Safety and immunogenicity of an Ad26.ZEBOV booster vaccine in Human Immunodeficiency Virus positive (HIV+) adults previously vaccinated with the Ad26.ZEBOV, MVA-BN-Filo vaccine regimen against Ebola: A single-arm, open-label Phase II clinical trial in Kenya and Uganda.

BACKGROUND: People living with HIV constitute an important part of the population in regions at risk of Ebola virus disease outbreaks. The two-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine regimen induces strong immune responses in HIV-positive (HIV+) adults but the durability of this response is unknown. It is also unclear whether this regimen can establish immune memory to enable an anamnestic response upon re-exposure to antigen. METHODS: This paper describes an open-label, phase 2 trial, conducted in Kenya and Uganda, of Ad26.ZEBOV booster vaccination in HIV+ participants who had previously received the Ad26.ZEBOV, MVA-BN-Filo primary regimen. HIV+ adults with well-controlled infection and on highly active antiretroviral therapy were enrolled, vaccinated with booster, and followed for 28 days. The primary objectives were to assess Ad26.ZEBOV booster safety and antibody responses against the Ebola virus glycoprotein using the Filovirus Animal Non-Clinical Group ELISA. RESULTS: The Ad26.ZEBOV booster was well-tolerated in HIV+ adults with mostly mild to moderate symptoms. No major safety concerns or serious adverse events were reported. Four and a half years after the primary regimen, 24/26 (92 %) participants were still classified as responders, with a pre-booster antibody geometric mean concentration (GMC) of 726 ELISA units (EU)/mL (95 %CI 447-1179). Seven days after the booster, the GMC increased 54-fold to 38,965 EU/mL (95 %CI 23532-64522). Twenty-one days after the booster, the GMC increased 176-fold to 127,959 EU/mL (95 %CI 93872-174422). The responder rate at both post-booster time points was 100 %. CONCLUSIONS: The Ad26.ZEBOV booster is safe and highly immunogenic in HIV+ adults with well-controlled infection. The Ad26.ZEBOV, MVA-BN-Filo regimen can generate long-term immune memory persisting for at least 4·5 years, resulting in a robust anamnestic response. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR202102747294430). CLINICALTRIALS: gov (NCT05064956).

Differential absolute plasma IL-6 concentrations between two immunoassay platforms in intensive care unit patients with COVID-19.

Objectives: Explore whether plasma IL-6 levels are similar across biomarker platforms and association with COVID-19 clinical outcomes. Methods: Plasma IL-6 concentrations were measured on 191 COVID-19 patients using the Roche Elecsys IL-6 assay and the Meso Scale Discovery assay. Results: Correlation of IL-6 levels between platforms was high (r = 0.87; 95% CI: 0.82-0.89); however, agreement was low (bias: 147.2 pg/ml; 95% limits of agreement: -489.5-783.9 pg/ml). The optimal IL-6 threshold to predict invasive mechanical ventilation and in-hospital mortality were 3- and 3.4-fold higher in Roche compared with Meso Scale Discovery, respectively. Conclusion: The absolute IL-6 threshold to predict outcomes was consistently higher using the Roche platform, and IL-6 thresholds to inform prognosis vary based on the biomarker platform.

Biomarker Signatures of Severe Acute Kidney Injury in a Critically Ill Cohort of COVID-19 and Non-COVID-19 Acute Respiratory Illness.

