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Patients with non–Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B-cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared with those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. Patients with NHL/CLL demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential. Significance: Limited data exist on antibody responses against current SARS-CoV-2 variants after booster vaccination in patients with NHL/CLL. We showed inferior antibody responses against Omicron variants after booster vaccination in these patients but some generated anti-Omicron titers. This stresses the importance of vaccinating patients with updated formulations.

Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)–specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells.Significance:Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb.This article is highlighted in the In This Issue feature, p. 101

PURPOSE To examine COVID-19 mRNA vaccine–induced binding and neutralizing antibody responses in patients with non–small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the primary 2-dose and booster vaccination. METHODS Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2–specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively. RESULTS A majority of patients with NSCLC generated binding and neutralizing antibody titers comparable with the healthy vaccinees after mRNA vaccination, but a subset of patients with NSCLC (25%) made poor responses, resulting in overall lower (six- to seven-fold) titers compared with the healthy cohort ( P = < .0001). Although patients age > 70 years had lower immunoglobulin G titers ( P = < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a combination of both did not have a significant impact on the antibody response. Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in particular, B.1.1.529 (Omicron) variants were significantly lower ( P = < .0001) compared with the 614D (WT) strain. Booster vaccination led to a significant increase ( P = .0001) in the binding and neutralizing antibody titers to the WT and Omicron variant. However, 2-4 months after the booster, we observed a five- to seven-fold decrease in neutralizing titers to WT and Omicron viruses. CONCLUSION A subset of patients with NSCLC responded poorly to the SARS-CoV-2 mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron variant. Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant.

AI technologies have the potential to help deaf individuals communicate. Due to the complexity of sign fragmentation and the inadequacy of capturing hand gestures, the authors present a sign language recognition (SLR) system and wearable surface electromyography (sEMG) biosensing device based on a Deep SLR that converts sign language into printed message or speech, allowing people to better understand sign language and hand motions. On the forearms, two armbands containing a biosensor and multi-channel sEMG sensors are mounted to capture quite well arm and finger actions. Deep SLR was tested on an Android and iOS smartphone, and its usefulness was determined by comprehensive testing. Sign Speaker has a considerable limitation in terms of recognising two-handed signs with smartphone and smartwatch. To solve these issues, this research proposes a new real-time end-to-end SLR method. The average word error rate of continuous sentence recognition is 9.6%, and detecting signals and recognising a sentence with six sign words takes less than 0.9 s, demonstrating Deep SLR's recognition.

This file contains supplementary figures 1-25

Supplementary Table 3. Univariate analyses of clinical variables associated with booster response

Suppl Table 1. Correlative analysis of breakthrough SARS CoV-2 infection following booster vaccination.

Supplemental Table 2. Clinical characteristics of NHL/CLL patients with high anti-spike IgG titers prior to booster vaccination

Supplemental Table 1. Clinical and vaccination characteristics of NHL/CLL patients in this study

Supplemental Figure 2. Positive correlations in antibody binding titers between anti-Spike IgG and anti-RBD, anti-NTD IgG, and anti-spike IgA and IgM

Supplemental Figure 1. Anti-nucleocapsid IgG and spike IgM titers in NHL/CLL patients.

Supplemental Figure 3. Kinetics of serologic response after booster vaccination.

Supplemental Figure 5. Reduced IgG binding titers against the spike protein of SARS-CoV-2 variants in NHL/CLL patients.

Patients with non–Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B-cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared with those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. Patients with NHL/CLL demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential.Significance:Limited data exist on antibody responses against current SARS-CoV-2 variants after booster vaccination in patients with NHL/CLL. We showed inferior antibody responses against Omicron variants after booster vaccination in these patients but some generated anti-Omicron titers. This stresses the importance of vaccinating patients with updated formulations.

Supplementary Table 2: Antibodies used for immune-phenotyping (CyTOF analysis). Supplementary Table 3: Antibodies used for flow cytometry. Supplementary Table 4: Antibodies used for AIM Assay (CyTOF analysis).

Supplemental Figure 4. Anti-spike binding IgG titers after booster correlate with conventional B cell numbers in the blood prior booster.

Aim: To carry out a case–control study of the association of GST gene polymorphisms in pediatric asthma-related oxidative stress. Materials & methods: Asthma patients (n = 250) and age-matched healthy subjects (n = 250) DNA were genotyped for GSTM1/GSTT1 (+/+, +/-, -/+ and -/-) frequencies using multiplex-PCR and plasma oxidative stress markers (examined spectrophotometrically). Results: Asthma patients had significantly more common null-genotype GSTM1-/GSTT1- (10.4%; p = 0.002) and elevated levels of malondialdehyde, protein carbonyl and 8-hydroxy-2-deoxyguanosine as compared with controls. In addition, the level of plasma glutathione, GST activity and ferric-reducing ability were significantly decreased as compared with controls. Conclusion: Our data revealed significant associations between GSTM1-/GSTT1- genotype and oxidative stress markers in asthmatic children, which may very likely contribute to increased incidence of bronchial asthma.

