Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

BACKGROUND: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. METHODS: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. INTERPRETATION: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. FUNDING: Bill & Melinda Gates Foundation.

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.

BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Intra-axonal translation of Khsrp mRNA slows axon regeneration by destabilizing localized mRNAs.

Axonally synthesized proteins support nerve regeneration through retrograde signaling and local growth mechanisms. RNA binding proteins (RBP) are needed for this and other aspects of post-transcriptional regulation of neuronal mRNAs, but only a limited number of axonal RBPs are known. We used targeted proteomics to profile RBPs in peripheral nerve axons. We detected 76 proteins with reported RNA binding activity in axoplasm, and levels of several change with axon injury and regeneration. RBPs with altered levels include KHSRP that decreases neurite outgrowth in developing CNS neurons. Axonal KHSRP levels rapidly increase after injury remaining elevated up to 28 days post axotomy. Khsrp mRNA localizes into axons and the rapid increase in axonal KHSRP is through local translation of Khsrp mRNA in axons. KHSRP can bind to mRNAs with 3'UTR AU-rich elements and targets those transcripts to the cytoplasmic exosome for degradation. KHSRP knockout mice show increased axonal levels of KHSRP target mRNAs, Gap43, Snap25, and Fubp1, following sciatic nerve injury and these mice show accelerated nerve regeneration in vivo. Together, our data indicate that axonal translation of the RNA binding protein Khsrp mRNA following nerve injury serves to promote decay of other axonal mRNAs and slow axon regeneration.

Selective axonal translation of the mRNA isoform encoding prenylated Cdc42 supports axon growth.

The small Rho-family GTPase Cdc42 has long been known to have a role in cell motility and axon growth. The eukaryotic Ccd42 gene is alternatively spliced to generate mRNAs with two different 3' untranslated regions (UTRs) that encode proteins with distinct C-termini. The C-termini of these Cdc42 proteins include CaaX and CCaX motifs for post-translational prenylation and palmitoylation, respectively. Palmitoyl-Cdc42 protein was previously shown to contribute to dendrite maturation, while the prenyl-Cdc42 protein contributes to axon specification and its mRNA was detected in neurites. Here, we show that the mRNA encoding prenyl-Cdc42 isoform preferentially localizes into PNS axons and this localization selectively increases in vivo during peripheral nervous system (PNS) axon regeneration. Functional studies indicate that prenyl-Cdc42 increases axon length in a manner that requires axonal targeting of its mRNA, which, in turn, needs an intact C-terminal CaaX motif that can drive prenylation of the encoded protein. In contrast, palmitoyl-Cdc42 has no effect on axon growth but selectively increases dendrite length. Together, these data show that alternative splicing of the Cdc42 gene product generates an axon growth promoting, locally synthesized prenyl-Cdc42 protein. This article has an associated First Person interview with one of the co-first authors of the paper.

Insights into the perinatal phenotype of Kabuki syndrome in infants identified by genome-wide sequencing.

Increasing use of unbiased genomic sequencing in critically ill infants can expand understanding of rare diseases such as Kabuki syndrome (KS). Infants diagnosed with KS through genome-wide sequencing performed during the initial hospitalization underwent retrospective review of medical records. Human phenotype ontology terms used in genomic analysis were aggregated and analyzed. Clinicians were surveyed regarding changes in management and other care changes. Fifteen infants met inclusion criteria. KS was not suspected prior to genomic sequencing. Variants were classified as Pathogenic (n = 10) or Likely Pathogenic (n = 5) by American College of Medical Genetics and Genomics Guidelines. Fourteen variants were de novo (KMT2D, n = 12, KDM6A, n = 2). One infant inherited a likely pathogenic variant in KMT2D from an affected father. Frequent findings involved cardiovascular (14/15) and renal (7/15) systems, with palatal defects also identified (6/15). Three infants had non-immune hydrops. No minor anomalies were universally documented; ear anomalies, micrognathia, redundant nuchal skin, and hypoplastic nails were common. Changes in management were reported in 14 infants. Early use of unbiased genome-wide sequencing enabled a molecular diagnosis prior to clinical recognition including infants with atypical or rarely reported features of KS while also expanding the phenotypic spectrum of this rare disorder.

Neurally Adjusted Ventilatory Assist Versus Pressure Support Ventilation: A Comprehensive Review.