Kidney and lung injury are closely inter-related during acute respiratory illness, but the molecular risk factors that these organ injuries share are not well defined. OBJECTIVES: We identified plasma biomarkers associated with severe acute kidney injury (AKI) during acute respiratory illness, and compared them to biomarkers associated with severe acute respiratory failure (ARF). DESIGN SETTINGS AND PARTICIPANTS: Prospective observational cohort study enrolling March 2020 through May 2021, at three hospitals in a large academic health system. We analyzed 301 patients admitted to an ICU with acute respiratory illness. MAIN OUTCOMES AND MEASURES: Outcomes were ascertained between ICU admission and day 14, and included: 1) severe AKI, defined as doubling of serum creatinine or new dialysis and 2) severe ARF, which included new or persistent need for high-flow oxygen or mechanical ventilation. We measured biomarkers of immune response and endothelial function, pathways related to adverse kidney and lung outcomes, in plasma collected within 24 hours of ICU admission. Severe AKI occurred in 48 (16%), severe ARF occurred in 147 (49%), and 40 (13%) patients experienced both. Two-fold higher concentrations of soluble tumor necrosis factor receptor-1 (sTNFR-1) (adjusted relative risk [aRR], 1.56; 95% CI, 1.24-1.96) and soluble triggering receptor on myeloid cells-1 (sTREM-1) (aRR, 1.85; 95% CI, 1.42-2.41), biomarkers of innate immune activation, were associated with higher risk for severe AKI after adjustment for age, sex, COVID-19, and Acute Physiology and Chronic Health Evaluation-III. These biomarkers were not significantly associated with severe ARF. Soluble programmed cell death receptor-1 (sPDL-1), a checkpoint pathway molecule, as well as soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), molecules involved with endothelial-vascular leukocyte adhesion, were associated with both severe AKI and ARF. CONCLUSIONS AND RELEVANCE: sTNFR-1 and sTREM-1 were linked strongly to severe AKI during respiratory illness, while sPDL-1, sICAM-1 and sVCAM-1 were associated with both severe AKI and ARF. These biomarker signatures may shed light on pathophysiology of lung-kidney interactions, and inform precision medicine strategies for identifying patients at high risk for these organ injuries.

Mitochondrial N-formyl methionine peptides contribute to exaggerated neutrophil activation in patients with COVID-19.

Neutrophil dysregulation is well established in COVID-19. However, factors contributing to neutrophil activation in COVID-19 are not clear. We assessed if N-formyl methionine (fMet) contributes to neutrophil activation in COVID-19. Elevated levels of calprotectin, neutrophil extracellular traps (NETs) and fMet were observed in COVID-19 patients (n = 68), particularly in critically ill patients, as compared to HC (n = 19, p < 0.0001). Of note, the levels of NETs were higher in ICU patients with COVID-19 than in ICU patients without COVID-19 (p < 0.05), suggesting a prominent contribution of NETs in COVID-19. Additionally, plasma from COVID-19 patients with mild and moderate/severe symptoms induced in vitro neutrophil activation through fMet/FPR1 (formyl peptide receptor-1) dependent mechanisms (p < 0.0001). fMet levels correlated with calprotectin levels validating fMet-mediated neutrophil activation in COVID-19 patients (r = 0.60, p = 0.0007). Our data indicate that fMet is an important factor contributing to neutrophil activation in COVID-19 disease and may represent a potential target for therapeutic intervention.

Safety and immunogenicity of an Ad26.ZEBOV booster dose in children previously vaccinated with the two-dose heterologous Ad26.ZEBOV and MVA-BN-Filo Ebola vaccine regimen: an open-label, non-randomised, phase 2 trial.

