Antenatal dexamethasone for early preterm birth in low-resource countries

BACKGROUND: The safety and efficacy of antenatal glucocorticoids in women in low-resource countries who are at risk for preterm birth are uncertain. METHODS: We conducted a multicountry, randomized trial involving pregnant women between 26 weeks 0 days and 33 weeks 6 days of gestation who were at risk for preterm birth. The participants were assigned to intramuscular dexamethasone or identical placebo. The primary outcomes were neonatal death alone, stillbirth or neonatal death, and possible maternal bacterial infection; neonatal death alone and stillbirth or neonatal death were evaluated with superiority analyses, and possible maternal bacterial infection was evaluated with a noninferiority analysis with the use of a prespecified margin of 1.25 on the relative scale. RESULTS: A total of 2852 women (and their 3070 fetuses) from 29 secondary- and tertiary-level hospitals across Bangladesh, India, Kenya, Nigeria, and Pakistan underwent randomization. The trial was stopped for benefit at the second interim analysis. Neonatal death occurred in 278 of 1417 infants (19.6%) in the dexamethasone group and in 331 of 1406 infants (23.5%) in the placebo group (relative risk, 0.84; 95% confidence interval [CI], 0.72 to 0.97; P=0.03). Stillbirth or neonatal death occurred in 393 of 1532 fetuses and infants (25.7%) and in 444 of 1519 fetuses and infants (29.2%), respectively (relative risk, 0.88; 95% CI, 0.78 to 0.99; P=0.04); the incidence of possible maternal bacterial infection was 4.8% and 6.3%, respectively (relative risk, 0.76; 95% CI, 0.56 to 1.03). There was no significant between-group difference in the incidence of adverse events. CONCLUSIONS: Among women in low-resource countries who were at risk for early preterm birth, the use of dexamethasone resulted in significantly lower risks of neonatal death alone and stillbirth or neonatal death than the use of placebo, without an increase in the incidence of possible maternal bacterial infection.Fil: Oladapo, Olufemi T.. Organizacion Mundial de la Salud; ArgentinaFil: Vogel, Joshua P.. Organizacion Mundial de la Salud; ArgentinaFil: Piaggio, Gilda. Organizacion Mundial de la Salud; ArgentinaFil: Nguyen, My-Huong. Organizacion Mundial de la Salud; ArgentinaFil: Althabe, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; ArgentinaFil: Metin Gülmezoglu, A.. Organizacion Mundial de la Salud; ArgentinaFil: Bahl, Rajiv. Organizacion Mundial de la Salud; ArgentinaFil: Rao, Suman P.N.. Organizacion Mundial de la Salud; ArgentinaFil: de Costa, Ayesha. Organizacion Mundial de la Salud; ArgentinaFil: Gupta, Shuchita. Organizacion Mundial de la Salud; ArgentinaFil: Shahidullah, Mohammod. No especifíca;Fil: Chowdhury, Saleha B.. No especifíca;Fil: Ara, Gulshan. No especifíca;Fil: Akter, Shaheen. No especifíca;Fil: Akhter, Nasreen. No especifíca;Fil: Dey, Probhat R.. No especifíca;Fil: Abdus Sabur, M.. No especifíca;Fil: Azad, Mohammad T.. No especifíca;Fil: Choudhury, Shahana F.. No especifíca;Fil: Matin, M.A.. No especifíca;Fil: Goudar, Shivaprasad S.. No especifíca;Fil: Dhaded, Sangappa M.. No especifíca;Fil: Metgud, Mrityunjay C.. No especifíca;Fil: Pujar, Yeshita V.. No especifíca;Fil: Somannavar, Manjunath S.. No especifíca;Fil: Vernekar, Sunil S.. No especifíca;Fil: Herekar, Veena R.. No especifíca;Fil: Bidri, Shailaja R.. No especifíca;Fil: Mathapati, Sangamesh S.. No especifíca;Fil: Patil, Preeti G.. No especifíca;Fil: Patil, Mallanagouda M.. No especifíca;Fil: Gudadinni, Muttappa R.. No especifíca;Fil: Bijapure, Hidaytullah R.. No especifíca;Fil: Mallapur, Ashalata A.. No especifíca;Fil: Katageri, Geetanjali M.. No especifíca;Fil: Chikkamath, Sumangala B.. No especifíca;Fil: Yelamali, Bhuvaneshwari C.. No especifíca;Fil: Pol, Ramesh R.. No especifíca;Fil: Misra, Sujata S.. No especifíca;Fil: Das, Leena. No especifíca

