in children. Hence it can be a useful adjunct in differentiating bacterial and non-bacterial meningitis for prompt and better management of the children.
Asunto(s)
Calcitonina/sangre , Meningitis Bacterianas/diagnóstico , Meningitis/diagnóstico , Adolescente , Biomarcadores/sangre , Líquido Cefalorraquídeo/química , Niño , Preescolar , Estudios Transversales , Diagnóstico Diferencial , Diagnóstico Precoz , Femenino , Histocitoquímica , Humanos , Lactante , Recuento de Leucocitos , Masculino , Meningitis/sangre , Meningitis Bacterianas/sangre , Nepal , Sensibilidad y EspecificidadRESUMEN
Introduction and importance: Infantile tremor syndrome (ITS) affects children aged 6-18 months, and is characterized by tremors, pallor, developmental regression, skin pigmentation changes, and sparse hypopigmented hair. This case report highlights an ITS presentation in a 16-month-old exclusively breastfed male, emphasizing the significance of complementary feeding. Case presentation: The patient presented with abnormal body movements, loss of developmental milestones, hyperpigmented skin changes, hypopigmented scalp hairs, pallor, and microcephaly. Born to a vegetarian mother with inadequate prenatal care, the child's exclusive breastfeeding till 16 months of age without complementary feeding led to severe developmental delay and moderate malnutrition. Diagnostic workup revealed vitamin B12 deficiency, anaemia, and neurologic abnormalities. Clinical discussion: ITS is associated with various manifestations, including pallor, hyperpigmentation, and tremors, commonly linked to vitamin B12 deficiency. In this case, developmental delays and malnutrition underscored the importance of early recognition. Despite neurological improvement with vitamin B12 supplementation, ITS's long-term impact on cognitive functions necessitates vigilance and appropriate nutritional interventions. Conclusion: Early recognition of ITS is vital for the prevention of long-term neurodevelopmental sequelae. Injectable vitamin B12 supplementation and nutritional interventions have demonstrated significant developmental gains. Increased awareness among mothers about nutritional intake during pregnancy and lactation is crucial, especially among vegetarians.
RESUMEN
BACKGROUND: In October, 2017, WHO launched a strategy to eliminate cholera by 2030. A primary challenge in meeting this goal is the limited global supply capacity of oral cholera vaccine and the worsening of cholera outbreaks since 2021. To help address the current shortage of oral cholera vaccine, a WHO prequalified oral cholera vaccine, Euvichol-Plus was reformulated by reducing the number of components and inactivation methods. We aimed to evaluate the immunogenicity and safety of Euvichol-S (EuBiologics, Seoul, South Korea) compared with an active control vaccine, Shanchol (Sanofi Healthcare India, Telangana, India) in participants of various ages in Nepal. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Nepal. Eligible participants were healthy individuals aged 1-40 years without a history of cholera vaccination. Individuals with a history of hypersensitivity reactions to other preventive vaccines, severe chronic disease, previous cholera vaccination, receipt of blood or blood-derived products in the past 3 months or other vaccine within 4 weeks before enrolment, and pregnant or lactating women were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block sizes of two, four, six, or eight) to one of four groups (groups A-D); groups C and D were stratified by age (1-5, 6-17, and 18-40 years). Participants in groups A-C were assigned to receive two 1·5 mL doses of Euvichol-S (three different lots) and participants in group D were assigned to receive the active control vaccine, Shanchol. All participants and site staff (with the exception of those who prepared and administered the study vaccines) were masked to group assignment. The primary immunogenicity endpoint was non-inferiority of immunogenicity of Euvichol-S (group C) versus Shanchol (group D) at 2 weeks after the second vaccine dose, measured by the seroconversion rate, defined as the proportion of participants who had achieved seroconversion (defined as ≥four-fold increase in V cholerae O1 Inaba and Ogawa titres