Prevention of respiratory virus transmission by resident memory CD8+ T cells.

An ideal vaccine both attenuates virus growth and disease in infected individuals and reduces the spread of infections in the population, thereby generating herd immunity. Although this strategy has proved successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to respond rapidly to respiratory virus infections2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to the extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8+ T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8+ T cells requires the antiviral cytokine interferon-γ (IFNγ) and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8+ T cells in the respiratory tract can have important roles in protecting the host against viral disease and limiting viral spread throughout the population.

Study of Empiric Antibiotic Prescription Patterns and Microbiological Isolates in Hemodynamically Stable and Unstable ICU Patients With Community-Acquired Sepsis.

Background: The efficacy of combination empiric antibiotic therapy for all intensive care unit (ICU) patients with community-acquired sepsis is a subject of ongoing debate in the era of increasing antibiotic resistance. This study was conducted to evaluate the patterns of antibiotic usage and microbial resistance in sepsis patients admitted to the ICU with both hemodynamically stable (HS) and unstable states and to analyze their clinical outcomes. Methods: In this observational study, patients aged 18 years and above who received antibiotics upon admission and had a culture report were included. These patients were categorized into the following groups: HS and hemodynamically unstable (HU), single or combined antibiotics group (more than one antibiotic used empirically to cover one or more groups of organisms), culture-positive and culture-negative group. The microbiological isolates were grouped according to their identified resistance patterns. The outcome parameters involved assessing the differences in empiric antibiotics use upon admission and microbial resistance with hemodynamic stability and investigating any associations with ICU and hospital outcomes. Results: The study included a total of 2675 patients, of which 70.3% were in the HS group, and 29.7% in the HU group. The use of combination antibiotics was significantly higher (p < 0 .0001) across all groups. Carbapenems were used more frequently in the single antibiotic group (p < 0 .001). The culture was positive in 27.8% (n = 747) of patients. A significantly higher number of patients in the HU group (p < 0 .001) were found to have carbapenem-resistant and multidrug-resistant organisms. The ICU and hospital mortality rates were significantly higher in the HU group (p < 0 .001), the culture-positive group with resistance (p < 0 .001), and the HS patients who received combination antibiotics. Conclusion: The usage of combination antibiotics, coupled with the presence of resistant organisms, emerged as an important variable in predicting ICU and hospital mortality rates in cases of community-acquired sepsis.

Study protocol for an individually randomized control trial for India's first roleplay-based mobile game for reproductive health for adolescent girls.

BACKGROUND: Go Nisha Go™ (GNG), is a mobile game combining behavioural science, human-centric design, game-based learning, and interactive storytelling. The model uses a direct-to-consumer (DTC) approach to deliver information, products, services, interactive learning, and agency-building experiences directly to girls. The game's five episodes focus on issues of menstrual health management, fertility awareness, consent, contraception, and negotiation for delay of marriage and career. The game's effectiveness on indicators linked to these issues will be measured using an encouragement design in a randomized controlled trial (RCT). METHODS: A two-arm RCT will be conducted in three cities in India: Patna, Jaipur, and Delhi-NCR. The first arm is the treatment (encouragement) arm (n = 975) where the participants will be encouraged to download and play the game, and the second arm (n = 975) where the participants will not receive any nudges/encouragement to play the game. They may or may not have access to the game. After the baseline recruitment, participants will be randomly assigned to these two arms across the three locations. Participants of the treatment/encouragement arm will receive continuous support as part of the encouragement design to adopt, install the game from the Google Play Store at no cost, and play all levels on their Android devices. The encouragement activity will continue for ten weeks, during which participants will receive creative messages via weekly phone calls and WhatsApp messages. We will conduct the follow-up survey with all the participants (n = 1950) from the baseline survey after ten weeks of exposure. We will conduct 60 in-depth qualitative interviews (20 at each location) with a sub-sample of the participants from the encouragement arm to augment the quantitative surveys. DISCUSSION: Following pre-testing of survey tools for feasibility of methodologies, we will recruit participants, randomize, collect baseline data, execute the encouragement design, and conduct the follow-up survey with eligible adolescents as written in the study protocol. Our study will add insights for the implementation of an encouragement design in RCTs with adolescent girls in the spectrum of game-based learning on sexual and reproductive health in India. Our study will provide evidence to support the outcome evaluation of the digital mobile game app, GNG. To our knowledge this is the first ever outcome evaluation study for a game-based application, and this study is expected to facilitate scalability of a direct-to-consumer approach to improve adolescent sexual and reproductive health outcomes in India. TRIAL REGISTRATION NUMBER: ctri.nic.in: CTRI/2023/03/050447.