RAPIDIRON Trial Follow-Up Study - the RAPIDIRON-KIDS Study: Protocol of a Prospective Observational Follow-Up Study

BACKGROUND: Anemia is a worldwide problem with iron deficiency being the most common cause. When anemia occurs in pregnancy, it increases the risk of adverse maternal, fetal, and postnatal outcomes. It induces preterm births and low birth weight (LBW) deliveries, long-term neurodevelopmental sequelae, and an increased risk of earlier onset of postnatal iron deficiency. Anemia rates are among the highest in South Asia, and India\u27s National Family Health Survey (NFHS-5) for 2019-2021 indicated that over half of pregnant women, and more than 65% of children, in the country are classified as anemic (Sciences IIfP, National Family Health Survey-5, 2019-21, India Fact Sheet). In 2021, the parent RAPIDIRON Trial (Derman et al., Trials 22:649, 2021) was initiated in two states in India, with the goal of assessing whether a dose of intravenous (IV) iron given to anemic women during early pregnancy results in a greater proportion of participants with normal hemoglobin concentrations in the third trimester and a lower proportion of participants with LBW deliveries compared to oral iron. As a follow-up to the RAPIDIRON Trial, the RAPIDIRON-KIDS Study will follow the offspring of previously randomized mothers to assess, neurobehavioral, hematological, and health outcomes. METHODS: This prospective observational cohort study will follow a subset of participants previously randomized as part of the RAPIDIRON Trial and their newborns. Study visits occur at birth, 6 weeks, 4 months, 12 months, 24 months, and 36 months and include blood sample collection with both maternal and infant participants and specific neurobehavioral assessments conducted with the infants (depending on the study visit). The primary outcomes of interest are (1) infant iron status as indicated by both hemoglobin and ferritin (a) at birth and (b) at 4 months of age and (2) the developmental quotient (DQ) for the cognitive domain of the Bayley Scales of Infant Development Version IV (BSID-IV) at 24 months of age. DISCUSSION: This RAPIDIRON-KIDS Study builds upon its parent RAPIDIRON Trial by following a subset of the previously randomized participants and their offspring through the first 3 years of life to assess neurodevelopmental and neurobehavioral (infants, children), hematological, and health outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05504863 , Registered on 17 August 2022. Clinical Trials Registry - India CTRI/2022/05/042933 . Registered on 31 May 2022

Effects of the WHO Labour Care Guide on cesarean section in India: a pragmatic, stepped-wedge, cluster-randomized pilot trial

Cesarean section rates worldwide are rising, driven by medically unnecessary cesarean use. The new World Health Organization Labour Care Guide (LCG) aims to improve the quality of care for women during labor and childbirth. Using the LCG might reduce overuse of cesarean; however, its effects have not been evaluated in randomized trials. We conducted a stepped-wedge, cluster-randomized pilot trial in four hospitals in India to evaluate the implementation of an LCG strategy intervention, compared with routine care. We performed this trial to pilot the intervention and obtain preliminary effectiveness data, informing future research. Eligible clusters were four hospitals with >4,000 births annually and cesarean rates ≥30%. Eligible women were those giving birth at ≥20 weeks' gestation. One hospital transitioned to intervention every 2 months, according to a random sequence. The primary outcome was the cesarean rate among women in Robson Group 1 (that is, those who were nulliparous and gave birth to a singleton, term pregnancy in cephalic presentation and in spontaneous labor). A total of 26,331 participants gave birth. A 5.5% crude absolute reduction in the primary outcome was observed (45.2% versus 39.7%; relative risk 0.85, 95% confidence interval 0.54-1.33). Maternal process-of-care outcomes were not significantly different, though labor augmentation with oxytocin was 18.0% lower with the LCG strategy. No differences were observed for other health outcomes or women's birth experiences. These findings can guide future definitive effectiveness trials, particularly in settings where urgent reversal of rising cesarean section rates is needed. Clinical Trials Registry India number: CTRI/2021/01/03069

Molecular characterisation of tumours and biomarker identification for personalised radiation oncology using genomic data of patients with locally advanced head and neck squamous cell carcinoma