Mechanical ventilation serves as crucial life support for critically ill patients. Although it is life-saving prolonged ventilation carries risks and complications like barotrauma, Ventilator-associated pneumonia, sepsis, and many others. Optimizing patient-ventilator interactions and facilitating early weaning is necessary for improved intensive care unit (ICU) outcomes. Traditionally Pressure support ventilation (PSV) mode is widely used for weaning patients who are intubated and mechanically ventilated. Neurally adjusted ventilatory assist (NAVA) mode of the ventilator is an emerging ventilator mode that delivers pressure depending on the patient's respiratory drive, which in turn prevents over-inflation and improves the patient's ventilator interactions. Our article revises and compares the effectiveness of NAVA compared to PSV ventilation under different contexts. Overall we conclude that NAVA level of ventilation can be safely administered in a patient with acute respiratory failure, provided diaphragmatic paralysis is not considered. NAVA improves asynchrony index, wean-off time, and sleep quality and is associated with increased ventilator-free days. These results are based on small-scale studies with low power, and further studies are warranted in large-scale cohorts with more diverse populations to confirm these results.

Prevalence and correlates of adolescent pregnancy, motherhood and adverse pregnancy outcomes in Uttar Pradesh and Bihar.

Pregnancy during adolescence is a major risk factor for adverse pregnancy outcomes. Further, Motherhood during the adolescent period is identified as a major global health burden. Considering the widely known importance of the negative impact of adolescent pregnancy, motherhood at an early age, and adverse pregnancy outcomes, this paper aims to provide insight into correlates of teen pregnancy, adolescent motherhood and adverse pregnancy outcome. This study utilizes the data from UDAYA survey conducted in Uttar Pradesh and Bihar. The eligible sample size for the study was 4897 married adolescent girls between the ages of 15 and 19 years. Bivariate analysis with a chi-square test of association and Multivariable logistic regression analysis was performed to fulfill the aim of the study. Our study shows that a major proportion of married adolescents (61%) got pregnant before the age of 20 years and around 42% of all adolescent married women gave birth to a child before reaching the age of 20 years. Adolescents who married before the age of 18 years were 1.79 times more likely to experience pregnancy (OR: 1.79; CI: 1.39-2.30) and 3.21 times more likely to experience motherhood (OR: 3.21; CI: 2.33-4.43). In the present study, women who experienced physical violence were at higher risk for having an adverse pregnancy outcome (OR: 1.41; CI: 1.08-1.84) than those who did not experience physical violence. To conclude, regional and national level efforts focused on improving early marriage, education and empowering women and girls can be beneficial.

The burden of disease-specific multimorbidity among older adults in India and its states: evidence from LASI.

BACKGROUND: Around the world, advances in public health and changes in clinical interventions have resulted in increased life expectancy. Multimorbidity is becoming more of an issue, particularly in countries where the population is rapidly ageing. We aimed to determine the prevalence of multimorbidity and disease-specific multimorbidity and examine its association with demographic and socioeconomic characteristics among older adults in India and its states. METHODS: The individual data from the longitudinal ageing study in India (LASI) were used for this study, with 11 common chronic conditions among older adults aged 60 and above years (N = 31,464). Descriptive statistics were used to report the overall prevalence of multimorbidity and disease-specific burden of multimorbidity. Multinomial logistic regression has been used to explore the factors associated with multimorbidity. RESULTS: Prevalence of single morbidity was 30.3%, and multimorbidity was 32.1% among older people in India. Multimorbidity was higher among females and in urban areas and increased with age and among those living alone. Hypertension, arthritis and thyroid were highly prevalent among females and chronic lung diseases and stroke were highly prevalent among males. The older people in the state of Kerala had a high prevalence of multimorbidity (59.2%). Multimorbidity was found to be more likely in older age groups of 75-79 years (RR-1.69; CI: 1.53-1.87) and 80 years and above (RR-1.40; CI: 1.27-1.56) and in the Western (RR-2.16; CI: 1.90-2.44) and Southern regions (RR-2.89; CI: 2.57-3.24). Those who were living with a spouse (RR-1.60; CI: 1.15-2.23) were more likely to have multimorbidity. Disease-specific multimorbidity was high in chronic heart disease (91%) and low in angina (64.8%). CONCLUSIONS: The findings suggest that multimorbidity has a positive relationship with advancing age, and disease-specific burden of multimorbidity is higher among chronic heart patients. Comorbidity, especially among those who already have chronic heart disease, stroke, cholesterol or thyroid disorder can have severe consequences on physical functioning, therefore, disease-specific health management needs to be enhanced.

