Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Immunogenicity and safety of a 14-valent pneumococcal polysaccharide conjugate vaccine (PNEUBEVAX 14™) administered to 6-8 weeks old healthy Indian Infants: A single blind, randomized, active-controlled, Phase-III study.

BACKGROUND: Introduction of pneumococcal conjugate vaccines (PCVs) reduced the number of cases of pneumococcal disease (PD). However, there is an increase in clinical and economic burden of PD from serotypes that are not part of the existing pneumococcal vaccines, particularly impacting pediatric and elder population. In addition, the regions where the PCV is not available, the disease burden remains high. In this study, immunogenicity and safety of the BE's 14-valent PCV (PNEUBEVAX 14™; BE-PCV-14) containing two additional epidemiologically important serotypes (22F and 33F) was evaluated in infants in comparison to licensed vaccine, Prevenar-13 (PCV-13). METHODS: This is a pivotal phase-3 single blind randomized active-controlled study conducted at 12 sites across India in 6-8 weeks old healthy infants at 6-10-14 weeks dosing schedule to assess immunogenic non-inferiority and safety of a candidate BE-PCV-14. In total, 1290 infants were equally randomized to receive either BE-PCV-14 or PCV-13. Solicited local reactions and systemic events, adverse events (AEs), serious AEs (SAEs), and medically attended AEs (MAAEs) were recorded. Immunogenicity was assessed by measuring anti-PnCPS (anti-pneumococcal capsular polysaccharide) IgG concentration and functional antibody titers through opsonophagocytic activity (OPA), one month after completing three dose schedule. Cross protection to serotype 6A offered by serotype 6B was also assessed in this study. FINDINGS: The safety profile of BE-PCV-14 was comparable to PCV-13 vaccine. Majority of reported AEs were mild in nature. No severe or serious AEs were reported in both the treatment groups. For the twelve common serotypes and for the additional serotypes (22F and 33F) in BE-PCV-14, NI criteria was demonstrated as defined by WHO TRS-977. Primary immunogenicity endpoint was met in terms of IgG immune responses for all 14 serotypesof BE-PCV-14. Moreover, a significant proportion of subjects (69%) seroconverted against serotype 6A, even though this antigen was not present in BE-PCV-14. This indicates that serotype 6B of BE-PCV-14 cross protects serotype 6A. BE-PCV-14 also elicited comparable serotype specific functional OPA immune responses to all the serotypes common to PCV-13. INTERPRETATIONS: BE-PCV-14 was found to be safe and induced robust and functional serotype specific immune responses to all 14 serotypes. It also elicited cross protective immune response against serotype 6B.These findings suggest that BE-PCV-14 can be safely administered to infants and achieve protection against pneumococcal disease caused by serotypes covered in the vaccine. The study was prospectively registered with clinical trial registry of India - CTRI/2020/02/023129.

Electroanalytical Overview: The Sensing of Mesalamine (5-Aminosalicylic Acid).

Mesalamine, known as 5-aminosalicylic acid, is a medication used primarily in the treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. 5-Aminosalicylic acid can be measured using various benchtop laboratory techniques which involve liquid chromatography-mass spectroscopy, but these are sophisticated and large, meaning that they cannot be used on-site because transportation of the samples, chemicals, and physical and biological reactions can potentially occur, which can affect the sample's composition and potentially result in inaccurate results. An alternative approach is the use of electrochemical based sensing platforms which has the advantages of portability, cost-efficiency, facile miniaturization, and rapid analysis while nonetheless providing sensitivity and selectivity. We provide an overview of the use of the electroanalytical techniques for the sensing of 5-aminosalicylic acid and compare them to other laboratory-based measurements. The applications, challenges faced, and future opportunities for electroanalytical based sensing platforms are presented in this review.

Multiomic Analysis of Neuroinflammation and Occult Infection in Sudden Infant Death Syndrome.

Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.

Clinical and Metagenomic Characterization of Neurological Infections of People With Human Immunodeficiency Virus in the Peruvian Amazon.