Background: Head and neck squamous cell carcinomas (HNSCCs) are complex and highly aggressive tumours that develop in the mouth, throat, salivary glands and nose. HNSCCs account for more than half a million cases annually and are the sixth most common cancer worldwide. Alcohol, tobacco and human papilloma virus (HPV) infection are the well-known causes for HNSCC. The current options for treatment are surgery, radiotherapy, chemotherapy or a combination of therapies. Locally advanced HNSCC patients show heterogenous response to standard treatments and the survival after 5 years is about 50%. Therefore, there is a need to identify biomarkers to predict outcome and improve personalised therapies. The recent advancement in next generation sequencing technologies has allowed for understanding the molecular characteristics of the tumour and identify patients at high risk that are unresponsive to the standard treatment. HPV-associated oropharyngeal carcinoma have shown a very high rate of loco-regional control (LRC) and overall survival (OS) after postoperative radio- chemotherapy (PORT-C) and are being assessed for treatment de-escalation strategies to reduce toxicity in clinical trials. The treatment response of HPV-negative HNSCC, however, is still heterogeneous and novel biomarkers are required to identify subgroups of patients for treatment adaptation. Objectives: The overall aim of the thesis is to develop biomarkers to identify patients at high risk for future treatment adaptations and improve personalised radiotherapy based on the biological differences in HNSCC patients. For this purpose, novel gene signatures were developed and validated using machine learning approaches and biological information in order to predict LRC in patients with locally advanced HNSCC. The novel gene signatures will help to identify patients at high risk that do not respond to standard treatments and to further understand the molecular mechanisms involved in heterogenous treatment response. Materials and methods: The data from a total of 504 locally advanced HNSCC patients of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG) treated with postoperative radiotherapy (PORT) or postoperative radiochemotherapy (PORT-C) were evaluated. Data from 60 mice bearing xenografts of ten established human HNSCC cell lines were also evaluated. Gene expression analyses was performed using the GeneChip Human Transcriptome Array 2.0 and nanoString analyses. Differential gene expression analysis, Cox regression analysis and machine learning algorithms were used to develop gene signatures. Models were built on the training cohort and then applied on an independent validation cohort. Results: The patients with HPV-negative HNSCC that were treated with PORT-C were classified into the four molecular subtypes basal, mesenchymal, atypical and classical that were previously reported for HNSCC patients treated with primary radio(chemo)therapy or surgery and were related to LRC. The mesenchymal subtype had the worst prognosis as compared to the other subtypes. These tumours were associated with overexpression of epithelial-mesenchymal transition genes and DNA repair genes. A novel 6-gene signature was developed and validated based on full-transcriptome data using machine-learning approaches that was prognostic for LRC in patients with HPV-negative HNSCC treated with PORT-C. The 6-gene signature consisted of four individual genes CAV1, GPX8, IGLV3-25, TGFBI and one metagene combining the highly correlated genes, INHBA and SERPINE1. The identified gene signature was combined with the clinical parameters, T stage and tumour localisation as well as the stem-cell marker CD44 and the 15-gene hypoxia- associated classifier and this improved the performance of the model. Previously identified prognostic gene signatures and molecular-subtype classification were back-translated from HNSCC patients to pre-clinical tumour models. The tumour models were classified into the four subtypes basal, mesenchymal, atypical and classical, similar to the patients. The mesenchymal tumours were significantly associated with a higher TCD50 as compared to other subtypes. A novel 2-gene signature consisting of FN1 and SERPINE1 was developed based on tumour models and patient data using differential gene expression analysis. The 2-gene signature was prognostic for the TCD50 in tumour models and was successfully validated on an independent PORT-C patient cohort for LRC. A matched-pair analysis was performed between patients that were treated with postoperative radiochemotherapy and patients that were treated with postoperative radiotherapy. A 2- metagene signature, consisting of KRT6A, KRT6B, KRT6C forming one metagene and