Hepatitis B Vaccination Impact and the Unmet Need for Antiviral Treatment in Blantyre, Malawi.

BACKGROUND: Hepatitis B is the leading cause of cirrhosis and liver cancer in sub-Saharan Africa. To reduce mortality, antiviral treatment programs are needed. We estimated prevalence, vaccine impact, and need for antiviral treatment in Blantyre, Malawi. METHODS: We conducted a household study in 2016-2018. We selected individuals from a census using random sampling and estimated age-sex-standardized hepatitis B surface antigen (HBsAg) seroprevalence. Impact of infant hepatitis B vaccination was estimated by binomial log-linear regression comparing individuals born before and after vaccine implementation. In HBsAg-positive adults, eligibility for antiviral therapy was assessed. RESULTS: Of 97386 censused individuals, 6073 (median age 18 years; 56.7% female) were sampled. HBsAg seroprevalence was 5.1% (95% confidence interval [CI], 4.3%-6.1%) among adults and 0.3% (95% CI, .1%-.6%) among children born after vaccine introduction. Estimated vaccine impact was 95.8% (95% CI, 70.3%-99.4%). Of HBsAg-positive adults, 26% were HIV-positive. Among HIV-negative individuals, 3%, 6%, and 9% were eligible for hepatitis B treatment by WHO, European, and American hepatology association criteria, respectively. CONCLUSIONS: Infant HBV vaccination has been highly effective in reducing HBsAg prevalence in urban Malawi. Up to 9% of HBsAg-positive HIV-negative adults are eligible, but have an unmet need, for antiviral therapy.

A clinical and molecular epidemiological survey of hepatitis C in Blantyre, Malawi, suggests a historic mechanism of transmission.

Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. There are no previous representative community HCV prevalence studies from Southern Africa, and limited genotypic data. Epidemiological data are required to inform an effective public health response. We conducted a household census-based random sampling serological survey, and a prospective hospital-based study of patients with cirrhosis and hepatocellular carcinoma (HCC) in Blantyre, Malawi. We tested participants with an HCV antigen/antibody ELISA (Monolisa, Bio-Rad), confirmed with PCR (GeneXpert, Cepheid) and used line immunoassay (Inno-LIA, Fujiribio) for RNA-negative participants. We did target-enrichment whole-genome HCV sequencing (NextSeq, Illumina). Among 96,386 censused individuals, we randomly selected 1661 people aged ≥16 years. Population-standardized HCV RNA prevalence was 0.2% (95% CI 0.1-0.5). Among 236 patients with cirrhosis and HCC, HCV RNA prevalence was 1.9% and 5.0%, respectively. Mapping showed that HCV RNA+ patients were from peri-urban areas surrounding Blantyre. Community and hospital HCV RNA+ participants were older than comparator HCV RNA-negative populations (median 53 vs 30 years for community, p = 0.01 and 68 vs 40 years for cirrhosis/HCC, p < 0.001). Endemic HCV genotypes (n = 10) were 4v (50%), 4r (30%) and 4w (10%). In this first census-based community serological study in Southern Africa, HCV was uncommon in the general population, was centred on peri-urban regions and was attributable for <5% of liver disease. HCV infection was observed only among older people, suggesting a historic mechanism of transmission. Genotype 4r, which has been associated with treatment failure with ledipasvir and daclatasvir, is endemic.

Secular trends in incidence and mortality of cervical cancer in India and its states, 1990-2019: data from the Global Burden of Disease 2019 Study.