Background: Neurological opportunistic infections cause significant morbidity and mortality in people with human immunodeficiency virus (HIV) but are difficult to diagnose. Methods: One hundred forty people with HIV with acute neurological symptoms from Iquitos, Peru, were evaluated for cerebral toxoplasmosis with quantitative polymerase chain reaction (qPCR) of cerebrospinal fluid (CSF) and for cryptococcal meningitis with cryptococcal antigen test (CrAg) in serum or CSF. Differences between groups were assessed with standard statistical methods. A subset of samples was evaluated by metagenomic next-generation sequencing (mNGS) of CSF to compare standard diagnostics and identify additional diagnoses. Results: Twenty-seven participants were diagnosed with cerebral toxoplasmosis by qPCR and 13 with cryptococcal meningitis by CrAg. Compared to participants without cerebral toxoplasmosis, abnormal Glasgow Coma Scale score (P = .05), unilateral focal motor signs (P = .01), positive Babinski reflex (P = .01), and multiple lesions on head computed tomography (CT) (P = .002) were associated with cerebral toxoplasmosis. Photophobia (P = .03) and absence of lesions on head CT (P = .02) were associated with cryptococcal meningitis. mNGS of 42 samples identified 8 cases of cerebral toxoplasmosis, 7 cases of cryptococcal meningitis, 5 possible cases of tuberculous meningitis, and incidental detections of hepatitis B virus (n = 1) and pegivirus (n = 1). mNGS had a positive percentage agreement of 71% and a negative percentage agreement of 91% with qPCR for T gondii. mNGS had a sensitivity of 78% and specificity of 100% for Cryptococcus diagnosis. Conclusions: An infection was diagnosed by any method in only 34% of participants, demonstrating the challenges of diagnosing neurological opportunistic infections in this population and highlighting the need for broader, more sensitive diagnostic tests for central nervous system infections.

Immunogenicity and safety of Mebella™ vaccine developed by Human Biologicals Institute in a Phase II/III, randomized, multicentric, non-inferiority study.

BACKGROUND: The goal of 'Measles and Rubella Strategic Framework 2021-2030' is to make "A world free from measles and rubella". To be a part of this journey, Human Biologicals Institute has developed Mebella™ vaccine, which is a lyophilized Measles and Rubella (Live) vaccine. A randomized, single blind, comparative, multicenter Phase II/III trial was conducted to compare the immunogenicity and safety of Mebella™ vaccine with MR-VAC® vaccine in healthy subjects. METHODS: A total of 888 subjects were enrolled in four age groups (222 subjects in each group) of 18 years to 49 years; 2 years to below 18 years; 12 months to below 24 months; and 9 months to below 12 months of age. The subjects were randomized in 2:1 ratio to receive single dose of either Mebella™ vaccine of Human Biologicals Institute or MR-VAC® vaccine. Immunogenicity was assessed at 42 days after the vaccination and was compared between the vaccine arms in each group. Safety was also assessed and compared between the vaccine arms during the study period. RESULTS: A total of 875 subjects completed the study out of 888 enrolled subjects. The seroprotection rates, seroconversion rates, and geometric mean titres for both Measles and Rubella components of Mebella™ vaccine were found to be comparable and non-inferior to the MR-VAC® vaccine after 42 days of vaccination. Injection site pain was the most common local adverse event reported whereas fever was the only systemic adverse event reported in both the vaccine arms. No serious adverse event was reported. CONCLUSION: It was concluded from the study results that the test vaccine, Mebella™, was immunogenic and well tolerated and was non-inferior to the comparator vaccine, MR-VAC®, when administered to healthy subjects of 9 months to 49 years of age. Clinical Trial Registry of India Identifier: CTRI/2020/07/026930.

Pannexin-1 opening in neuronal edema causes cell death but also leads to protection via increased microglia contacts.