compared with baseline). The primary immunogenicity endpoint was assessed in the per-protocol analysis set, which included all participants who received all their planned vaccine administrations, had no important protocol deviations, and who provided blood samples for all immunogenicity assessments. The primary safety endpoint was the number of solicited adverse events, unsolicited adverse events, and serious adverse events after each vaccine dose in all ages and each age stratum, assessed in all participants who received at least one dose of the Euvichol-S or Shanchol. Non-inferiority of Euvichol-S compared with Shanchol was shown if the lower limit of the 95% CI for the difference between the seroconversion rates in Euvichol-S group C versus Shanchol group D was above the predefined non-inferiority margin of -10%. The trial was registered at ClinicalTrials.gov, NCT04760236. FINDINGS: Between Oct 6, 2021, and Jan 19, 2022, 2529 healthy participants (1261 [49·9%] males; 1268 [50·1%] females), were randomly assigned to group A (n=330; Euvichol-S lot number ES-2002), group B (n=331; Euvichol-S ES-2003), group C (n=934; Euvichol-S ES-2004]), or group D (n=934; Shanchol). Non-inferiority of Euvichol-S versus Shanchol in seroconversion rate for both serotypes at 2 weeks after the second dose was confirmed in all ages (difference in seroconversion rate for V cholerae O1 Inaba -0·00 [95% CI -1·86 to 1·86]; for V cholerae O1 Ogawa -1·62 [-4·80 to 1·56]). Treatment-emergent adverse events were reported in 244 (9·7%) of 2529 participants in the safety analysis set, with a total of 403 events; 247 events were reported among 151 (9·5%) of 1595 Euvichol-S recipients and 156 events among 93 (10·0%) of 934 Shanchol recipients. Pyrexia was the most common adverse event in both groups (57 events among 56 [3·5%] of 1595 Euvichol-S recipients and 37 events among 35 [3·7%] of 934 Shanchol recipients). No serious adverse events were deemed to be vaccine-related. INTERPRETATION: A two-dose regimen of Euvichol-S vaccine was non-inferior to the active control vaccine, Shanchol, in terms of seroconversion rates 2 weeks after the second dose. The simplified formulation and production requirements of the Euvichol-S vaccine have the potential to increase the supply of oral cholera vaccine and reduce the gap between the current oral cholera vaccine supply and demand. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.
Asunto(s)
Vacunas contra el Cólera , Cólera , Vibrio cholerae O1 , Masculino , Embarazo , Femenino , Humanos , Cólera/prevención & control , Vacunas contra el Cólera/efectos adversos , Nepal/epidemiología , LactanciaRESUMEN
Typhoid remains one of the major serious health concerns for children in developing countries. With extremely drug-resistant cases emerging, preventative measures like sanitation and vaccination, including typhoid conjugate vaccines (TCV) remain the mainstay in its prevention and control. Different types of TCVs are being developed to meet the global demand. This report outlines the results from a study done to assess the immunogenicity and safety of Vi-Diphtheria toxoid (Vi-DT) TCV in Nepal. The study was a randomized, active-controlled, immunological non-inferiority and safety study. Eligible participants from Sunsari and Morang districts of eastern Nepal were randomized into 4 study groups (A-D) within 3 age strata (6 months to <2 years, 2 to <18 years, and 18 to 45 years). Groups A to C received a single dose (25 µg) of Vi-DT test vaccine from any of the 3 lots, while group D received the comparator, Typbar-TCV®, Vi-tetanus toxoid (Vi-TT) vaccine (25 µg) in 1:1:1:1 ratio and evaluated at 4 weeks postvaccination with 6 months follow-up. Amongst 400 randomized participants, anti-Vi-IgG seroconversion rates for all age strata in Vi-DT pooled groups (A+B+C) were 100.00% (97.5% CI 98.34-100.00) vs 98.99% (97.5% CI 93.99-99.85) in Vi-TT group (D) at 4 weeks. Comparable safety events were reported between the groups. Three serious adverse events (1 in Vi-DT; 2 in Vi-TT group) were reported during the 6 months follow-up, none being related to the investigational product. Thus, Vi-DT vaccine is safe, immunogenic, and immunologically non-inferior to Vi-TT when analyzed at 4 weeks postvaccination.
