Category: Nevin Manimala

BMJ Open. 2021 Jul 12;11(7):e046227. doi: 10.1136/bmjopen-2020-046227.

ABSTRACT

INTRODUCTION: Telemedicine gained strength in primary healthcare (PHC) during the COVID-19 pandemic. Thus, there is a need to know its scope, technologies used and impacts on people’s health. This study will map telemedicine use in PHC around the world and its impacts on quality of care in the context of the COVID-19 pandemic.

METHODS: This is a scoping review protocol developed according to Arksey and O’Malley and Levac et al, based on the Joanna Briggs Institute manual, and guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR). The records will be mapped in the following multidisciplinary health sciences databases: Virtual Health Library, PubMed, Scopus, Web of Science, CINAHL and Embase. Searches will also be conducted on Google Scholar, preprint repositories and specific COVID-19 databases (grey literature). Quantitative data will be analysed using descriptive statistics, while thematic analysis will be performed for qualitative data. Preliminary findings will be presented to stakeholders to identify missing studies and develop effective dissemination strategies.

ETHICS AND DISSEMINATION: Results will be disseminated through publication in an open access scientific journal, scientific events, and academic and community newspapers. Ethical approval was obtained due to stakeholder consultation, but will not involve the direct participation of patients. Link to the protocol record in the Open Science Framework (OSF) (osf.io/q94en).

PMID:34253666 | DOI:10.1136/bmjopen-2020-046227

BMJ Open. 2021 Jul 12;11(7):e050519. doi: 10.1136/bmjopen-2021-050519.

ABSTRACT

OBJECTIVE: To systematically review evidence on effectiveness of contact tracing apps (CTAs) for SARS-CoV-2 on epidemiological and clinical outcomes.

DESIGN: Rapid systematic review.

DATA SOURCES: EMBASE (OVID), MEDLINE (PubMed), BioRxiv and MedRxiv were searched up to 28 October 2020.

STUDY SELECTION: Studies, both empirical and model-based, assessing effect of CTAs for SARS-CoV-2 on reproduction number (R), total number of infections, hospitalisation rate, mortality rate, and other epidemiologically and clinically relevant outcomes, were eligible for inclusion.

DATA EXTRACTION: Empirical and model-based studies were critically appraised using separate checklists. Data on type of study (ie, empirical or model-based), sample size, (simulated) time horizon, study population, CTA type (and associated interventions), comparator and outcomes assessed, were extracted. The most important findings were extracted and narratively summarised. Specifically for model-based studies, characteristics and values of important model parameters were collected.

RESULTS: 2140 studies were identified, of which 17 studies (2 empirical, 15 model-based studies) were eligible and included in this review. Both empirical studies were observational (non-randomised) studies and at high risk of bias, most importantly due to risk of confounding. Risk of bias of model-based studies was considered low for 12 out of 15 studies. Most studies demonstrated beneficial effects of CTAs on R, total number of infections and mortality rate. No studies assessed effect on hospitalisation. Effect size was dependent on model parameters values used, but in general, a beneficial effect was observed at CTA adoption rates of 20% or higher.

CONCLUSIONS: CTAs have the potential to be effective in reducing SARS-CoV-2 related epidemiological and clinical outcomes, though effect size depends on other model parameters (eg, proportion of asymptomatic individuals, or testing delays), and interventions after CTA notification. Methodologically sound comparative empirical studies on effectiveness of CTAs are required to confirm findings from model-based studies.

PMID:34253676 | DOI:10.1136/bmjopen-2021-050519

J Immunother Cancer. 2021 Jul;9(7):e002101. doi: 10.1136/jitc-2020-002101.

ABSTRACT

BACKGROUND: A major current challenge is to exploit tertiary lymphoid structures (TLSs) to promote the lymphocyte infiltration, activation and differentiation by tumor antigens to increase antitumor immune responses. The mechanisms that underlie the role of TLS formation in the adaptive immune responses against nasopharyngeal carcinoma (NPC) remain largely unknown.