Neuronal swelling during cytotoxic edema is triggered by Na+ and Cl- entry and is Ca2+ independent. However, the causes of neuronal death during swelling are unknown. Here, we investigate the role of large-conductance Pannexin-1 (Panx1) channels in neuronal death during cytotoxic edema. Panx1 channel inhibitors reduce and delay neuronal death in swelling triggered by voltage-gated Na+ entry with veratridine. Neuronal swelling causes downstream production of reactive oxygen species (ROS) that opens Panx1 channels. We confirm that ROS activates Panx1 currents with whole-cell electrophysiology and find scavenging ROS is neuroprotective. Panx1 opening and subsequent ATP release attract microglial processes to contact swelling neurons. Depleting microglia using the CSF1 receptor antagonist PLX3397 or blocking P2Y12 receptors exacerbates neuronal death, suggesting that the Panx1-ATP-dependent microglia contacts are neuroprotective. We conclude that cytotoxic edema triggers oxidative stress in neurons that opens Panx1 to trigger death but also initiates neuroprotective feedback mediated by microglia contacts.

Embelin targets PI3K/AKT and MAPK in age-related ulcerative colitis: an integrated approach of microarray analysis, network pharmacology, molecular docking, and molecular dynamics.

Vaibhdang, an Ayurvedic treatment for Crohn's and UC, has been used for centuries. The main component of Vaibhdang is embelin derived from Embelia ribes. However, the pharmacological and molecular mechanisms of embelin in UC remain unclear. This study investigated the molecular targets and mechanisms of action of embelin in UC using microarray analysis, network pharmacology, molecular docking, and molecular dynamics simulations. Embelin targets were obtained by Swiss Target, TargetNet, STITCH, ChEMBL, and TCMSP. Ulcerative colitis targets were mapped using DisGenNET, Genecards, TCMSP, Therapeutic targets, and GEO databases (GSE87466). Co-targets between ulcerative colitis and embelin were identified, and a PPI network was constructed using the STRING database. To identify the core targets, we used Cytoscape to analyze the topology of the PPI network. There were 545 effective Embelin targets and 5171 effective ulcerative colitis targets, including 1470 DEG targets. ShinyGo and AutoDock were used to analyze GO and KEGG enrichment pathways and docking studies, respectively. Venn diagram analysis revealed 327 core targets of embelin in UC. An enrichment study showed that embelin is involved in PI3K-AKT, MAPK, RAS, and chemokine signalling. The top ten core targets docked with embelin and AKT1, MAPK1, and SRC complexes were utilized as representations and simulated using GROMACS for 100 ns. A comparison of native proteins and their complex interactions with embelin revealed that embelin might act on various PI3K/AKT and MAPK targets to treat ulcerative colitis. This study provides insights into the molecular targets and mechanisms of action of embelin against ulcerative colitis.Communicated by Ramaswamy H. Sarma.

Electroanalytical overview: the sensing of carbendazim.

Carbendazim is a broad-spectrum systemic fungicide that is used to control various fungal diseases in agriculture, horticulture, and forestry. Carbendazim is also used in post-harvest applications to prevent fungal growth on fruits and vegetables during storage and transportation. Carbendazim is regulated in many countries and banned in others, thus, there is a need for the sensing of carbendazim to ensure that high levels are avoided which can result in potential health risks. One approach is the use of electroanalytical sensors which present a rapid, but highly selective and sensitive output, whilst being economical and providing portable sensing platforms to support on-site analysis. In this minireview, we report on the electroanalytical sensing of carbendazim overviewing recent advances, helping to elucidate the electrochemical mechanism and provide conclusions and future perspectives of this field.

Complement Factor I Gene Variant as a Treatable Cause of Recurrent Aseptic Neutrophilic Meningitis: A Case Report.

Mutations in the complement factor I (CFI) gene have previously been identified as causes of recurrent CNS inflammation. We present a case of a 26-year-old man with 18 episodes of recurrent meningitis, who had a variant in CFI(c.859G>A,p.Gly287Arg) not previously associated with neurologic manifestations. He achieved remission with canakinumab, a human monoclonal antibody targeted at interleukin-1 beta.

Electroanalytical overview: the sensing of hydroxylamine.

One of the principal raw ingredients used in the manufacturing of pharmaceuticals, nuclear fuel, and semiconductors is hydroxylamine, a mutagenic and carcinogenic substance, ranking high on the list of environmental contaminants. Electrochemical methods for monitoring hydroxylamine have the advantage of being portable, quick, affordable, simple, sensitive, and selective enough to maintain adequate constraints in contrast with conventional yet laboratory based quantification methods. This review outlines the most recent advancements in electroanalysis directed toward the sensing of hydroxylamine. Potential future advancements in this field are also offered, along with a discussion of method validation and the use of such devices in real samples for the determination of hydroxylamine.