Asunto(s)
Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Niño , Humanos , Lactante , Preescolar , Fiebre Tifoidea/prevención & control , Vacunas Conjugadas , Toxoide Tetánico , Nepal , Voluntarios Sanos , Toxoide Diftérico , Anticuerpos AntibacterianosRESUMEN
Heavy-ion radiotherapy utilizing high linear energy transfer (high-LET) ionizing radiation (IR) is a promising cancer treatment modality owing to advantageous physical properties of energy deposition and associated toxicity over X-rays. Therapies utilizing high-LET radiation will benefit from a better understanding of the molecular mechanisms underpinning their increased biological efficacy. Towards this goal, we investigate here the biological consequences of well-defined clusters of DNA double-strand breaks (DSBs), a form of DNA damage, which on theoretical counts, has often been considered central to the enhanced toxicity of high-LET IR. We test clonal cell lines harboring in their genomes constructs with appropriately engineered I-SceI recognition sites that convert upon I-SceI expression to individual DSBs, or DSB-clusters comprising known numbers of DSBs with defined DNA-ends. We find that, similarly to high-LET IR, DSB-clusters of increasing complexity, i.e. increasing numbers of DSBs, with compatible or incompatible ends, compromise classical non-homologous end-joining, favor DNA end-resection and promote resection-dependent DSB-processing. Analysis of RAD51 foci shows increased engagement of error-free homologous recombination on DSB-clusters. Multicolor fluorescence in situ hybridization analysis shows that complex DSB-clusters markedly increase the incidence of structural chromosomal abnormalities (SCAs). Since RAD51-knockdown further increases SCAs-incidence, we conclude that homologous recombination suppresses SCAs-formation. Strikingly, CtIP-depletion inhibits SCAs-formation, suggesting that it relies on alternative end-joining or single-strand annealing. Indeed, ablation of RAD52 causes a marked reduction in SCAs, as does also inhibition of PARP1. We conclude that increased DSB-cluster formation that accompanies LET-increases, enhances IR-effectiveness by promoting DNA end-resection, which suppresses c-NHEJ and enhances utilization of alt-EJ or SSA. Although increased resection also favors HR, on balance, error-prone processing dominates, causing the generally observed increased toxicity of high-LET radiation. These findings offer new mechanistic insights into high-LET IR-toxicity and have translational potential in the clinical setting that may be harnessed by combining high-LET IR with inhibitors of PARP1 or RAD52.
RESUMEN
INTRODUCTION: Due to heterogeneity in the organs involved and a variety of influencing factors, a wide range of clinical manifestations are possible in systemic lupus erythematosus (SLE). In our knowledge, a combination of leg ulcer and dysentery as presenting symptoms of SLE has never been reported previously. PATIENT CONCERNS: A 13-year-old female child presented with a chronic wound over right medial malleolus for 6 months, and passing of watery stool, later mixed with blood, for 4 days. On examination, she had a fever of 38.5°C. Lab reports revealed anemia, thrombocytopenia, proteinuria, and features of urinary tract infection. Renal biopsy showed membranous glomerulonephropathy. She was positive for antinuclear antibodies (ANA) and antidouble stranded DNA (anti-dsDNA). Immunofluorescence revealed reduced C4 and C3 levels. Abdominal ultrasound showed symmetrical circumscribed thickening, and edematous cecum and ascending colon. DIAGNOSIS: The patient was diagnosed with SLE based on the Systemic Lupus International Collaborating Clinics classification criteria. INTERVENTIONS: The patient was treated with prednisolone, hydroxychloroquine, metronidazole, ciprofloxacin, trypsin-chymotrypsin, zinc, calcium, and calcitriol tablets. OUTCOMES: Fever subsided within 3 days of treatment. Gastrointestinal symptoms subsided within 1 week of treatment. On 31 day of treatment, the wound had been reduced and showed features of healing. CONCLUSION: Dysentery and leg ulcers can be the manifestations of SLE. Therefore, SLE should also be considered when a patient presents with such symptoms. Any suspicion of infection in SLE should be treated aggressively with antibiotics.