BACKGROUND: Cervical cancer is the fourth most common cancer that occurs to women worldwide. This study aims to assess trends in incidence and mortality of cervical cancer in India and its states over past three decades for tracking the progress of strategies for the prevention and control of cervical cancer. METHODS: Data on cervical cancer incidence and mortality from 1990 to 2019 for India and its states were extracted from Global Burden of Disease study and were utilized for the analysis. Spatial and rank map has been used to see the changes in incidence and mortality of cervical cancer in different Indian states. Further, joinpoint regression analysis is applied to determine the magnitude of the time trends in the age standardized incidence and mortality rates of cervical cancer. We obtained the average annual percent change (AAPC) and corresponding 95% confidence intervals (CI) for each state. RESULTS: Overall, from 1990 to 2019 Jharkhand (Incidence: -50.22%; Mortality: -56.16%) recorded the highest percentage decrement in cervical cancer incidence and mortality followed by the Himachal Pradesh (Incidence: -48.34%; Mortality: -53.37%). Tamilnadu (1st rank), Jammu & Kashmir and Ladakh (32nd rank) maintained the same rank over the period of three decade for age standardized cervical cancer incidence and mortality. The regression model showed a significant declining trend in India between 1990 and 2019 for age standardized incidence rate (AAPC: -0.82; 95%CI: -1.39 to -0.25; p < 0.05) with highest decline in the period 1998-2005 (AAPC: -3.22; 95%CI: -3.83 to -2.59; p < 0.05). Similarly, a significant declining trend was observed in the age standardized mortality rate of India between 1990 and 2019(AAPC: -1.35; 95%CI: -1.96 to -0.75; p < 0.05) with highest decline in the period 1998-2005 (AAPC: -3.52; 95%CI: -4.17 to -2.86; p < 0.05). CONCLUSION: Though the incidence and mortality of cervical cancer declined over past three decades but it is still a major public health problem in India. Information, education and communication activities for girls, boys, parents and community for the prevention and control of cervical cancer should be provided throughout the country.

Inhibition of Phospholipase by Orlistat as an Alternate Therapy to Combat Opportunistic Mycosis Caused by C. albicans.

Candida albicans is one of the most important etiological agents causing an opportunistic mycosis, candidiasis. In the past, it was perceived to be associated with immunocompromised patients only. However, it has now been reported with several clinical complications with varying severity. Additionally, increasing incidences of multiple drug resistance associated with the infections have complicated its treatment as well. Therefore, an investigation of alternate therapy, for instance, inhibition of the virulence factors is desperately needed. In the present study, a multidrug-resistant Candida albicans SDL-4 was screened for secretion of the virulence factors: aspartyl proteases and phospholipases. The pathogen secreted phospholipases potentially compared to aspartyl proteases. Therefore, C. albicans SDL-4 phospholipase was purified to homogeneity, characterized, and its inhibition was studied subsequently. It catalysed the substrate, p-nitrophenyl palmitate, optimally in 0.1 M acetate buffer, pH 5, at 37 °C. In the present study, we also aimed to re-purpose orlistat, which is a commercially available anti-obesity drug. Orlistat, at the concentration of 360 µg/ml, could diminish the activity and stability of the candidal virulence factor. Its half-life was reduced in the presence of orlistat at 37 °C. As well, increase in Km and unaltered Vmax indicated that orlistat inhibited phospholipase competitively. The inhibition kinetics was supported by measuring alterations in the secondary structure of the candidal phospholipase upon treatment with orlistat by the circular dichroism spectroscopy and K2D3. Moreover, validation of the study at clinical level may establish orlistat as a supportive treatment to reduce invasiveness and related medical intricacies during candidiasis.

Widespread Prevalence of Antibodies Against Swine Influenza A (pdm H1N1 09) Virus in Pigs of Eastern Uttar Pradesh, India.

Swine influenza virus (SIV) belongs to family Orthomyxoviridae and can cause acute respiratory infection in pigs. Several pandemic H1N1 human fatal influenza cases were reported in India. Though pigs are predisposed to both avian and human influenza virus infections with the potential to generate novel reassortants, there are only a few reports of SIV in Indian pigs. We conducted a serological survey to assess the status of H1N1 infection in pigs of various states in India, between 2009 and 2016. Based on Haemagglutination inhibition (HI) assay, seroprevalence rate of H1N1 virus ranged between 5.2% (2009) and 36.3% (2011). Widespread prevalence of antibody was observed in eastern Uttar Pradesh from 6.2 to 37.5% during the study period. Co-circulation of seasonal H1N1 virus along with pandemic H1N1 virus was indicated by the presence of specific antibodies against seasonal H1N1 virus in eastern part of Uttar Pradesh. Seroprevalence rate in pigs and influenza infection trend in human shows the possible spill over transmission of influenza to pigs from human. Hence, besides serological surveillance, continuous and systematic molecular surveillance should be implemented in pig population to reduce/quantify the risk and emergence of pandemic influenza.