Interlink between ExoD (Alr2882), exopolysaccharide synthesis and metal tolerance in Nostoc sp. strain PCC 7120: Insight into its role, paralogs and evolution.

Exopolysaccharides (EPS) produced by bacterial species are an important component of bacteria's survival strategy. Synthesis of EPS, principal component of extracellular polymeric substance, occurs through multiple pathways involving multitude of genes. While stress-induced concomitant increase in exoD transcript levels and EPS content have been shown earlier, experimental evidence for direct correlation is lacking. In the present study, role of ExoD in Nostoc sp. strain PCC 7120 was evaluated by generating a recombinant Nostoc strain AnexoD+, wherein the ExoD (Alr2882) protein was constitutively overexpressed. AnexoD+ exhibited higher EPS production, propensity for formation of biofilms and tolerance to Cd stress compared to vector control AnpAM cells. Both Alr2882 and its paralog All1787 exhibited 5 transmembrane domains, with only All1787 predicted to interact with several proteins in polysaccharide synthesis. Phylogenetic analysis of orthologs of these proteins across cyanobacteria indicated that the two paralogs Alr2882 and All1787 and their corresponding orthologs arose divergently during evolution, and could have distinct roles to perform in the biosynthesis of EPS. This study has thrown open the possibility of engineering overproduction of EPS and inducing biofilm formation through genetic manipulation of EPS biosynthesis genes in cyanobacteria, thus building a cost-effective green platform for large scale production of EPS.

Dynamics of redox signaling in aging via autophagy, inflammation, and senescence.

Review paper attempts to explain the dynamic aspects of redox signaling in aging through autophagy, inflammation, and senescence. It begins with ROS source in the cell, then states redox signaling in autophagy, and regulation of autophagy in aging. Next, we discuss inflammation and redox signaling with various pathways involved: NOX pathway, ROS production via TNF-α, IL-1ß, xanthine oxidase pathway, COX pathway, and myeloperoxidase pathway. Also, we emphasize oxidative damage as an aging marker and the contribution of pathophysiological factors to aging. In senescence-associated secretory phenotypes, we link ROS with senescence, aging disorders. Relevant crosstalk between autophagy, inflammation, and senescence using a balanced ROS level might reduce age-related disorders. Transducing the context-dependent signal communication among these three processes at high spatiotemporal resolution demands other tools like multi-omics aging biomarkers, artificial intelligence, machine learning, and deep learning. The bewildering advancement of technology in the above areas might progress age-related disorders diagnostics with precision and accuracy.

Feasibility of Minimal Enteral Nutrition During Therapeutic Hypothermia for Perinatal Asphyxia: A Five-Year Multicenter Experience from South India.

Limited evidence shows minimal enteral nutrition (MEN) during therapeutic hypothermia (TH) in neonates to be feasible and have benefits of shorter time to full-feeds. This study aimed to assess the feasibility of MEN during TH. MEN was initiated after 12 h if there were no altered aspirates, abdominal distension, and inotrope requirement. The authors retrospectively analyzed the records from May 2017 to April 2022. The number of episodes of feed intolerance and the length of hospital stay were the key outcomes. A total of 99 neonates were fed during cooling. MEN could be initiated at a median duration (IQR) of 24 (24-30) h. There were 9 (9%) neonates with feed intolerance during TH. None had necrotizing enterocolitis. Ninety-two (93%) neonates were discharged, with a median hospital stay (IQR) of 9 d (6-15). Hence, MEN during TH is feasible and provides a rationale for future controlled trials.

Pathogen and Antibody Identification in Children with Encephalitis in Myanmar.