SPRR1A, SPRR1B, SPRR2A, SPRR2C forming the second metagene, was identified. The novel predictive signature stratified patients into high and low risk groups. The high-risk group patients that received PORT-C showed higher LRC as compared to the high-risk patients that received PORT. Thus, the predictive gene signature identified patients that were considered to be at intermediate risk according to clinical factors but were at biologically high risk for the development of loco-regional recurrences after PORT. These patients might benefit from PORT-C treatment. Conclusions: In this thesis, novel gene signatures were identified by combining machine learning and biological information to stratify locally advanced HNSCC patients into high and low risk groups for loco-regional control. This information could be used in the future, e.g. to adjust radiotherapy doses based on the risk group. The developed gene signatures could be combined with other gene signatures or the molecular subtype stratification to develop potential combined treatment approaches. Within the DKTK-ROG framework, the gene signatures will be incorporated with biomarkers developed on the same cohort at the other DKTK-ROG partner sites using the data from different omics platforms in the future. This would help to better understand the molecular basis of heterogenous treatment response in HNSCC patients and uncover novel targets for therapies. The thesis also provides a valuable insight into the applicability of preclinical tumour models to study the efficacy of personalised radiotherapy treatments. Overall, the gene signatures identified in this thesis were from retrospective studies and have to be validated in prospective studies before their application in interventional clinical trials to improve personalised radiotherapy treatments. Additionally, the methods used in the thesis to identify the gene signatures could be used and applied across different cancer datasets for identification of biomarkers. Therefore, this thesis has provided a basis for future studies on personalized treatment of HNSCC based on their genetic profile.:Content Abbreviations VII Tables XII 1 Introduction 1 2 Biological and statistical background 6 2.1 Head and neck squamous cell carcinoma 6 2.1.1 Tumourigenesis 6 2.1.2 Biomarkers: clinical and genomics 9 2.2 Statistics 12 General statistical analyses 17 2.3 Gene expression analyses 18 3 Molecular subtypes and mechanisms of radioresistance 20 3.1 Introduction and motivation 20 3.2 Patient cohort and experimental design 21 3.2.1 Patient cohort 21 3.2.2 Clinical endpoints and statistical analysis 23 3.2.3 Experimental design 23 3.3 Results 26 3.3.1 Prognostic factors for LRC and OS 26 3.3.2 Death as competing risk 26 3.3.3 Multivariable Cox regression for improved prognosis 29 3.3.4 Molecular subtypes in HPV-negative HNSCC patients 31 3.3.5 Molecular subtypes are prognostic for LRC after PORT-C 33 3.4 Discussion 36 4 A novel 6-gene signature for LRC prognosis 39 4.1 Introduction and motivation 39 4.2 Patient cohort and experimental design 40 4.2.1 Patient cohorts 40 4.2.2 Clinical endpoints and statistical analysis 41 4.2.3 Experimental design 41 4.3 Results 44 4.3.1 Characteristics of the patient cohorts 44 4.3.2 Development of the 6-gene signature prognostic for LRC 45 4.3.3 Combination of the 6-gene signature and clinical parameters 47 4.3.4 Extension with CD44 and the 15-gene hypoxia signature 48 4.3.5 Prognostic for secondary endpoints 49 4.3.6 Technical validation using nanoString technology 52 4.3.7 Death as competing risk 56 4.4 Discussion 58 5 Biomarker development in preclinical tumour models and HNSCC patients 62 5.1 Introduction and motivation 62 5.2 Patient cohort and experimental design 64 5.2.1 Patient derived xenograft tumour models 64 5.2.2 Patient cohorts 64 5.2.3 Clinical endpoints and statistical analysis 65 5.2.4 Experimental design 65 5.3 Results 68 5.3.1 Molecular subtypes 68 5.3.2 Development of the 2-gene signature 70 5.3.3 Technical validation using the nanoString technology 71 5.3.4 Back-translation of gene signatures in xenograft models 75 5.4 Discussion 79 6 PORT-C improves LRC in intermediate-risk patients 82 6.1 Introduction and motivation 82 6.2 Patient cohort and experimental design 83 6.2.1 Patient cohorts 84 6.2.2 Clinical endpoints and statistical analysis 84 6.2.3 Experimental design 84 6.3 Results 87 6.3.1 Characteristics of the patient cohorts 87 6.3.2 Propensity score matching analysis 88 6.3.3 Development of the predictive 2-metagene signature 90 6.4 Discussion 93 7 Conclusion and future perspectives 96 8 Summary 99 9 Zusammenfassung 102 Appendix 105 A. Supplementary Figures 105 B. Supplementary Tables 110 Bibliography 116 Erklärungen 14