METHODS: Cell populations and the corresponding markers were identified by single-cell RNA sequencing and fluorescence-activated cell sorting analysis. In vitro differentiation experiments were used to simulate the generation, regulation and function of the Th-CXCL13 cell subset in the tumor microenvironment of NPC. These were followed by histological evaluation of the colocalization of tumor-associated B cells (TABs) and Th-CXCL13 cells within TLSs, and statistical analysis of the relationship between the cells in TLSs and overall survival.

RESULTS: A PD-1⁺CXCR5^–CD4⁺ Th-CXCL13 cell subset was identified in NPC. This subset was a major source of CXCL13, representing the majority of the CD4⁺ T cells at levels comparable with Th1 and Tfh cells present in the TLSs. Monocytes activated by toll-like receptor 4 agonists served as the antigen-presenting cells that most efficiently triggered the expansion of Th-CXCL13 cells. Transforming growth factor beta 1 (TGF-β1) stimulation and activation of Sox4 were critical for the induction and polarization of Th-CXCL13 cells in this process. The potential functional contributions of TABs recruited by Th-CXCL13 cells which induced plasma cell differentiation and immunoglobulin production via interleukin-21 and CD84 interactions in the TLSs demonstrated improved survival.

CONCLUSIONS: Induction of Th-CXCL13 cells links innate inflammation to immune privilege in tumor-associated TLSs and might predict better survival.

PMID:34253636 | DOI:10.1136/jitc-2020-002101

BMJ Mil Health. 2021 Jul 12:bmjmilitary-2021-001845. doi: 10.1136/bmjmilitary-2021-001845. Online ahead of print.

ABSTRACT

INTRODUCTION: Medication-assisted treatment (MAT) is a combination of behavioural therapy and medications to assist with recovery and has been administered to individuals with alcohol and opioid withdrawal symptoms. Military veterans seeking MAT could have barriers preventing them from receiving the care they desire. The present study sought to compare outcomes in individuals who received MAT or those who participated in self-help groups for opioid or alcohol use disorder. In addition, the present study sought to compare outcomes between veterans and non-military-connected individuals.

METHODS: We used the 2015-2017 United States Treatment Episode Data Set Discharges data from the Substance Abuse and Mental Health Services Administration. The data set included 138 594 unique discharges. A multinomial logistic regression model was used to examine differences in substance use outcomes for veterans/non-veterans in MAT and a self-help group.

RESULTS: Fewer veterans (2.58%) than non-veterans (4.28%) reported usage of MAT. Fewer veterans (38.94%) than non-veterans (40.17%) reported signing up for a self-help group. Finally, those who participated in MAT and a self-help group had a better outcome (66.64%)-defined as no substance use at discharge-than those who only received MAT (43.02%) and those who did not participate in MAT or self-help groups (34.84%).

CONCLUSIONS: Recommendations for future research on MAT and implementation for the veteran population would benefit the literature base.

PMID:34253642 | DOI:10.1136/bmjmilitary-2021-001845

Mol Cancer Ther. 2021 Jul 12:molcanther.MCT-21-0035-A.2021. doi: 10.1158/1535-7163.MCT-21-0035. Online ahead of print.

ABSTRACT

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma (MM) and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug-conjugate approved for the treatment of relapsed/refractory MM. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo. GSK2857916 treatment enhances intra-tumor immune cell infiltration and activation, delays tumor growth and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to re-challenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T-cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance anti-tumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators.

PMID:34253590 | DOI:10.1158/1535-7163.MCT-21-0035

Proc Natl Acad Sci U S A. 2021 Jul 20;118(29):e2104013118. doi: 10.1073/pnas.2104013118.