BACKGROUND: Children account for a substantial proportion of cases and deaths during Ebola virus disease outbreaks. We aimed to evaluate the safety and immunogenicity of a booster dose of the Ad26.ZEBOV vaccine in children who had been vaccinated with a two-dose regimen comprising Ad26.ZEBOV as dose one and MVA-BN-Filo as dose two. METHODS: We conducted an open-label, non-randomised, phase 2 trial at one clinic in Kambia Town, Sierra Leone. Healthy children, excluding pregnant or breastfeeding girls, who had received the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen in a previous study, and were aged 1-11 years at the time of their first vaccine dose, received an intramuscular injection of Ad26.ZEBOV (5 × 1010 viral particles) and were followed up for 28 days. Primary outcomes were safety (measured by adverse events) and immunogenicity (measured by Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration) of the booster vaccine dose. Safety was assessed in all participants who received the booster vaccination; immunogenicity was assessed in all participants who received the booster vaccination, had at least one evaluable sample after the booster, and had no major protocol deviations that could have influenced the immune response. This trial is registered with ClinicalTrials.gov, NCT04711356. FINDINGS: Between July 8 and Aug 18, 2021, 58 children were assessed for eligibility and 50 (27 aged 4-7 years and 23 aged 9-15 years) were enrolled and received an Ad26.ZEBOV booster vaccination, more than 3 years after receiving dose one of the Ad26.ZEBOV and MVA-BN-Filo vaccine regimen. The booster was well tolerated. The most common solicited local adverse event during the 7 days after vaccination was injection site pain, reported in 18 (36%, 95% CI 23-51) of 50 participants. The most common solicited systemic adverse event during the 7 days after vaccination was headache, reported in 11 (22%, 12-36) of 50 participants. Malaria was the most common unsolicited adverse event during the 28 days after vaccination, reported in 25 (50%, 36-64) of 50 participants. No serious adverse events were observed during the study period. 7 days after vaccination, the Ebola virus glycoprotein-specific IgG binding antibody geometric mean concentration was 28 561 ELISA units per mL (95% CI 20 255-40 272), which was 44 times higher than the geometric mean concentration before the booster dose. 21 days after vaccination, the geometric mean concentration reached 64 690 ELISA units per mL (95% CI 48 356-86 541), which was 101 times higher than the geometric mean concentration before the booster dose. INTERPRETATION: A booster dose of Ad26.ZEBOV in children who had received the two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen more than 3 years earlier was well tolerated and induced a rapid and robust increase in binding antibodies against Ebola virus. These findings could inform Ebola vaccination strategies in paediatric populations. FUNDING: Innovative Medicines Initiative 2 Joint Undertaking. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Plasma Interleukin-6 Predicts Clinical Decline After Completion of Dexamethasone Therapy in Severe COVID-19.

To identify and characterize clinical decline after completion of dexamethasone in severe COVID-19 and determine whether interleukin (IL)-6 and other inflammatory biomarkers predict the occurrence of clinical decline. DESIGN: Prospective observational cohort. SETTING: ICUs in three University of Washington affiliated hospitals between July 2020 and April 2021. PATIENTS: Patients admitted to an ICU with COVID-19 who completed a course of dexamethasone. MEASUREMENTS AND MAIN RESULTS: We identified 65 adult patients with severe COVID-19 who completed a 10-day course of dexamethasone, of whom 60 had plasma samples collected within 3 days of dexamethasone completion. We measured IL-6 with a clinical-grade electrochemiluminescent assay and a larger panel of inflammatory biomarkers (IL-8, Monocyte Chemoattractant Protein-1, Monocyte Inflammatory Protein-1 alpha, interferon gamma, C-X-C Motif Chemokine Ligand 10, WBC, bicarbonate) with a research immunoassay. We defined clinical decline by the occurrence of incident severe kidney injury, incident or escalating shock or fever, worsening hypoxemia, or death within 5 days of completion of dexamethasone. We estimated risk for clinical decline by standardized log2 transformed biomarker concentration using multivariable logistic regression. Clinical decline post-dexamethasone was common, occurring in 49% of patients (n = 32). Among all biomarkers, IL-6 levels were most strongly associated with clinical decline. After adjustment for age, sex, and study site, the odds of post-dexamethasone clinical decline were 7.33 times higher per one sd increase in log2 transformed IL-6 concentrations (adjusted odds ratio, 7.33; CI, 2.62-20.47; p < 0.001). The discriminatory power of IL-6 for clinical decline was high (cross-validated mean area under the receiver operating characteristic curve, 0.90; 95% CI, 0.79-0.95). CONCLUSIONS: Clinical decline after completion of dexamethasone for severe COVID-19 is common. IL-6 concentrations obtained prior to completion of dexamethasone may have utility in identifying those at highest risk for subsequent worsening. If validated, future work might test whether plasma IL-6 could be used as a tool for a personalized approach to duration of dexamethasone treatment in severe COVID-19.

General Synthetic Approach to Diverse Taxane Cores.