Background No rabies post-exposure prophylaxis (PEP) failure has been documented in humans in the United States using modern cell-culture vaccines. In January 2021, an 84-year-old male died from rabies six months after being bitten by a rabid bat despite receiving timely rabies post-exposure prophylaxis (PEP). We investigated the cause of breakthrough infection. Methods We reviewed medical records, laboratory results, and autopsy findings, and performed whole genome sequencing (WGS) to compare patient and bat virus sequences. Storage, administration, and integrity of PEP biologics administered to the patient were assessed; samples from leftover rabies immunoglobulin were evaluated for potency. We conducted risk assessments for persons potentially exposed to the bat and for close contacts of the patient. Results Rabies virus antibodies present in serum and cerebrospinal fluid were non-neutralizing. Antemortem blood testing revealed the patient had unrecognized monoclonal gammopathy of unknown significance. Autopsy findings showed rabies meningoencephalitis and metastatic prostatic adenocarcinoma. Rabies virus sequences from the patient and the offending bat were identical by WGS. No deviations were identified in potency, quality control, administration, or storage of administered PEP. Of 332 persons assessed for potential rabies exposure to the case patient, three (0.9%) warranted PEP. Conclusion This is the first reported failure of rabies PEP in the Western Hemisphere using a cell culture vaccine. Host-mediated primary vaccine failure attributed to previously unrecognized impaired immunity is the most likely explanation for this breakthrough infection. Clinicians should consider measuring rabies neutralizing antibody titers after completion of PEP if there is any suspicion for immunocompromise.

Antimicrobial resistance (AMR) is an emerging and growing global health challenge that could result in 10.2 million deaths annually by 2050. The unrestricted and haphazard use of antibiotics is contributing to the rapid emergence and spread of AMR, and the problem is exacerbated by release of untreated waste water from high-risk sources like hospitals into rivers. Bacteria often develop resistance through horizontal gene transfer mechanism and gut flora can act as a source for new Antimicrobial Resistance Genes (ARG). Upcoming methods like metagenomics can identify the resistance profile (AMR) of gut microbiome, and detect bacterial infections that otherwise go unnoticed. Our study focused on understanding the presence of AMR mutations and gene transfer dynamics in human, animal and environmental samples collected in one of the temporary settlements of Kathmandu (Nepal) using One Health approach. Current AMR reporting based on clinical cases is limited and does not provide information on specific pathogen and associated AMR genes-our study is an effort to contribute information to fulfill this gap.Twenty-one samples were collected from a temporary settlement in Thapathali (Kathmandu), which included fecal samples from birds (n=3) and humans (n=14), and environmental samples (n=4). Microbiological assessment was carried out based on 16S sequence metagenomic analysis using MiSeq (Illumina, USA). Taxonomic classification on obtained 16S sequences were determined by using Metaphlan 2 and Qiime 2 bioinformatics tools. ShortBRED was used to classify ARG and virulence factors, and WAFFLE was used for horizontal gene transfer event prediction. The network analysis was carried out using Gephi v0.9 and the ResistoXplorer web tool to identify ARG in the collected samples.Prevotella spp. was the dominant gut microbiome in humans. We detected diverse phages and viruses, including Stx-2 converting phages. 72 virulence factors and 53 ARG subtypes were detected, with poultry samples having the highest number of subtypes. The cluster and network analysis showed a strong association between gut microbiome and ARG, which was also supported by Horizontal Gene Transfer (HGT) analysis. One-Health interface showed ARG dynamics and revealed gut microbiomes of humans and animals serving as a reservoir for the circulating ARG.

Increased demand for novel, highly effective vaccination strategies necessitates a better understanding of long-lived memory CD8 T cell differentiation. To achieve this understanding, we used the mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection. We reexamined classical memory CD8 T cell subsets and performed in-depth, longitudinal analysis of their phenotype, transcriptional programming, and anatomic location within the spleen. All analyses were performed at multiple time points from 8 days to 1 year postinfection. Memory subsets are conventionally defined by their expression of KLRG1 and IL-7Rα, as follows: KLRG1(+)IL-7Rα(−) terminal effectors (TEs) and KLRG1(−)IL-7Rα(+) memory precursors (MPs). But we also characterized a third KLRG1(+)IL-7Rα(+) subset which we refer to as KLRG1(+) MPs. In these analyses, we defined a comprehensive memory phenotype that is associated with higher levels of CD28 expression. We also demonstrated that MPs, KLRG1(+) MPs, and TEs have distinct localization programs within the spleen. We found that MPs became preferentially enriched in the white pulp as early as 1 to 2 weeks postinfection, and their predominance in the white pulp was maintained throughout the course of a year. On the other hand, KLRG1(+) MPs and TEs localized to the red pulp just as early, and they consistently localized to the red pulp thereafter. These findings indicate that location may be crucial for memory formation and that white pulp-derived signals may contribute to long-term memory survival. Achieving robust memory responses following vaccination may require more deliberate consideration of which memory phenotypes are induced, as well as where they traffic, as these factors could impact their longevity. IMPORTANCE CD8 T cells play a critical role in viral immunity and it is important to understand how memory cells are formed and what processes lead to their long-term maintenance. Here, we use a mouse model of acute infection to perform an in-depth, longitudinal analysis of memory CD8 T cell differentiation, examining the phenotype and location of memory cells out to 1 year postinfection.