ABSTRACT

Somatic hypermutation (SHM) and class-switch recombination (CSR) of the immunoglobulin (Ig) genes allow B cells to make antibodies that protect us against a wide variety of pathogens. SHM is mediated by activation-induced deaminase (AID), occurs at a million times higher frequency than other mutations in the mammalian genome, and is largely restricted to the variable (V) and switch (S) regions of Ig genes. Using the Ramos human Burkitt’s lymphoma cell line, we find that H3K79me2/3 and its methyltransferase Dot1L are more abundant on the V region than on the constant (C) region, which does not undergo mutation. In primary naïve mouse B cells examined ex vivo, the H3K79me2/3 modification appears constitutively in the donor Sμ and is inducible in the recipient Sγ1 upon CSR stimulation. Knockout and inhibition of Dot1L in Ramos cells significantly reduces V region mutation and the abundance of H3K79me2/3 on the V region and is associated with a decrease of polymerase II (Pol II) and its S2 phosphorylated form at the IgH locus. Knockout of Dot1L also decreases the abundance of BRD4 and CDK9 (a subunit of the P-TEFb complex) on the V region, and this is accompanied by decreased nascent transcripts throughout the IgH gene. Treatment with JQ1 (inhibitor of BRD4) or DRB (inhibitor of CDK9) decreases SHM and the abundance of Pol II S2P at the IgH locus. Since all these factors play a role in transcription elongation, our studies reinforce the idea that the chromatin context and dynamics of transcription are critical for SHM.

PMID:34253616 | DOI:10.1073/pnas.2104013118

J Neurosci. 2021 Jul 12:JN-RM-2137-20. doi: 10.1523/JNEUROSCI.2137-20.2021. Online ahead of print.

ABSTRACT

In everyday life, we have no trouble categorizing objects varying in position, size, and orientation. Previous fMRI research shows that higher-level object processing regions in the human lateral occipital cortex may link object responses from different affine states (i.e. size and viewpoint) through a general linear mapping function capable of predicting responses to novel objects. In this study, we extended this approach to examine the mapping for both Euclidean (e.g. position and size) and non-Euclidean (e.g. image statistics and spatial frequency) transformations across the human ventral visual processing hierarchy, including areas V1, V2, V3, V4, ventral occipitotemporal cortex (VOT), and lateral occipitotemporal cortex (LOT). The predicted pattern generated from a linear mapping function could capture a significant amount of the changes associated with the transformations throughout the ventral visual stream. The derived linear mapping functions were not category independent, as performance was better for the categories included than those not included in training and better between two similar versus two dissimilar categories in both lower and higher visual regions. Consistent with object representations being stronger in higher than lower visual regions, pattern selectivity and object category representational structure were somewhat better preserved in the predicted patterns in higher than lower visual regions. There were no notable differences between Euclidean and non-Euclidean transformations. These findings demonstrate a near-orthogonal representation of object identity and these non-identity features throughout the human ventral visual processing pathway, with these non-identity features largely untangled from the identity features early in visual processing.Significance StatementPresently we still do not fully understand how object identity and non-identity (e.g. position, size) information are simultaneously represented in the primate ventral visual system to form invariant representations. Previous work suggests that the human lateral occipital cortex may be linking different affine states of object representations through general linear mapping functions. Here we show that across the entire human ventral processing pathway, we could link object responses in different states of non-identity transformations through linear mapping functions for both Euclidean and non-Euclidean transformations. These mapping functions are not identity-independent, suggesting that object identity and non-identity features are represented in a near, rather than a completely, orthogonal manner.

PMID:34253629 | DOI:10.1523/JNEUROSCI.2137-20.2021

Clin Cancer Res. 2021 Jul 12:clincanres.CCR-21-2051-E.2021. doi: 10.1158/1078-0432.CCR-21-2051. Online ahead of print.

ABSTRACT

PURPOSE: The Cancer Immune Monitoring and Analysis Centers – Cancer Immunologic Data Commons (CIMAC-CIDC) network supported by the NCI Cancer Moonshot initiative was established to provide correlative analyses for clinical trials in cancer immunotherapy, using state-of-the-art technology. Fundamental to this initiative is implementation of multiplex immunohistochemical assays to define the composition and distribution of immune infiltrates within tumors in the context of their potential role as biomarkers. A critical unanswered question involves the relative fidelity of such assays to reliably quantify tumor associated immune cells across different platforms.

EXPERIMENTAL DESIGN: Three CIMAC sites compared across their laboratories: 1) image analysis algorithms, 2) image acquisition platforms, 3) multiplex staining protocols. Two distinct high-dimensional approaches were employed: multiplexed immunohistochemical consecutive staining on single slide (MICSSS) and multiplexed immunofluorescence (mIF). To eliminate variables potentially impacting assay performance, we completed a multistep harmonization process, first comparing assay performance using independent protocols followed by the integration of laboratory-specific protocols and finally, validating this harmonized approach in an independent set of tissues.