Chemical synthesis of natural products is typically inspired by the structure and function of a target molecule. When both factors are of interest, such as in the case of taxane diterpenoids, a synthesis can both serve as a platform for synthetic strategy development and enable new biological exploration. Guided by this paradigm, we present here a unified enantiospecific approach to diverse taxane cores from the feedstock monoterpenoid (S)-carvone. Key to the success of our approach was the use of a skeletal remodeling strategy which began with the divergent reorganization and convergent coupling of two carvone-derived fragments, facilitated by Pd-catalyzed C-C bond cleavage tactics. This coupling was followed by additional restructuring using a Sm(II)-mediated rearrangement and a bioinspired, visible-light induced, transannular [2 + 2] photocycloaddition. Overall, this divergent monoterpenoid remodeling/convergent fragment coupling approach to complex diterpenoid synthesis provides access to structurally disparate taxane cores which have set the stage for the preparation of a wide range of taxanes.

Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case-control analysis.

OBJECTIVE: Risk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved preventive measures and antibiotic stewardship. METHODS: Five sites in Bangladesh, India and Pakistan enrolled mother-child pairs via population-based pregnancy surveillance by community health workers. Medical, sociodemographic and epidemiological risk factor data were collected. Young infants aged 0-59 days with signs of possible serious bacterial infection (pSBI) and age-matched controls provided blood and respiratory specimens that were analysed by blood culture and real-time PCR. These tests were used to build a Bayesian partial latent class model (PLCM) capable of attributing the probable cause of each infant's infection in the ANISA study. The collected risk factors from all mother-child pairs were classified and analysed against the PLCM using bivariate and stepwise logistic multivariable regression modelling to determine risk factors of probable bacterial infection. RESULTS: Among 63 114 infants born, 14 655 were assessed and 6022 had signs of pSBI; of these, 81% (4859) provided blood samples for culture, 71% (4216) provided blood samples for quantitative PCR (qPCR) and 86% (5209) provided respiratory qPCR samples. Risk factors associated with bacterial-attributed infections included: low (relative risk (RR) 1.73, 95% credible interval (CrI) 1.42 to 2.11) and very low birth weight (RR 5.77, 95% CrI 3.73 to 8.94), male sex (RR 1.27, 95% CrI 1.07 to 1.52), breathing problems at birth (RR 2.50, 95% CrI 1.96 to 3.18), premature rupture of membranes (PROMs) (RR 1.27, 95% CrI 1.03 to 1.58) and being in the lowest three socioeconomic status quintiles (first RR 1.52, 95% CrI 1.07 to 2.16; second RR 1.41, 95% CrI 1.00 to 1.97; third RR 1.42, 95% CrI 1.01 to 1.99). CONCLUSION: Distinct risk factors: birth weight, male sex, breathing problems at birth and PROM were significantly associated with the development of bacterial sepsis across South Asian community settings, supporting refined clinical discernment and targeted use of antimicrobials.

Presence of Antibodies to Severe Acute Respiratory Syndrome Coronavirus-2 on Admission Is Associated With Decreased Mortality in COVID-19 Critical Illness.

To determine whether the early serologic response in COVID-19 critical illness is associated with hospital mortality. To evaluate if time-to-seroconversion differs by receipt of dexamethasone therapy. DESIGN: Patients were prospectively enrolled within 24 hours of ICU admission from two University of Washington Hospitals. Plasma was collected on enrollment and on days 3, 7, 10, and 14. SETTING: ICUs between March 2020 and April 2021. PATIENTS: Consecutive adults with COVID-19 admitted to an ICU. MEASUREMENTS AND MAIN RESULTS: We measured longitudinal total antispike protein antibody levels (anti-S abs) and total antinucleocapsid antibody levels (anti-N ab) using a U.S. Food and Drug Administration-authorized Roche instrument. We evaluated whether detectable anti-S abs on ICU admission were associated with host factors, initial disease severity, and hospital mortality. We evaluated whether dexamethasone therapy was associated with time-to-seroconversion. Among 93 unvaccinated participants, 47 (51%) had detectable anti-S abs on ICU admission. There was no difference in Acute Physiology and Chronic Health Evaluation II score or time between first positive severe acute respiratory syndrome coronavirus-2 PCR and ICU admission in those with detectable versus undetectable anti-S abs. Adjusting for age, body mass index, and sex, patients with detectable anti-S abs had a lower risk of inhospital death (hazard ratio, 0.40; 95% CI, 0.17-0.94; p = 0.04). Among 21 patients with undetectable anti-S abs on ICU admission and serial measurements available, time-to-seroconversion was not significantly affected by receipt of dexamethasone therapy. CONCLUSIONS: In COVID-19 critical illness, a significant proportion of patients do not have detectable antibodies at ICU admission, and this is independent of severity of illness. Detectable anti-S abs were associated with lower risk of inhospital death. Despite concern that corticosteroids may impair an appropriate antiviral serologic response, early antibody kinetics were not significantly affected by administration of dexamethasone; however, CIs were wide and require further study.