OBJECTIVE: Prospective studies of encephalitis are rare in regions where encephalitis is prevalent, such as low middle-income Southeast Asian countries. We compared the diagnostic yield of local and advanced tests in cases of pediatric encephalitis in Myanmar. METHODS: Children with suspected subacute or acute encephalitis at Yangon Children's Hospital, Yangon, Myanmar, were prospectively recruited from 2016-2018. Cohort 1 (n = 65) had locally available diagnostic testing, whereas cohort 2 (n = 38) had advanced tests for autoantibodies (ie, cell-based assays, tissue immunostaining, studies with cultured neurons) and infections (ie, BioFire FilmArray multiplex Meningitis/Encephalitis multiplex PCR panel, metagenomic sequencing, and pan-viral serologic testing [VirScan] of cerebrospinal fluid). RESULTS: A total of 20 cases (13 in cohort 1 and 7 in cohort 2) were found to have illnesses other than encephalitis. Of the 52 remaining cases in cohort 1, 43 (83%) had presumed infectious encephalitis, of which 2 cases (4%) had a confirmed infectious etiology. Nine cases (17%) had presumed autoimmune encephalitis. Of the 31 cases in cohort 2, 23 (74%) had presumed infectious encephalitis, of which one (3%) had confirmed infectious etiology using local tests only, whereas 8 (26%) had presumed autoimmune encephalitis. Advanced tests confirmed an additional 10 (32%) infections, 4 (13%) possible infections, and 5 (16%) cases of N-methyl-D-aspartate receptor antibody encephalitis. INTERPRETATION: Pediatric encephalitis is prevalent in Myanmar, and advanced technologies increase identification of treatable infectious and autoimmune causes. Developing affordable advanced tests to use globally represents a high clinical and research priority to improve the diagnosis and prognosis of encephalitis. ANN NEUROL 2023;93:615-628.

Safety and Efficacy of Prophylactic Amiodarone After Left Ventricular Assist Device.

The prophylactic use of amiodarone to reduce the incidence of postoperative arrhythmias is effective for patients undergoing general cardiac surgeries; however, no data exists for the use of prophylactic amiodarone to prevent postoperative arrhythmias after CF-LVAD. This single-center, retrospective analysis compared patients with CF-LVADs placed between April 2014 and June 2020 who received prophylactic postoperative amiodarone to those who did not. Based on institution practice at the respective times, patients with a CF-LVAD placed between April 2014 and June 2018 were included in the group receiving postoperative amiodarone arrhythmia prophylaxis and patients with a CF-LVAD placed July 2018 to June 2020 were included in the group not receiving arrhythmia prophylaxis. The primary outcome was the incidence of first occurring atrial or ventricular arrhythmia from CF-LVAD placement to 21 days or hospital discharge. Sixty patients received amiodarone for arrhythmia prophylaxis and 27 patients did not receive prophylaxis. The primary outcome occurred in 40% of the prophylaxis group and 66.7% in the no prophylaxis group (RR, 0.60; 95% CI, 0.40-0.90; p = 0.038). In patients receiving CF-LVADs, the use of prophylactic amiodarone was associated with a reduction in the incidence of postoperative arrhythmias, which was driven primarily by a reduction in postoperative atrial arrhythmias, without significantly increasing the rate of amiodarone-related adverse events.

Recurrence of Symptoms Following Cryptococcal Meningitis: Characterizing a Diagnostic Conundrum With Multiple Etiologies.

BACKGROUND: Cryptococcal meningitis is a common cause of AIDS-related mortality. Although symptom recurrence after initial treatment is common, the etiology is often difficult to decipher. We sought to summarize characteristics, etiologies, and outcomes among persons with second-episode symptomatic recurrence. METHODS: We prospectively enrolled Ugandans with cryptococcal meningitis and obtained patient characteristics, antiretroviral therapy (ART) and cryptococcosis histories, clinical outcomes, and cerebrospinal fluid (CSF) analysis results. We independently adjudicated cases of second-episode meningitis to categorize patients as (1) microbiological relapse, (2) paradoxical immune reconstitution inflammatory syndrome (IRIS), (3) persistent elevated intracranial pressure (ICP) only, or (4) persistent symptoms only, along with controls of primary cryptococcal meningitis. We compared groups with chi-square or Kruskal-Wallis tests as appropriate. RESULTS: 724 participants were included (n = 607 primary episode, 81 relapse, 28 paradoxical IRIS, 2 persistently elevated ICP, 6 persistent symptoms). Participants with culture-positive relapse had lower CD4 (25 cells/µL; IQR: 9-76) and lower CSF white blood cell (WBC; 4 cells/µL; IQR: 4-85) counts than paradoxical IRIS (CD4: 78 cells/µL; IQR: 47-142; WBC: 45 cells/µL; IQR: 8-128). Among those with CSF WBC <5 cells/µL, 86% (43/50) had relapse. Among those with CD4 counts <50 cells/µL, 91% (39/43) had relapse. Eighteen-week mortality (from current symptom onset) was 47% among first episodes of cryptococcal meningitis, 31% in culture-positive relapses, and 14% in paradoxical IRIS. CONCLUSIONS: Poor immune reconstitution was noted more often in relapse than IRIS as evidenced by lower CSF WBC and blood CD4 counts. These easily obtained laboratory values should prompt initiation of antifungal treatment while awaiting culture results. CLINICAL TRIALS REGISTRATION: NCT01802385.