Trends in incidence and mortality of tuberculosis in India over past three decades: a joinpoint and age-period-cohort analysis.

BACKGROUND: Tuberculosis, as a communicable disease, is an ongoing global epidemic that accounts for high burden of global mortality and morbidity. Globally, with an estimated 10 million new cases and around 1.4 million deaths, TB has emerged as one of the top 10 causes of morbidity and mortality in 2019. Worst hit 8 countries account for two thirds of the new TB cases in 2019, with India leading the count. Despite India's engagement in various TB control activities since its first recognition through the resolution passed in the All-India Sanitary Conference in 1912 and launch of first National Tuberculosis Control Programme in 1962, it has remained a major public health challenge to overcome. To accelerate progress towards the goal of ending TB by 2025, 5 years ahead of the global SDG target, it is imperative to outline the incidence and mortality trends of tuberculosis in India. This study aims to provide deep insights into the recent trends of TB incidence and mortality in India from 1990 to 2019. METHODS: This is an observational study based on the most recent data from the Global Burden of Disease (GBD) Study 2019. We extracted numbers, age-specific and age-standardized incidence and mortality rates of Tuberculosis for the period 1990-2019 from the Global Health Data Exchange. The average annual percent change (AAPC) along with 95% Confidence Interval (CI) in incidence and mortality were derived by joinpoint regression analysis; the net age, period, and cohort effects on the incidence and mortality rates were estimated by using Age-Period-Cohort model. RESULTS: During the study period, age-standardized incidence and mortality rates of TB in India declines from 390.22 to 223.01 and from 121.72 to 36.11 per 100,000 population respectively. The Joinpoint regression analysis showed a significant decreasing pattern in incidence rates in India between 1990 and 2019 for both male and female; but larger decline was observed in case of females (AAPC: - 2.21; 95% CI: - 2.29 to - 2.12; p < 0.001) as compared to males (AAPC: - 1.63; 95% CI: - 1.71 to - 1.54; p < 0.001). Similar pattern was observed for mortality where the declining trend was sharper for females (AAPC: - 4.35; 95% CI: - 5.12 to - 3.57; p < 0.001) as compared to males (AAPC: - 3.88; 95% CI: - 4.63 to - 3.11; p < 0.001). For age-specific rates, incidence and mortality rates of TB decreased for both male and female across all ages during this period. The age effect showed that both incidence and mortality significantly increased with advancing age; period effect showed that both incidence and mortality decreased with advancing time period; cohort effect on TB incidence and mortality also decreased from earlier birth cohorts to more recent birth cohorts. CONCLUSION: Mortality and Incidence of TB decreased across all age groups for both male and female over the period 1990-2019. The incidence as well as mortality was higher among males as compared to females. The net age effect showed an unfavourable trend while the net period effect and cohort effect presented a favourable trend. Aging was likely to drive a continued increase in the mortality of TB. Though the incidence and mortality of tuberculosis significantly decreased from 1990 to 2019, the annual rate of reduction is not sufficient enough to achieve the aim of India's National Strategic plan 2017-2025. Approximately six decades since the launch of the National Tuberculosis Control Programme, TB still remains a major public health problem in India. Government needs to strengthen four strategic pillars "Detect-Treat-Prevent-Build" (DTPB) in order to achieve TB free India as envisaged in the National Tuberculosis Elimination Programme (2020).

Early Insights From Clinical Trials of Typhoid Conjugate Vaccine.

Clinical trials of typhoid conjugate vaccine (TCV) are ongoing in 4 countries. Early data confirm safety, tolerability, and immunogenicity of typhoid conjugate vaccine, and early efficacy results are promising. These data support World Health Organization recommendations and planned country introductions. Forthcoming trial data will continue to inform programmatic use of typhoid conjugate vaccine.

Beyond chemoradiotherapy: improving treatment outcomes for patients with stage III unresectable non-small-cell lung cancer through immuno-oncology and durvalumab (Imfinzi®â–¼, AstraZeneca UK Limited).