Asunto(s)
Disentería , Úlcera de la Pierna , Leucopenia , Lupus Eritematoso Sistémico , Femenino , Niño , Humanos , Adolescente , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Prednisolona/uso terapéutico , Fiebre , Anticuerpos Antinucleares , Úlcera de la Pierna/etiologíaRESUMEN
BACKGROUND: Typhoid fever is a common disease in developing countries especially in the Indian subcontinent and Africa. The available typhoid conjugate vaccines (TCV) have been found to be highly immunogenic in infants and children less than 2 years of age. Many countries are planning to adopt TCV in their routine EPI programs around 9 months of age when measles containing vaccines are given. Therefore, Vi-DT TCV was tested in 9-15 months aged healthy infants in Nepal to demonstrate non-interference with a measles containing vaccine. METHODS: This was a randomized, open label, phase III study to assess the immune non-interference, safety, and reactogenicity of Vi-DT typhoid conjugate vaccine when given concomitantly with measles, mumps and rubella (MMR) vaccine. A total of 360 participants aged 9-15 months were enrolled and randomized equally into Vi-DT + MMR (180 participants) or MMR alone (180 participants) group and were evaluated for immunogenicity and safety 28 days post vaccination. RESULTS: Using the immunogenicity set, difference between proportions (95% CI) of the Vi-DT + MMR group vs MMR alone group were -2.73% (-8.85, 3.38), -3.19% (-11.25, 4.88) and 2.91% (-3.36, 9.18) for sero-positivity rate of anti-measles, anti-mumps and anti- rubella, respectively. Only the lower bound of the range in difference of the proportions for sero-positivity rate of anti-mumps did not satisfy the non-inferiority criteria as it was above the -10% limit, which may not be of clinical significance. These results were confirmed in the per protocol set. There were no safety concerns reported from the study and both Vi-DT + MMR and MMR alone groups were comparable in terms of solicited and unsolicited adverse events . CONCLUSIONS: Results indicated that there is non-interference of MMR vaccine with Vi-DT and Vi-DT conjugate vaccine could be considered as an addition to the EPI schedule among children at risk of contracting typhoid.
Asunto(s)
Sarampión , Paperas , Rubéola (Sarampión Alemán) , Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Anticuerpos Antivirales , Niño , Preescolar , Vacuna contra Difteria y Tétanos , Humanos , Lactante , Sarampión/prevención & control , Vacuna Antisarampión , Vacuna contra el Sarampión-Parotiditis-Rubéola/efectos adversos , Paperas/prevención & control , Nepal , Rubéola (Sarampión Alemán)/prevención & control , Fiebre Tifoidea/prevención & control , Vacunas Conjugadas/efectos adversosRESUMEN
BACKGROUND: Typhoid fever is an endemic disease in many low-income and middle-income countries. The 2018 WHO position paper recommends that countries should consider typhoid vaccination in high-risk groups and for outbreak control. To address the typhoid vaccine supply and demand gap, a typhoid Vi polysaccharide-diphtheria toxoid (Vi-DT) conjugate vaccine development effort was undertaken to achieve WHO prequalification and contribute to the global supply of typhoid conjugate vaccine. The main aim of this study was to show immune non-inferiority of the Vi-DT vaccine compared with the WHO prequalified Vi polysaccharide-tetanus toxoid (Vi-TT) conjugate vaccine (Typbar TCV; Bharat Biotech India, Hyderabad, India) in participants of various ages from an endemic country. METHODS: We did an observer-blind, active-controlled, randomised, non-inferiority, phase 3 trial at four hospitals in Kathmandu, Dhulikhel, Dharan, and Nepalgunj in Nepal. Eligible participants were healthy individuals aged 6 months to 45 years for whom informed consent was obtained, were willing to follow the study procedures and were available for the duration of the study. Patients with an acute or chronic illness that could interfere with interpretation of the study endpoints, or who were involved in any other clinical trial were excluded. Participants were randomly assigned (1:1:1:1) by block randomisation (block size of four and eight), stratified by age (6 months to <2 years, 2 years to <18 years, and 18 years to 45 years), into one of four groups (A-D). Participants in groups