Our paper describes implementation of a study protocol for an outcome evaluation of a mobile game app called Go Nisha Go™, produced by the Game of Choice, Not Chance™ project, funded by USAID. Consenting adolescent girls, aged 15­19, from three cities in India will be enrolled to participate in an encouragement design led RCT. Girls will be randomly assigned to either, a) a treatment (encouragement) arm where they will be nudged to play the game for ten weeks, or b) a control arm where participants will not be provided any encouragement to download or play the game. The study will be evaluated using surveys at baseline and follow-up. The findings from this study will support the measurement of effectiveness of the digital intervention and facilitate scalability of a direct-to-consumer approach, using a game-based application to improve adolescent sexual and reproductive health outcomes in India.

Pre-existing resistance in the latent reservoir can compromise VRC01 therapy during chronic HIV-1 infection.

Passive immunization with broadly neutralizing antibodies (bNAbs) of HIV-1 appears a promising strategy for eliciting long-term HIV-1 remission. When administered concomitantly with the cessation of antiretroviral therapy (ART) to patients with established viremic control, bNAb therapy is expected to prolong remission. Surprisingly, in clinical trials on chronic HIV-1 patients, the bNAb VRC01 failed to prolong remission substantially. Identifying the cause of this failure is important for improving VRC01-based therapies and unraveling potential vulnerabilities of other bNAbs. In the trials, viremia resurged rapidly in most patients despite suppressive VRC01 concentrations in circulation, suggesting that VRC01 resistance was the likely cause of failure. ART swiftly halts viral replication, precluding the development of resistance during ART. If resistance were to emerge post ART, virological breakthrough would have taken longer than without VRC01 therapy. We hypothesized therefore that VRC01-resistant strains must have been formed before ART initiation, survived ART in latently infected cells, and been activated during VRC01 therapy, causing treatment failure. Current assays preclude testing this hypothesis experimentally. We developed a mathematical model based on the hypothesis and challenged it with available clinical data. The model integrated within-host HIV-1 evolution, stochastic latency reactivation, and viral dynamics with multiple-dose VRC01 pharmacokinetics. The model predicted that single but not higher VRC01-resistant mutants would pre-exist in the latent reservoir. We constructed a virtual patient population that parsimoniously recapitulated inter-patient variations. Model predictions with this population quantitatively captured data of VRC01 failure from clinical trials, presenting strong evidence supporting the hypothesis. We attributed VRC01 failure to single-mutant VRC01-resistant proviruses in the latent reservoir triggering viral recrudescence, particularly when VRC01 was at trough levels. Pre-existing resistant proviruses in the latent reservoir may similarly compromise other bNAbs. Our study provides a framework for designing bNAb-based therapeutic protocols that would avert such failure and maximize HIV-1 remission.

Trigger Tools for Adverse Drug Events: Useful Addition to the Quality Tool Box.

How to cite this article: Todi S, Saha A. Trigger Tools for Adverse Drug Events: Useful Addition to the Quality Tool Box. Indian J Crit Care Med 2020;24(3):151-152.

Urinary L-FABP Assay in the Detection of Acute Kidney Injury following Haematopoietic Stem Cell Transplantation.

Background: Acute Kidney Injury (AKI) is a condition that affects a significant proportion of acutely unwell patients and is associated with a high mortality rate. Patients undergoing haemopoietic stem cell transplantation (HSCT) are in an extremely high group for AKI. Identifying a biomarker or panel of markers that can reliably identify at-risk individuals undergoing HSCT can potentially impact management and outcomes. Early identification of AKI can reduce its severity and improve prognosis. We evaluated the urinary Liver type fatty acid binding protein (L-FABP), a tubular stress and injury biomarker both as an ELISA and a point of care (POC) assay for AKI detection in HSCT. Methods: 85 patients that had undergone autologous and allogenic HSCT (35 and 50, respectively) had urinary L-FABP (uL-FABP) measured by means of a quantitative ELISA and a semi-quantitative POC at baseline, day 0 and 7 post-transplantation. Serum creatinine (SCr) was also measured at the same time. Patients were followed up for 30 days for the occurrence of AKI and up to 18 months for mortality. The sensitivity and specificity of uL-FABP as an AKI biomarker were evaluated and compared to the performance of sCr using ROC curve analysis and logistic regression. Results: 39% of participants developed AKI within 1 month of their transplantation. The incidence of AKI was higher in the allogenic group than in the autologous HTSC group (57% vs. 26%, p = 0.008) with the median time to AKI being 25 [range 9-30] days. This group was younger (median age 59 vs. 63, p < 0.001) with a lower percentage of multiple myeloma as the primary diagnosis (6% vs. 88%, p < 0.001). The median time to AKI diagnosis was 25 [range 9-30] days. uL-FABP (mcg/gCr) at baseline, day of transplant and on the 7th day post-transplant were 1.61, 5.39 and 10.27, respectively, for the allogenic group and 0.58, 4.36 and 5.14 for the autologous group. Both SCr and uL-FABP levels rose from baseline to day 7 post-transplantation, while the AUC for predicting AKI for baseline, day 0 and day 7 post-transplant was 0.54, 0.59 and 0.62 for SCr and for 0.49, 0.43 and 0.49 uL-FABP, respectively. Univariate logistic regression showed the risk of AKI to be increased in patients with allogenic HSCT (p = 0.004, 95%CI [0.1; 0.65]) and in those with impaired renal function at baseline (p = 0.01, 95%CI [0.02, 0.54]). The risk of AKI was also significantly associated with SCr levels on day 7 post-transplant (p = 0.03, 95%CI [1; 1.03]). Multivariate logistic regression showed the type of HSCT to be the strongest predictor of AKI at all time points, while SCr levels at days 0 and 7 also correlated with increased risk in the model that included uL-FABP levels at the corresponding time points. The POC device for uL-FABP measurement correlated with ELISA (p < 0.001, Spearman 'correlation' = 0.54) Conclusions: The urinary biomarker uL-FABP did not demonstrate an independent predictive value in the detection of AKI at all stages. The most powerful risk predictor of AKI in this setting appears to be allograft recipients and baseline renal impairment, highlighting the importance of clinical risk stratification. Urinary L-FAPB as a POC biomarker was comparable to ELISA, which provides an opportunity for simple and rapid testing. However, the utility of LFABP in AKI is unclear and needs further exploration. Whether screening through rapid testing of uL-FABP can prevent or reduce AKI severity is unknown and merits further studies.