Immunogenicity and safety of one-dose human papillomavirus vaccine compared with two or three doses in Tanzanian girls (DoRIS): an open-label, randomised, non-inferiority trial.

BACKGROUND: An estimated 15% of girls aged 9-14 years worldwide have been vaccinated against human papillomavirus (HPV) with the recommended two-dose or three-dose schedules. A one-dose HPV vaccine schedule would be simpler and cheaper to deliver. We report immunogenicity and safety results of different doses of two different HPV vaccines in Tanzanian girls. METHODS: In this open-label, randomised, phase 3, non-inferiority trial, we enrolled healthy schoolgirls aged 9-14 years from Government schools in Mwanza, Tanzania. Eligible participants were randomly assigned to receive one, two, or three doses of either the 2-valent vaccine (Cervarix, GSK Biologicals, Rixensart) or the 9-valent vaccine (Gardasil-9, Sanofi Pasteur MSD, Lyon). The primary outcome was HPV 16 specific or HPV 18 specific seropositivity following one dose compared with two or three doses of the same HPV vaccine 24 months after vaccination. Safety was assessed as solicited adverse events up to 30 days after each dose and unsolicited adverse events up to 24 months after vaccination or to last study visit. The primary outcome was done in the per-protocol population, and safety was analysed in the total vaccinated population. This study was registered in ClinicalTrials.gov, NCT02834637. FINDINGS: Between Feb 23, 2017, and Jan 6, 2018, we screened 1002 girls for eligibility. 72 girls were excluded. 930 girls were enrolled and randomly assigned to receive one dose of Cervarix (155 participants), two doses of Cervarix (155 participants), three doses of Cervarix (155 participants), one dose of Gardasil-9 (155 participants), two doses of Gardasil-9 (155 participants), or three doses of Gardasil-9 (155 participants). 922 participants received all scheduled doses within the defined window (three withdrew, one was lost to follow-up, and one died before completion; two received their 6-month doses early, and one received the wrong valent vaccine in error; all 930 participants were included in the total vaccinated cohort). Retention at 24 months was 918 (99%) of 930 participants. In the according-to-protocol cohort, at 24 months, 99% of participants who received one dose of either HPV vaccine were seropositive for HPV 16 IgG antibodies, compared with 100% of participants who received two doses, and 100% of participants who received three doses. This met the prespecified non-inferiority criteria. Anti-HPV 18 seropositivity at 24 months did not meet non-inferiority criteria for one dose compared to two doses or three doses for either vaccine, although more than 98% of girls in all groups had HPV 18 antibodies. 53 serious adverse events (SAEs) were experienced by 42 (4·5%) of 930 girls, the most common of which was hospital admission for malaria. One girl died of malaria. Number of events was similar between groups and no SAEs were considered related to vaccination. INTERPRETATION: A single dose of the 2-valent or 9-valent HPV vaccine in girls aged 9-14 years induced robust immune responses up to 24 months, suggesting that this reduced dose regimen could be suitable for prevention of HPV infection among girls in the target age group for vaccination. FUNDING: UK Department for International Development/UK Medical Research Council/Wellcome Trust Joint Global Health Trials Scheme, The Bill & Melinda Gates Foundation, and the US National Cancer Institute. TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

Infectious aetiologies of neonatal illness in south Asia classified using WHO definitions: a primary analysis of the ANISA study.