A-C received a single dose (25 µg; 0·5 mL) of Vi-DT test vaccine via intramuscular injection from one of three good manufacturing practice lots (group A received lot 1, group B received lot 2, and group C received lot 3), and those in group D received a single dose (25 µg; 0·5 mL) of the Vi-TT vaccine via intramuscular injection. All participants, site staff (except for those who administered the study vaccines), and those assessing the outcomes were masked to group assignment. The co-primary endpoints were: (1) non-inferiority of immunogenicity of the Vi-DT vaccine (pooled groups A-C) versus the Vi-TT vaccine (group D), measured by the anti-Vi IgG seroconversion rate at 4 weeks after vaccination; and (2) the lot-to-lot consistency of the Vi-DT vaccine, measured by immune equivalence of the anti-Vi IgG geometric mean titre (GMT) at 4 weeks after receipt of the three Vi-DT vaccine lots (lot 1 vs lot 2, lot 1 vs lot 3, and lot 2 vs lot 3). Non-inferiority of the Vi-DT vaccine compared with the Vi-TT vaccine was shown if the lower limit of the 97·5% CI for the difference between the seroconversion rates in Vi-DT vaccine groups A-C combined versus Vi-TT vaccine group D was above the predefined non-inferiority margin of -10%. Lot-to-lot immune equivalence was shown if the upper and lower bounds of the two-sided 99·17% CI around the GMT ratio for each pairwise lot-to-lot comparison was between 0·67 and 1·50, which is the predefined equivalence margin recommended by WHO. The co-primary immunogenicity endpoints were assessed in all randomised participants who had received their assigned vaccine and had completed at least one post-baseline immunogenicity assessment. Safety was descriptively summarised by group and age strata, and was assessed in all participants who had received one dose of the investigational vaccine. The trial is registered with ClinicalTrials.gov, NCT03933098. FINDINGS: Between Nov 20, 2019, and March 10, 2020, 1854 individuals were screened, of whom 1800 were enrolled and randomly assigned to groups A-D (450 participants in each group). 1786 (99·2%; 443 in group A, 450 in group B, 447 in group C, and 446 in group D) were included in the immunogenicity assessments at 4 weeks post vaccination, and all 1800 participants were included in the safety analysis. In the immunogenicity analysis, the anti-Vi-IgG seroconversion rate in all age strata was 99·33% (97·5% CI 98·61 to 99·68; 1331 of 1340 participants) in Vi-DT vaccine groups A-C and 98·88% (97·10 to 99·57; 441 of 446) in Vi-TT vaccine group D. The difference in seroconversion rates between Vi-DT vaccine groups A-C combined versus Vi-TT group D was 0·47% (97·5% CI -0·68 to 1·61), indicating non-inferiority of the Vi-DT vaccine. Anti-Vi-IgG GMT ratios at 4 weeks post-vaccination were 1·02 (99·17% CI 0·85 to 1·22) for lot 1 versus lot 2, 1·02 (0·85 to 1·23) for lot 1 versus lot 3, and 1·01 (0·84 to 1·21) for lot 2 versus lot 3, indicating lot-to-lot equivalence according to the predefined, WHO-recommended equivalence margin. The proportion of participants reporting adverse events was similar between Vi-DT vaccine groups A-C and Vi-TT vaccine group D; 260 (19·3%) of 1350 participants in Vi-DT vaccine groups A-C and 115 (25·6%) of 450 in Vi-TT vaccine group D reported solicited adverse events within 7 days after vaccination, and 208 (15·4%) in Vi-DT vaccine groups A-C and 76 (16·9%) in Vi-TT vaccine group D reported unsolicited adverse events within 4 weeks after vaccination. Seven serious adverse events (four [0·3%] participants in Vi-DT vaccine groups A-C and three [0·7%] in Vi-TT vaccine group D), including one death in the Vi-TT vaccine group, were reported during the 24-week follow-up period, none of which were considered related to the investigational product. INTERPRETATION: When administered as a single dose, the Vi-DT test vaccine was safe, immunogenic, and non-inferior to the Vi-TT vaccine at 4 weeks post vaccination. Equivalent immunogenicity of the three lots of Vi-DT vaccine was also shown, supporting the manufacturing process of this vaccine. Once prequalified by WHO, this vaccine could be an option for purchase by UN agencies. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATION: For the Nepali translation of the abstract see Supplementary Materials section.