Urinary Liver-Type Fatty Acid Binding Protein, a Biomarker for Disease Progression, Dialysis and Overall Mortality in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a major public health concern with an increasing proportion of sufferers progressing to renal replacement therapy (RRT). Early identification of those at risk of disease progression could be key in improving outcomes. We hypothesise that urinary liver-type fatty acid binding protein (uL-FABP) may be a suitable biomarker for CKD progression and can add value to currently established biomarkers such as the urinary protein-to-creatinine ratio (uPCR). A total of 583 participants with CKD 1-5 (not receiving renal replacement therapy) entered a 2 yr prospective longitudinal study. UPCR and uL-FABP were measured at baseline and CKD progression was defined as either (i) a decline in eGFR of >5 mL/min/1.73 m2 or an increase in serum creatinine by 10% at 1 yr; (ii) a decline in eGFR of >6 mL/min/1.73 m2 or an increase in serum creatinine by 20% at 2 yrs; or (iii) the initiation of RRT. A combined outcome of initiating RRT or death was also included. Approximately 40% of participants showed CKD progression. uL-FABP predicted CKD progression at both years 1 and 2 (OR 1.01, p < 0.01). Sensitivity and specificity were comparable to those of uPCR (AUC 0.623 v 0.706) and heat map analysis suggested that uL-FABP in the absence of significant proteinuria can predict an increase in serum creatinine of 10% at 1 yr and 20% at 2 yrs. The risk of the combined outcome of initiating RRT or death was 23% higher in those with high uL-FABP (p < 0.01) independent of uPCR. uL-FABP appears to be a highly sensitive and specific biomarker of CKD progression. The use of this biomarker could enhance the risk stratification of CKD and its progression and should be assessed further.

Platinum-based chemotherapy attenuates the effector response of CD8 T cells to concomitant PD-1 blockade.

PURPOSE: Combination of chemotherapy (CT) with programmed cell death (PD)-1 blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how CT affects the response of exhausted CD8 T cells to PD-1 blockade. EXPERIMENTAL DESIGN: We used the well-established mouse model of T cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of CT (cisplatin+pemetrexed) on T cell response to PD-1 blockade, in the absence of the impact of CT on antigen release and presentation observed in tumor models. RESULTS: When concomitantly administered with PD-1 blockade, CT affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of interferon (IFN)-γ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared to PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed CT, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by CT partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant CT, ultimately resulting in impaired overall CD8 T cell effector functions. CONCLUSIONS: In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T cell functions.

Assessing the Self-reported After Events Following Immunization of COVID-19 Vaccines in Turkey and Bangladesh.