BACKGROUND: Globally, neonatal mortality accounts for almost half of all deaths in children younger than 5 years. Aetiological agents of neonatal infection are difficult to identify because the clinical signs are non-specific. Using data from the Aetiology of Neonatal Infections in south Asia (ANISA) cohort, we aimed to describe the spectrum of infectious aetiologies of acute neonatal illness categorised post-hoc using the 2015 WHO case definitions of critical illness, clinical severe infection, and fast breathing only. METHODS: Eligible infants were aged 0-59 days with possible serious bacterial infection and healthy infants enrolled in the ANISA study in Bangladesh, India, and Pakistan. We applied a partial latent class Bayesian model to estimate the prevalence of 27 pathogens detectable on PCR, pathogens detected by blood culture only, and illness not attributed to any infectious aetiology. Infants with at least one clinical specimen available were included in the analysis. We assessed the prevalence of these aetiologies according to WHO's case definitions of critically ill, clinical severe infection, and infants with late onset, isolated fast breathing. For the clinical severe definition, we compared the prevalence of signs by bacterial versus viral aetiology. FINDINGS: There were 934 infants (992 episodes) in the critically ill category, 3769 (4000 episodes) in the clinical severe infection category, and 738 (771 episodes) in the late-onset isolated fast breathing category. We estimated the proportion of illness attributable to bacterial infection was 32·7% in infants in the critically ill group, 15·6% in the clinical severe infection group, and 8·8% among infants with late-onset isolated fast breathing group. An infectious aetiology was not identified in 58-82% of infants in these categories. Among 4000 episodes of clinical severe infection, those with bacterial versus viral attribution had higher proportions of hypothermia, movement only when stimulated, convulsions, and poor feeding. INTERPRETATION: Our modelled results generally support the revised WHO case definitions, although a revision of the most severe case definition could be considered. Clinical criteria do not clearly differentiate between young infants with and without infectious aetiologies. Our results highlight the need for improved point-of-care diagnostics, and further study into neonatal deaths and episodes with no identified aetiology, to ensure antibiotic stewardship and targeted interventions. FUNDING: The Bill and Melinda Gates Foundation.

Validation of community health worker identification of maternal puerperal sepsis using a clinical diagnostic algorithm in Bangladesh and Pakistan.

BACKGROUND: Puerperal sepsis (PP sepsis) is a leading cause of maternal mortality globally. The majority of maternal sepsis cases and deaths occur at home and remain undiagnosed and under-reported. In this paper, we present findings from a nested case-control study in Bangladesh and Pakistan which sought to assess the validity of community health worker (CHW) identification of PP sepsis using a clinical diagnostic algorithm with physician assessment and classification used as the gold standard. METHODS: Up to 300 postpartum women were enrolled in each of the 3 sites 1) Sylhet, Bangladesh (n = 278), 2) Karachi, Pakistan (n = 278) and 3) Matiari, Pakistan (n = 300). Index cases were women with suspected PP Sepsis as diagnosed by CHWs clinical assessment of one or more of the following signs and symptoms: temperature (recorded fever ≥38.1°C, reported history of fever, lower abdominal or pelvic pain, and abnormal or foul-smelling discharge. Each case was matched with 3 control women who were diagnosed by CHWs to have no infection. Cases and controls were assessed by trained physicians using the same algorithm implemented by the CHWs. Using physician assessment as the gold standard, Kappa statistics for reliability and diagnostic validity (sensitivity and specificity) are presented with 95% CI. Sensitivity and specificity were adjusted for verification bias. RESULTS: The adjusted sensitivity and specificity of CHW identification of PP sepsis across all sites was 82% (Karachi: 78%, Matiari: 78%, Sylhet: 95%) and 90% (Karachi: 95%, Matiari: 85%, Sylhet: 90%) respectively. CHW-Physician agreement was highest for moderate and high fever (range across sites: K = 0.84-0.97) and lowest for lower abdominal pain (K = 0.30-0.34). The clinical signs and symptoms for other conditions were reported infrequently, however, the CHW-physician agreement was high for all symptoms except severe headache/ blurred vision (K = 0.13-0.38) and reported "lower abdominal pain without fever" (K = 0.39-0.57). CONCLUSION: In all sites, CHWs with limited training were able to identify signs and symptoms and to classify cases of PP sepsis with high validity. Integrating postpartum infection screening into existing community-based platforms and post-natal visits is a promising strategy to monitor women for PP sepsis - improving delivery of cohesive maternal and child health care in low resource settings.