Herpesviruses in chronic and aggressive periodontitis patients in an Indian population

Many recent studies have assessed the prevalence and role of herpesviruses in the etiopathogenesis of periodontal diseases, which has led to the realization of intricate interactions between viruses and bacteria within periodontal pockets. It has also been shown that the occurrence of herpesviruses may vary depending upon the age of the patient and the race of the population studied. Thus, the present study aimed at detecting herpes simplex virus type 1 and 2 (HSV 1 and 2), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) in periodontal pockets of Indian patients with chronic and aggressive periodontitis. Subgingival plaque samples (n = 33) were collected from 19 randomly chosen chronic periodontitis and 14 aggressive periodontitis patients. Herpesviruses were detected using multiplex polymerase chain reaction technique. Chronic periodontitis patients revealed presence of HSV-1 in 19 (100) samples, HSV-2 in 3 (15.7), EBV in 15 (78.9) and HCMV in 5 (26.31) samples. Samples from aggressive periodontitis patients showed the presence of HSV-1 in 8 (57.14), EBV in 4 (28.57) and HCMV in 1 (7.14), whereas HSV-2 was not detected in any specimen. In this population, herpesviruses were found more frequently in chronic periodontitis than in aggressive periodontitis patients and their prevalence may vary according to the age and race of the patient

Comprehensive Spinal Tuberculosis Score: A Clinical Guide for the Management of Thoracolumbar Spinal Tuberculosis

Study Design A newly proposed scoring tool was designed to assist in the clinical management of adult thoracolumbar spinal tuberculosis (TB). Purpose To formulate a comprehensive yet simple scoring tool to guide decision-making in the management of adult thoracolumbar spinal TB. Overview of Literature Spine surgeons have differing consensus in defining the threshold grade for clinico-radiological parameters when deciding between operative or conservative treatment for adult thoracolumbar spinal TB. Currently, the void in decision-making from the lack of well-defined guidelines is compensated by the surgeon’s experience in treating these patients. To the best of our knowledge, no scoring system holistically integrates multiple facets of spinal TB to guide clinical decision-making. Methods The RAND/University of California, Los Angeles appropriateness method was employed among an expert panel of 10 spine surgeons from four apex tertiary care centers. Vital characteristics that independently influenced treatment decisions in spinal TB were identified, and a scoring tool was formulated. Points were assigned for each component based on their severity. The cutoff scores to guide clinical management were determined from the receiver operating characteristic curve based on the retrospective records of 151 patients treated operatively or non-operatively with improved functional outcomes at the 1-year follow-up. Results The components of the comprehensive spinal TB score (CSTS) are pain, kyphosis angle, vertebral destruction, and neurological status. A score classification of 6.5 was established to guide the patient toward conservative, conservative/operative, and operative management, respectively. Conclusions The CSTS was designed to reflect the essential indicators of mechanical stability, neurological stability, and disease process stabilization in spinal TB. The scoring tool is devised to be practical and serve as a common language in the spine community to facilitate discussions and decision-making in thoracolumbar spinal TB. The validity, reliability, and reproducibility of this tool must be assessed through multicenter long-term studies

Neonatal mortality among preterm infants admitted to neonatal intensive care units in India and Pakistan: A prospective study

Objective: To explore potential reasons for differences in preterm neonatal mortality in neonatal intensive care units (NICUs) in India and Pakistan.Design: A prospective observational study, the Project to Understand and Research Stillbirth and Preterms in Southeast Asia (PURPOSe) was conducted July 2018 to February 2020.Setting: Three hospitals in Davangere, India, and a large public hospital in Karachi, Pakistan.Population: Of a total of 3,202 preterm infants enrolled, 1,512 were admitted to a study NICU.Methods: We collected data for neonates, including length of stay, diagnoses, and diagnostic tests.Main outcome measures: Neonatal mortality, tests performed, diagnoses ascertained.Results: For infants of equivalent weights and gestational ages, neonatal mortality in Pakistan was twice that in the Indian NICU. The mean newborn length of stay in Pakistan was 2 days compared with 10 days for India. Fewer diagnostics and other investigations were used to determine neonatal condition or guide treatment in the Pakistani NICU. Because of limited information from testing in Pakistan concerning clinical respiratory distress, respiratory distress syndrome appeared to be over-diagnosed, whereas other conditions including pneumonia, sepsis, necrotising entercolitis and intraventricular haemorrhage were rarely diagnosed.Conclusion: In the Pakistani site, the limited resources available to the NICU appeared related to a shorter length of stay and decreased diagnostic testing, likely explaining the higher mortality. With improved care, reduction in mortality among preterm neonates should be achievable

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