Correction: Computational investigation of the increased virulence and pathogenesis of SARS-CoV-2 lineage B.1.1.7.

Correction for 'Computational investigation of the increased virulence and pathogenesis of SARS-CoV-2 lineage B.1.1.7' by N. Arul Murugan et al., Phys. Chem. Chem. Phys., 2022, 24, 20371-20380, https://doi.org/10.1039/D2CP00469K.

Lot-to-lot consistency of a hexavalent DTwP-IPV-HB-PRP∼T vaccine and non-inferiority to separate DTwP-HB-PRP∼T and IPV antigen-matching vaccines at 6-8, 10-12, and 14-16 weeks of age co-administered with oral rotavirus vaccine in healthy infants in India: A multi-center, randomized, controlled study.

Background: Combination vaccines reduce the number of pediatric injections but must be as safe, immunogenic, and effective as each of the individual vaccines given separately. Additionally, consistency in manufacturing lots is essential for WHO prequalification. This study aimed to establish the lot-to-lot consistency of a fully liquid, hexavalent diphtheria (D)-tetanus (T)-whole-cell pertussis (wP)-inactivated poliovirus (IPV)-hepatitis B (HB)-Haemophilus influenzae b (PRP-T) (DTwP-IPV-HB-PRP∼T) vaccine and to demonstrate non-inferiority to licensed DTwP-HB-PRP∼T and IPV vaccines. Methods: A Phase III, randomized, active-controlled, and open-label study was conducted at multiple centers across India. Healthy infants who had received a birth dose of oral poliovirus vaccine and hepatitis B vaccine received one of three lots of DTwP-IPV-HB-PRP∼T or separate DTwP-HB-PRP∼T and IPV vaccines at 6-8, 10-12, and 14-16 weeks of age. Oral rotavirus vaccine was co-administered at 6-8 weeks of age and 10-12/14-16 weeks of age. DTwP-IPV-HB-PRP∼T lot-to-lot consistency and non-inferiority (pooled DTwP-IPV-HB-PRP∼T) versus DTwP-HB-PRP∼T and IPV post-third dose were assessed using seroprotection rates (anti-D, anti-T, anti-HBs, anti-PRP, anti-polio 1, 2, 3) and adjusted geometric mean concentrations (anti-PT, anti-FIM). Safety was assessed by parental reports. Results: Lot-to-lot consistency was demonstrated for DTwP-IPV-HB-PRP∼T and non-inferiority versus DTwP-HB-PRP∼T and IPV was confirmed with 95% CIs for seroprotection rate differences and adjusted geometric mean concentration ratios within pre-defined clinical margins. Pooled seroprotection rate was ≥ 99.7% for anti-D ≥ 0.01 IU/mL, anti-T ≥ 0.01 IU/mL, anti-HBs ≥ 10 mIU/mL, anti-PRP ≥ 0.15 µg/mL, and anti-polio 1, 2, and 3 ≥ 8 (1/dil) and vaccine response rate was 83.9% for anti-PT and 97.7% for anti-FIM. There were no safety concerns. Conclusions: Immunogenicity of three lots of the fully liquid DTwP-IPV-HB-PRP∼T vaccine was consistent and non-inferior to licensed comparators following vaccination at 6-8, 10-12, and 14-16 weeks of age. There were no safety concerns and no evidence of any effect of co-administration with rotavirus vaccine.