Total Syntheses of Xiamycins†A, C, F, H and Oridamycin†A and Preliminary Evaluation of their Anti-Fungal Properties.

Divergent and enantiospecific total syntheses of the indolosesquiterpenoids xiamycins A, C, F, H and oridamycin A have been accomplished. The syntheses, which commence from (R)-carvone, employ a key photoinduced benzannulation sequence to forge the carbazole moiety characteristic of these natural products. Late-stage diversification from a common intermediate enabled the first syntheses of xiamycins C and F, and an unexpected one-pot oxidative decarboxylation, which may prove general, led to xiamycin H. All synthetic intermediates and the natural products were tested for anti-fungal activity. Xiamycin H emerged as an inhibitor of three agriculturally relevant fungal pathogens.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study.

BACKGROUND: More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. METHODS: From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. FINDINGS: 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. INTERPRETATION: Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. FUNDING: Bill & Melinda Gates Foundation.

Occurrence and fate of Ascaris lumbricoides ova in biosolids in Victoria, Australia: a human health risk assessment of biosolids storage periods.

Reuse of sewage biosolids in Victoria, Australia, typically involves mesophilic anaerobic digestion followed by air-drying and long-term storage to ensure removal of ova of soil-transmitted helminths (STH) such as Ascaris lumbricoides. Long-term storage degrades the biosolids' agronomic quality due to the loss of key plant nutrients and takes up large areas of storage space. The impact of varying biosolids holding times and other processes on STH using Ascaris as the reference STH pathogen was examined in this study using a quantitative risk analysis approach. Risk modelling of the potential human health impacts from the presence of Ascaris ova in biosolids was undertaken for discrete holding periods of 1, 2 and 3 years. Modelling showed that to meet the WHO 1 µDALY·person-1·year-1 disease burdens guideline for limiting exposure category, a biosolids storage period of 1.24 years or 2.1 years would be required, depending on the data source of ova shedding rates per worm (Bangladesh or Nigeria, respectively). The soil exposure and salad/root vegetable consumption models included a number of variables with moderate to high degrees of uncertainty. Monte Carlo simulation was used to assess the effect of uncertainty in model input variables and to assist in highlighting areas for further research.

Helminth log reduction values for recycling water from sewage for the protection of human and stock health.

The LRVs required to decrease HE concentrations in raw sewage to an acceptable level to manage the risk to human and livestock health were determined. An LRV of 3.0 was required to meet the HBT of 1 µDALY pppy in SE Australia where human helminth infections are not endemic. In comparison, a similar exposure volume and LRV in endemic regions would result in a HBT of 100 µDALY pppy. The risks posed by cattle- and pig-related helminths were also managed acceptably with the treatment of sewage providing an LRV of 3.0. New design equations were derived to determine LRVs based on hydraulic residence times (HRTs) in an activated sludge plant (ASP) and lagoons. The new equation for lagoons indicated that an LRV of 3.0 could be achieved with a HRT of 18 days or less.

Centralized Data Management in a Multicountry, Multisite Population-based Study.