Asunto(s)
Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Adolescente , Adulto , Niño , Preescolar , Voluntarios Sanos , Humanos , Inmunogenicidad Vacunal , Lactante , Persona de Mediana Edad , Nepal/epidemiología , Fiebre Tifoidea/epidemiología , Fiebre Tifoidea/prevención & control , Vacunas Tifoides-Paratifoides/efectos adversos , Vacunas Conjugadas/efectos adversos , Adulto JovenRESUMEN
Clinical trials are complicated, time-consuming and costly. From the initial screening, informed consent and recruitment of the participants' to study completion, the sponsor must undertake a wide array of complex and closely monitored operations, complying with international standards for human subject research and local requirements. Conducting these studies in an underdeveloped country, with limited resources, infrastructure, and experience with regulated clinical trials adds to this complexity. The initial site selection, set up and preparatory activities for the clinical trial are crucial to minimizing the risks to both participants and to successful completion during the subsequent study execution.In this paper, we describe the experience and lessons learned of building clinical trial site capacity in terms of infrastructure and human resource development for a Phase III vaccine clinical trial. We believe that sharing the experience of setting up a clinical trial in a resource-limited country will enable other entities contemplating clinical research in these countries, to prepare and plan ahead, to minimize the impact of barriers, and to contribute to bringing more studies to the countries where people live with the burden of vaccine-preventable, poverty-associated diseases.
Asunto(s)
Vacunas , Países en Desarrollo , Humanos , Consentimiento Informado , Nepal , Proyectos de InvestigaciónRESUMEN
DNA double-strand break (DSB) complexity is invoked to explain the increased efficacy of high-linear energy transfer (LET) radiation. Complexity is usually defined as presence of additional lesions in the immediate proximity of the DSB. DSB-clusters represent a different level of complexity that can jeopardize processing by destabilizing chromatin in the vicinity of the cluster. DSB-clusters are generated after exposure of cells to ionizing radiation (IR), particularly high-LET radiation, and have been considered as particularly consequential in several mathematical models of IR action. Yet, experimental demonstration of their relevance to the adverse IR effects, as well as information on the mechanisms underpinning their severity as DNA lesions is lacking. We addressed this void by developing cell lines with especially designed, multiply integrated constructs modeling defined combinations of DSB-clusters through appropriately engineered I-SceI meganuclease recognition sites. Using this model system, we demonstrate efficient activation of the DNA damage response, as well as a markedly increased potential of DSB-clusters, as compared to single-DSBs, to kill cells, and cause Parp1- dependent chromosomal translocations. We propose that DSB repair relying on first line DSB-processing pathways (canonical non-homologous end joining and to some degree homologous recombination repair) is compromised within DSB clusters, presumably through the associated chromatin destabilization, leaving alternative end joining as last option and translocation formation as a natural consequence. Our observations offer a mechanistic explanation for the increased efficacy of high-LET radiation.
Asunto(s)
Técnicas de Cultivo de Célula , Roturas del ADN de Doble Cadena/efectos de la radiación , Transferencia Lineal de Energía , Modelos Biológicos , Translocación Genética/efectos de la radiación , Animales , Línea Celular , Supervivencia Celular/efectos de la radiación , Células Clonales , Cricetulus , Citometría de Flujo , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Microscopía Confocal , Plásmidos , Reacción en Cadena de la Polimerasa , Radiación Ionizante , TransfecciónRESUMEN
Parp inhibitors (Parpi) are commonly used as single agents for the management of tumors with homologous recombination repair (HRR) deficiencies, but combination with radiotherapy (RT) is not widely considered due to the modest radiosensitization typically observed. BMN673 is one of the most recently developed Parpi and has been shown to mediate strong cell sensitization to methylating agents. Here, we explore the mechanisms of BMN673 radiosensitization to killing, aiming to combine it with RT. We demonstrate markedly stronger radiosensitization by BMN673 at concentrations substantially lower (50 nmol/L) than olaparib (3 µmol/L) or AG14361 (0.4 µmol/L) and dramatically lower as compared with second-generation inhibitors such as PJ34 (5 µmol/L). Notably, BMN673 radiosensitization peaks after surprisingly short contact times (â¼1 hour) and at pharmacologically achievable concentrations in vivo BMN673 exerts a complex set of effects on DNA double-strand break (DSB) processing, including inhibition of classic nonhomologous end-joining (cNHEJ) and alternative end-joining (altEJ) pathway at high doses of ionizing radiation (IR). BMN673 enhances resection at DSB and favors HRR and altEJ at low clinically relevant IR doses. The combined outcome of these effects is an abrogation in the inherent balance of DSB processing culminating in the formation of chromosomal translocations that underpin radiosensitization. Our observations pave the way to clinical trials exploring inherent benefits in combining BMN673 with RT for the treatment of various forms of cancer. Mol Cancer Ther; 17(10); 2206-16. ©2018 AACR.