Though mass vaccination programs helped to reduce the severity of the ongoing pandemic, various unwanted effects were reported in Turkey and Bangladesh after taking vaccines. The purpose of this study was to evaluate and compare the adverse effects of several vaccines in Turkey and Bangladesh and how the population of both countries prioritizes the continuation of vaccination compared to the side effects. An online survey with a pretest was conducted to gather data over the research period from July 10, 2021 to December 10, 2021. Finally, the questionnaire was shared with the mass population of Turkey and Bangladesh who have received at least one or two doses of the COVID-19 vaccines. The quality of the questionnaire was evaluated with Cronbach's alpha test. The study consisted of 1508 respondents from Bangladesh and 602 respondents from Turkey. Among the total 2110 respondents, 50.0% were male 66.8% were from the 18-30 years age range, and 77.5% reported living in the city area. Among all the respondents, 64.99% of those vaccinated in Bangladesh and 67.28% of those vaccinated in Turkey reported side effects after vaccinations. Participants receiving mRNA vaccines (Pfizer and Moderna) experienced the most side effects, with many reporting pain at the injection site in both nations. Following that, fever, body pain, and headache were common in Bangladesh, whereas body pain, fatigue, and arm numbness were common in Turkey. The study found no significant adverse events reported in Turkey and Bangladesh following the first and second doses of COVID-19 vaccination. These COVID-19 vaccines showed similar patterns of efficacy and safety during the short period of analysis. Vaccines from different manufacturers showed a non-significant level of adverse events during this binational AEFI approach to COVID-19 vaccines. More studies are recommended on the efficacy and safety of several vaccines to discover unexpected effects.

A systematic review of the efficacy and safety of anticoagulants in advanced chronic kidney disease.

BACKGROUND: Patients with chronic kidney disease (CKD) have an increased risk of venous thromboembolism (VTE) and atrial fibrillation (AF). Anticoagulants have not been studied in randomised controlled trials with CrCl < 30 ml/min. The objective of this review was to identify the impact of different anticoagulant strategies in patients with advanced CKD including dialysis. METHODS: We conducted a systematic review of randomized controlled trials and cohort studies, searching electronic databases from 1946 to 2022. Studies that evaluated both thrombotic and bleeding outcomes with anticoagulant use in CrCl < 50 ml/min were included. RESULTS: Our initial search yielded 14,503 papers with 53 suitable for inclusion. RCTs comparing direct oral anticoagulants (DOACs) versus warfarin for patients with VTE and CrCl 30-50 ml/min found no difference in recurrent VTE events (RR 0.68(95% CI 0.42-1.11)) with reduced bleeding (RR 0.65 (95% CI 0.45-0.94)). Observational data in haemodialysis suggest lower risk of recurrent VTE and major bleeding with apixaban versus warfarin. Very few studies examining outcomes were available for therapeutic and prophylactic dose low molecular weight heparin for CrCl < 30 ml/min. Findings for patients with AF on dialysis were that warfarin or DOACs had a similar or higher risk of stroke compared to no anticoagulation. For patients with AF and CrCl < 30 ml/min not on dialysis, anticoagulation should be considered on an individual basis, with limited studies suggesting DOACs may have a preferable safety profile. CONCLUSION: Further studies are still required, some ongoing, in patients with advanced CKD (CrCl < 30 ml/min) to identify the safest and most effective treatment options for VTE and AF.

A Retrospective Cross-Sectional Study Assessing Self-Reported Adverse Events following Immunization (AEFI) of the COVID-19 Vaccine in Bangladesh.

BACKGROUND: The Oxford-AstraZeneca vaccine (Covishield) was the first to be introduced in Bangladesh to fight the ongoing global COVID-19 pandemic. As this vaccine had shown some side-effects in its clinical trial, we aimed to conduct a study assessing short-term adverse events following immunization (AEFIs) in Bangladesh. METHOD: A cross-sectional study was conducted on social and electronic media platforms by delivering an online questionnaire among people who had taken at least one dose of the COVID-19 vaccine. The collected data were then analysed to evaluate various parameters related to the AEFIs of the respondents. RESULTS: A total of 626 responses were collected. Of these, 623 were selected based on complete answers and used for the analysis. Most of the respondents were between 30-60 years of age, and 40.4% were female. We found that a total of 8.5% of the total respondents had been infected with the SARS-CoV-2 virus. Our survey revealed that out of 623 volunteers, 317 reported various side-effects after taking the vaccine, which is about 50.88% of the total participants. The majority of participants (37.07%, 231/623) reported swelling and pain at the injection site and fever (25.84%, 162/623); these were some of the common localized and generalized symptoms after the COVID-19 vaccine administration. CONCLUSION: The side-effects reported after receiving the Oxford-AstraZeneca vaccine (Covishield) are similar to those reported in clinical trials, demonstrating that the vaccines have a safe therapeutic window. Moreover, further research is needed to determine the efficacy of existing vaccines in preventing SARS-CoV-2 infections or after-infection hospitalization.

You Cannot Have Your Synergy and Efficacy Too.

Synergistic drugs are preferred in combination therapies for many diseases, including viral infections and cancers. Maximizing synergy, however, may come at the cost of efficacy. This synergy-efficacy trade-off appears to be widely prevalent and independent of the specific drug interactions yielding synergy. We present examples of the trade-off in drug combinations used in hepatitis C, HIV, and cancer therapies and believe that screens for optimal drug combinations that presently seek to maximize synergy may be improved by considering the trade-off.