The treatment paradigm of non-small-cell lung cancer (NSCLC) has rapidly changed in recent years following the introduction of immune-checkpoint inhibition (ICI). Pre-clinically, both chemotherapy and radiotherapy modulate the tumour microenvironment, providing the rationale for clinical trials evaluating their role in combination with immunotherapy. Standard-of-care treatment for patients with unresectable stage III disease is concurrent chemoradiotherapy (cCRT); however, only recently, the combination with ICI has been explored. The Phase 3 PACIFIC study randomised 713 patients with confirmed locally advanced, unresectable, stage III NSCLC, whose disease has not progressed following cCRT, to either the anti-programmed death-ligand 1 (PD-L1) agent durvalumab (Imfinzi®â–¼, AstraZeneca UK Limited) or placebo. Patients with a PD-L1 status ≥1% treated with durvalumab had a significantly longer median progression-free survival compared with placebo (17.2 vs. 5.6 months, respectively; HR: 0.51; 95% CI: 0.41-0.63), prolonged median overall survival (OS) (NR vs. 28.7 months, respectively; HR: 0.68; 99.73% CI: 0.47-0.997; P = 0.0025) and long-term clinical benefit (3-year OS HR: 0.69; 95% CI: 0.55-0.86). Grade 3 or 4 toxicity was marginally greater in the durvalumab cohort versus placebo (30.5% vs. 26.1%). Based on these results, durvalumab has been licensed in this setting, and further clinical trials are exploring the use of ICI in unresectable stage III NSCLC.

Compounding Benefits of Sentinel Lymph Node Biopsy for Perineal Melanoma: A Population-Based Retrospective Cohort Analysis.

INTRODUCTION: Sentinel lymph node biopsy (SLNB) in the treatment of melanoma is known to provide valuable prognostic information. However, there is no literature describing an overall or disease-specific survival (DDS) benefit of SLNB. In the perineum, melanoma is often more advanced at presentation with current treatment guidelines translated from nonanatomic specific melanoma. As a result, there is little understanding surrounding the role of SLNB in melanoma of the perineum. Our objective is to better understand the therapeutic benefits of SLNB in perineal melanoma. METHODS: The Surveillance, Epidemiology, and End Results program is a large population-based cancer registry including survival data from millions of patients in the United States. The registry was used to generate patient data for analysis from 2004 to 2016. Inclusion criteria included melanoma of the perineum; Breslow depth of 0.80 mm or greater and less than 0.80 mm with ulceration; SLNB or no intervention; clinically negative nodal disease; and available overall survival data. RESULTS: For 879 patients from 2004 to 2016 with perineal melanoma, significant predictors of reduced survival include older than 75 years, Clark level IV-V, Breslow depth of greater than 4.00 mm, positive ulceration status, regional and distant nodal micrometastases, and clinically positive nodes on presentation. Aggregates for overall survival (OS) and disease-specific survival (DSS) were improved with implementation of SLNB. The 5-year survival rates with SLNB versus no SLNB were 54.0% and 43.0% for OS (P = 0.001) and 57.8% and 53.1% for DSS (P = 0.044). Stratification by Breslow depth yielded significant OS and DSS advantage for greater than 1.00 to 2.00 mm (21.3% benefit, P =0.021, and 16.8% benefit, P = 0.044) and greater than 4.00 mm (30.3% benefit, P = 0.005, and 21.0% benefit, P = 0.007) Breslow depths. CONCLUSIONS AND RELEVANCE: Sentinel lymph node biopsy may provide therapeutic benefits in addition to prognostic information for melanoma of the perineum through an increase in 5-year OS.

Community Engagement Before Initiation of Typhoid Conjugate Vaccine Trial in Schools in Two Urban Townships in Blantyre, Malawi: Experience and Lessons.