Understanding disease burden and transmission dynamics in resource-limited, low-income countries like Nepal are often challenging due to inadequate surveillance systems. These issues are exacerbated by limited access to diagnostic and research facilities throughout the country. Nepal has one of the highest COVID-19 case rates (915 cases per 100,000 people) in South Asia, with densely-populated Kathmandu experiencing the highest number of cases. Swiftly identifying case clusters (hotspots) and introducing effective intervention programs is crucial to mounting an effective containment strategy. The rapid identification of circulating SARS-CoV-2 variants can also provide important information on viral evolution and epidemiology. Genomic-based environmental surveillance can help in the early detection of outbreaks before clinical cases are recognized and identify viral micro-diversity that can be used for designing real-time risk-based interventions. This research aimed to develop a genomic-based environmental surveillance system by detecting and characterizing SARS-CoV-2 in sewage samples of Kathmandu using portable next-generation DNA sequencing devices. Out of 22 sites in the Kathmandu Valley from June to August 2020, sewage samples from 16 (80%) sites had detectable SARS-CoV-2. A heatmap was created to visualize the presence of SARS-CoV-2 infection in the community based on viral load intensity and corresponding geospatial data. Further, 47 mutations were observed in the SARS-CoV-2 genome. Some detected mutations (n = 9, 22%) were novel at the time of data analysis and yet to be reported in the global database, with one indicating a frameshift deletion in the spike gene. SNP analysis revealed possibility of assessing circulating major/minor variant diversity on environmental samples based on key mutations. Our study demonstrated the feasibility of rapidly obtaining vital information on community transmission and disease dynamics of SARS-CoV-2 using genomic-based environmental surveillance.

Objective:Describe a severe acute respiratory coronavirus virus 2 (SARS-CoV-2) hospital outbreak and the role of serial testing of patients and healthcare personnel (HCP) in interrupting SARS-CoV-2 transmission.Design:Outbreak investigation.Setting:Medical floor of a tertiary-care center in Minnesota.Methods:Serial testing for SARS-CoV-2 and whole-genome sequencing (WGS) of positive specimens from HCP and patients were used. An outbreak-associated case was defined as a positive SARS-CoV-2 molecular test in an HCP who worked on the floor prior to testing positive or in a patient who was hospitalized on the medical floor bewteen October 27 and December 1, 2020. WGS was used to determine potential routes of transmission.Results:The outbreak was detected after a patient hospitalized for 12 days tested positive for SARS-CoV-2. Serial testing of patients and HCP was conducted in response. Overall, 247 HCP and 41 patients participated in serial SARS-CoV-2 testing; 52 HCP (21%) and 19 hospitalized patients (46%) tested positive. One additional HCP tested positive outside serial testing. The WGS of specimens from 27 (51%) HCP and 15 (79%) patients identified 3 distinct transmission clusters. WGS and epidemiologic evidence suggested intrafacility transmission. The proportions of asymptomatic and presymptomatic patients who tested positive (63%) and HCP who worked during their infectious period (75%) highlight the need for serial testing of asymptomatic patients and HCP during outbreaks.Conclusions:Coupled with preventive measures such as personal protective equipment use and physical distancing, serial testing of HCP and patients could help detect and prevent transmission within healthcare facilities during outbreaks and when nosocomial transmission is suspected.

One of the key factors that has helped the state of Tamil Nadu to make significant progress in the health sector, especially in maternal health, is an enabling political environment in the state that has prioritised programmes for the welfare of women and children, irrespective of the party in power. This article reviews 10 key innovations in maternal health and tribal health introduced in the state of Tamil Nadu from 2005–2006 to 2020–2021. The specific questions addressed are as follows: what are the special innovative schemes introduced by the state of Tamil Nadu to promote maternal health? Whether and to what extent utilisation of public delivery system for maternal services has increased over the past 15 years or so? The overall impact of these initiatives on the maternal health of the state is assessed by analysing two indicators: trends in maternal mortality ratio (MMR) and financial burden due to delivery in public and private facilities. MMR in the state of Tamil Nadu is steadily falling—from 111 in 2004–2006 to 60 in 2016–2018. While average out-of-pocket expenditure (OOPE) during delivery in the public sector has increased from ₹2,454 in 2014 to ₹3,465 in 2017–2018, in the private sector, it has increased from ₹32,182 in 2014 to ₹34,635 in 2017–2018. OOPE in private facilities is nearly ten times higher than OOPE in public facilities, in both rural and urban areas. While the overall status of maternal health has improved significantly in the state, there are wide variations within and across districts. However, significant improvements in the overall health status can be achieved only if such inequities are reduced systematically, and efforts are being made to reduce such inequities.

Tuning of opto-electrochemical and theoretical properties of D–A–D-based pyrido[2,3-b]pyrazine amine derivatives by modulating donor groups.