RESULTS: Data generated at the final validation step showed an inter-site Spearman correlation coefficient of {greater than or equal to}0.85 for each marker within and across tissue types, with an overall low average coefficient of variation {less than or equal to}0.1.

CONCLUSIONS: Our results support interchangeability of protocols and platforms to deliver robust, and comparable data using similar tissue specimens and confirm that CIMAC-CIDC analyses may therefore be used with confidence for statistical associations with clinical outcomes largely independent of site, antibody selection, protocol, and platform across different sites.

PMID:34253580 | DOI:10.1158/1078-0432.CCR-21-2051

Med Humanit. 2021 Jul 12:medhum-2021-012156. doi: 10.1136/medhum-2021-012156. Online ahead of print.

ABSTRACT

COVID-19 represents one of the most challenging global health issues in modern times. However, as epidemics have affected humans since our origins, many before us have described how significantly they compromise human lives. Leaving apart the aspects more linked to medicine and health sciences, we focus here on analysing how epidemics force people to change their habits, what type of emotions and behaviours they promote, and which roles are played by different social actors. For such a purpose, especially if we wish to draw some parallels between past epidemics and COVID-19, historical records seemed to be more suitable than literary works. Nonetheless, we have taken this approach relying on La Peste (Albert Camus, 1947), a novel based on a fictional epidemic of plague in the Algerian town of Oran. Far from creating a barrier separating fiction from reality, this reading allowed us to establish several links with our current situation. Recognising that context and solutions vary widely between the two scenarios, core matters concerning epidemics seemed to remain invariable. The important role of data and statistics, the leadership acquired by health authorities, the separations of relatives or the negative effects on trade and business are some issues which took place in Oran as well as nowadays. Besides that, epidemics also affect humans at an individual level, and certain thoughts and feelings in La Peste‘s main characters may make us identify with our own fears and desires.

PMID:34253585 | DOI:10.1136/medhum-2021-012156

Cardiovasc Revasc Med. 2021 Jun 25:S1553-8389(21)00488-7. doi: 10.1016/j.carrev.2021.06.123. Online ahead of print.

ABSTRACT

BACKGROUND: Most pivotal transcatheter aortic valve replacement (TAVR) trials have excluded patients with bicuspid aortic stenosis (AS). This study compared TAVR in low-risk patients with bicuspid AS to those with tricuspid AS, incorporating data from prospective trials.

METHODS: We selected prospective US low-risk TAVR trials containing a bicuspid arm for this meta-analysis, examining outcomes at 30 days. Study results were pooled using a hierarchical Bayesian random-effects model.

RESULTS: Included were 3 Food and Drug Administration (FDA)-approved investigational device exemption (IDE) trials that enrolled a total of 1810 low-risk patients with symptomatic severe AS for TAVR. We compared 380 bicuspid patients with 1430 tricuspid patients. Event rates at 30 days overall were low, with similar mortality (odds ratio [OR], 0.38; 95% credible interval [CrI]: 0.08, 1.78; I², 0%), non-disabling stroke (OR, 0.45; 95% CrI: 0.15, 1.07; I², 9%), and permanent pacemaker implantation (OR, 0.86; 95% CrI: 0.41, 1.47; I², 59%). There were statistically significant differences in disabling stroke (OR, 0.16; 95% CrI: 0.01, 0.90; I², NA) and coronary obstruction (OR, 0.21; 95% CrI: 0.05, 0.91) that disappeared after sensitivity analysis by adding a single event to the tricuspid arm. Hemodynamics were similar at 30 days.

CONCLUSIONS: Preliminary data from the FDA-approved IDE trials of low-risk patients with bicuspid AS undergoing TAVR demonstrated 30-day outcomes comparable to low-risk tricuspid patients, except for a trend toward higher stroke in bicuspid patients. Randomized trials are warranted to reassure the safety and long-term outcome of TAVR in patients with severe bicuspid AS.

PMID:34253474 | DOI:10.1016/j.carrev.2021.06.123