BACKGROUND: To determine the efficacy of a new typhoid conjugate vaccine in an endemic setting in sub-Saharan Africa, the Typhoid Vaccine Acceleration Consortium is conducting a phase-3 randomized controlled trial in Blantyre, Malawi. This article describes community and stakeholder engagement activities before and during the trial, challenges, and lessons learned. METHODS: In October 2017, Malawi-Liverpool Wellcome Trust (MLW) organized a wide range of community engagement activities, including meetings with Ministry of Health and Education officials at the district and facility level, local community leadership, and parent teacher association groups. We engaged media outlets to include local and international television, radio, and print media. Community members were informed directly through a study jingle played via loudspeaker from a van and by community-based activities.To review engagement activity effectiveness: The MLW team met to discuss progress and challenges; and a focus group discussion (FGD), consisting of trial staff, sought feedback from the community on each engagement modality. RESULTS: The school-based vaccine campaign increased community participation exceeding recruitment targets to date (on average, >200 children/day). CONCLUSIONS: The FGD concluded that the van and local activities improved awareness and turnout for the trial, but prior engagement with local government and community leadership is an essential mechanism to provide details of the study, answer questions, communicate the value of the study, and address safety concerns. Effective community engagement is essential in a large intervention trial. Multiple channels of communication are required to reach the community and deliver information needed for participation and provide opportunity for dialogue with the trial team.

Typhoid Vaccine Acceleration Consortium Malawi: A Phase III, Randomized, Double-blind, Controlled Trial of the Clinical Efficacy of Typhoid Conjugate Vaccine Among Children in Blantyre, Malawi.

BACKGROUND: Typhoid fever is an acute infection characterized by prolonged fever following the ingestion and subsequent invasion of Salmonella enterica serovar Typhi (S. Typhi), a human-restricted pathogen. The incidence of typhoid fever has been most reported in children 5-15 years of age, but is increasingly recognized in children younger than 5 years old. There has been a recent expansion of multidrug-resistant typhoid fever globally. Prior typhoid vaccines were not suitable for use in the youngest children in countries with a high burden of disease. This study aims to determine the efficacy of a typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization, by testing it in children 9 months through 12 years of age in Blantyre, Malawi. METHODS: In this Phase III, individually randomized, controlled, double-blind trial of the clinical efficacy of TCV, 28 000 children 9 months through 12 years of age will be enrolled and randomized in a 1:1 ratio to receive either Vi-TCV or a meningococcal serogroup A conjugate vaccine. A subset of 600 of these children will be further enrolled in an immunogenicity and reactogenicity sub-study to evaluate the safety profile and immune response elicited by Vi-TCV. Recruiting began in February 2018. RESULTS: All children will be under passive surveillance for at least 2 years to determine the primary outcome, which is blood culture-confirmed S. Typhi illness. Children enrolled in the immunogenicity and reactogenicity sub-study will have blood drawn before vaccination and at 2 timepoints after vaccination to measure their immune response to vaccination. They will also be followed actively for adverse events and serious adverse events. CONCLUSIONS: The introduction of a single-dose, efficacious typhoid vaccine into countries with high burden of disease or significant antimicrobial resistance could have a dramatic impact, protecting children from infection and reducing antimicrobial usage and associated health inequity in the world's poorest places. This trial, the first of a TCV in Africa, seeks to demonstrate the impact and programmatic use of TCVs within an endemic setting. CLINICAL TRIALS REGISTRATION: NCT03299426.

Axonal localization of neuritin/CPG15 mRNA is limited by competition for HuD binding.

HuD protein (also known as ELAVL4) has been shown to stabilize mRNAs with AU-rich elements (ARE) in their 3' untranslated regions (UTRs), including Gap43, which has been linked to axon growth. HuD also binds to neuritin (Nrn1) mRNA, whose 3'UTR contains ARE sequences. Although the Nrn1 3'UTR has been shown to mediate its axonal localization in embryonic hippocampal neurons, it is not active in adult dorsal root ganglion (DRG) neurons. Here, we asked why the 3'UTR is not sufficient to mediate the axonal localization of Nrn1 mRNA in DRG neurons. HuD overexpression increases the ability of the Nrn1 3'UTR to mediate axonal localizing in DRG neurons. HuD binds directly to the Nrn1 ARE with about a two-fold higher affinity than to the Gap43 ARE. Although the Nrn1 ARE can displace the Gap43 ARE from HuD binding, HuD binds to the full 3'UTR of Gap43 with higher affinity, such that higher levels of Nrn1 are needed to displace the Gap43 3'UTR. The Nrn1 3'UTR can mediate a higher level of axonal localization when endogenous Gap43 is depleted from DRG neurons. Taken together, our data indicate that endogenous Nrn1 and Gap43 mRNAs compete for binding to HuD for their axonal localization and activity of the Nrn1 3'UTR.