Asunto(s)
Roturas del ADN de Doble Cadena/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Ftalazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Animales , Células CHO , Línea Celular Tumoral , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Modelos Biológicos , Radiación Ionizante , Translocación Genética/efectos de los fármacos , Translocación Genética/efectos de la radiaciónRESUMEN
BACKGROUND: Osteopetrosis is a rare inherited metabolic bone disorder characterized by extensive sclerosis of skeletons, visual and hearing impairment, hepatosplenomegaly and anemia. It has two major clinical forms: the autosomal dominant adult (benign) form is associated with milder symptoms often appearing in later childhood and adulthood whereas the autosomal recessive infantile (malignant) form has severe presentations appearing in very early childhood, if untreated, is typically fatal during infancy or early childhood. A rare autosomal recessive (intermediate) form is present during childhood with some signs and symptoms of malignant osteopetrosis. Diagnosis is mainly based on clinical and typical generalized increase in bone density. CASE PRESENTATION: The two siblings of Indo-Aryan ethnicity, aged five and 8 years, were admitted with irregular low grade fever and gradually increasing abdominal mass for last 3 years. They also had history of hearing loss. On examination, the patients were found pale with poor nutritional status, short stature, frontal bossing and splenomegaly. We made a clinical diagnosis of hemolytic anemia and investigated accordingly. Peripheral Blood Smear was suggestive of leucoerythroblastic picture in both the siblings. We extended our investigations and radiological survey revealed generalized increase in bone density which was consistent with osteopetrosis. CONCLUSION: Osteopetrosis is a rare disease transmitted by autosomal dominant or recessive inheritance having variable penetrance. We report here milder form of disease in the two siblings having typical clinical features in the form of anemia, hepatosplenomegaly and hearing loss. Diagnosis was confirmed by typical generalized increase in bone density in both the patients.
Asunto(s)
Osteopetrosis/patología , Hermanos , Densidad Ósea , Humanos , Osteopetrosis/diagnóstico por imagen , Radiografía , Esclerosis , Cráneo/diagnóstico por imagen , Cráneo/patología , Columna Vertebral/diagnóstico por imagen , Columna Vertebral/patologíaRESUMEN
BACKGROUND: The understanding and management of neurological disorders is undergoing revolutionary changes over the last three decades in the background of ever increasing advances in medical technologies, diagnostic techniques, therapeutic processes and, molecular and genetic medicine. The fruits of these advances can reach patients only if the psychosocial hurdles in their delivery are identified, acknowledged and addressed. AIM: To explore the beliefs and practices of patients with neurological disorders in a tertiary care center in the eastern Nepal. MATERIALS AND METHODS: One hundred patients attending neurology/medicine outpatient for neurological disorders were interviewed about their beliefs regarding the triggering factors, causation and treatment-seeking behavior particularly from traditional healers. RESULT: Of the 100 patients (49 males, 51 females) recruited in the study, 51% expressed having 'no idea' about their illness. Only 20% patients gave medically congruent explanation for their illness. Psychological factors were attributed as triggering factors by 16% of patients, of which two-thirds were females. Chance, destiny and 'jadu tona' topped the list of triggering factors. Forty-four percent patients had sought help of traditional faith healers ('Dhami Jhakri') before seeking medical help. Traditional faith healers were approached by patients irrespective of their educational background. Fifty-nine percent of patients who first sought traditional faith healers, believed in 'jadu-tona'. Of those interviewed, 16% were planning to go to a faith healer in near future. CONCLUSION: The beliefs of patients with neurological disorders frequently do not conform to current medical opinion. There is need for greater communication and education of patients by their treating physicians.