BACKGROUND: A centralized data management system was developed for data collection and processing for the Aetiology of Neonatal Infection in South Asia (ANISA) study. ANISA is a longitudinal cohort study involving neonatal infection surveillance and etiology detection in multiple sites in South Asia. The primary goal of designing such a system was to collect and store data from different sites in a standardized way to pool the data for analysis. METHODS: We designed the data management system centrally and implemented it to enable data entry at individual sites. This system uses validation rules and audit that reduce errors. The study sites employ a dual data entry method to minimize keystroke errors. They upload collected data weekly to a central server via internet to create a pooled central database. Any inconsistent data identified in the central database are flagged and corrected after discussion with the relevant site. The ANISA Data Coordination Centre in Dhaka provides technical support for operations, maintenance and updating the data management system centrally. Password-protected login identifications and audit trails are maintained for the management system to ensure the integrity and safety of stored data. CONCLUSION: Centralized management of the ANISA database helps to use common data capture forms (DCFs), adapted to site-specific contextual requirements. DCFs and data entry interfaces allow on-site data entry. This reduces the workload as DCFs do not need to be shipped to a single location for entry. It also improves data quality as all collected data from ANISA goes through the same quality check and cleaning process.

Development and Implementation of the ANISA Labeling and Tracking System for Biological Specimens.

BACKGROUND: The Aetiology of Neonatal Infection in South Asia study is a major effort to determine the causes of community-acquired neonatal infections. It involves collecting epidemiological, clinical and laboratory data in 5 sites in 3 countries. The field and laboratory research operations are streamlined to maintain integrity and validity while operating in complex and variable environments. We developed a customized system for implementation of labeling and tracking biological specimen in both rural and urban community settings and integrated into all study laboratories. This report outlines the development and implementation of this harmonized system. DESIGN: The system links and tracks specimens with study participants and results generated from laboratory tests. Each biological specimen and its aliquots are tracked through key steps of the protocol, from collection and transport through molecular testing and long-term storage. CONCLUSION: The labeling and tracking system allows for standardization and monitoring of laboratory processes and improves the accuracy of Aetiology of Neonatal Infection in South Asia data. Community-based scientific projects could greatly benefit by adopting this, or a similar, system for specimen tracking and data linkage.

Using Text Messages for Critical Real-time Data Capture in the ANISA Study.

BACKGROUND: The Aetiology of Neonatal Infection in South Asia (ANISA) study takes advantage of text messaging technology to record information required for randomizing the study population into a control subcohort. The text message system is also used for monitoring various study activities. METHODS: When a child-health worker registers a newborn in the study, she sends a text message to a database server containing the study identification number and newborn's age at the time of registration. For each possible serious bacterial infection case, a study physician also sends a text message to the same server with the age of the young infant at the time of illness assessment. Using this information, a computer-based algorithm randomizes the newborn into a control subcohort. Text messages are also sent to alert the study physicians and study supervisors of a possible serious bacterial infection case being referred to health-care facilities. Phlebotomists working at remote specimen collection sites send text messages to the site laboratory personnel before sending the specimens through porters. DISCUSSION: Real-time data entry and monitoring are challenging for any population-based study conducted in remote areas. Our text messaging system provides an opportunity to overcome this barrier where availability of data entry facilities is limited.

Methods Employed in Monitoring and Evaluating Field and Laboratory Systems in the ANISA Study: Ensuring Quality.

BACKGROUND: The Aetiology of Neonatal Infection in South Asia (ANISA) study maintains operations in Bangladesh, India and Pakistan. We developed and deployed a multilayered monitoring system to measure performance indicators of field sites and laboratory operations. This system allows for real-time provision of feedback to study site teams and project stakeholders. The goal of this monitoring and evaluation system is to promote optimal performance and consistency in protocol application at all sites over the course of the study, thereby safeguarding the validity of project findings. This article describes each of the interdependent monitoring layers that were conceptualized, developed and employed by the ANISA coordination team. METHODS: Layers of monitoring include site-level, central and database-related activities along with periodic site visitation. We provide a number of real-world examples of how feedback from the ANISA monitoring system directly informs a number of crucial decisions and course corrections during the project. CONCLUSION: The ANISA monitoring system represents a transparent, understandable and practical resource for development of project monitoring systems in complex multisite health research projects.