Nevin Manimala

Neurologist. 2021 Dec 6. doi: 10.1097/NRL.0000000000000394. Online ahead of print.

ABSTRACT

BACKGROUND: Genome-wide association studies for neuromyelitis optica spectrum disorder (NMOSD) have established an association between HLA-DQ alpha 1 (DQA1) and risk for NMOSD. Though ethnicity is generally considered a major influencing factor in genetic analyses, little is known regarding the association of HLA-DQA1 polymorphisms with NMOSD in the Han population, especially the single-nucleotide polymorphisms (SNPs) at HLA-DQA1.

METHODS: We genotyped SNP at loci rs28383224 in a case-control study consisting of 137 subjects (51 patients with NMOSD and 86 unrelated controls were recruited) of Han ethnicity. Logistic regression was used to test the association of SNP with NMOSD susceptibility, the sex and age were adjusted, odds ratios and 95% confidence intervals were estimated.

RESULTS: The rs28383224 polymorphism and susceptibility to NMOSD were not statistically associated (P>0.05) in the Han population in the current study. No significant difference was found in allelic frequencies or genotypic distributions among different subsets of NMOSD patients (P>0.05).

CONCLUSION: In the current study, there is no evidence that polymorphism of rs28383224 in the HLA-DQA1 gene is associated with the risk of NMOSD in the Han Chinese population.

PMID:34873111 | DOI:10.1097/NRL.0000000000000394

AIDS. 2021 Dec 6. doi: 10.1097/QAD.0000000000003140. Online ahead of print.

ABSTRACT

OBJECTIVES: We examined whether molecular cluster membership was associated with public health identification of HIV transmission potential among named partners in Chicago.

DESIGN: Historical cohort study.

METHODS: We matched and analyzed HIV surveillance and partner services data from HIV diagnoses (2012-2016) prior to implementation of cluster detection and response interventions. We constructed molecular clusters using HIV-TRACE at a pairwise genetic distance threshold of 0·5% and identified clusters exhibiting recent and rapid growth according to the CDC’s definition (3 new cases diagnosed in past year). Factors associated with identification of partners with HIV transmission potential were examined using multivariable Poisson regression.

RESULTS: There were 5,208 newly diagnosed index clients over this time period. Average age of index clients in clusters was 28; 47% were Black, 29% Latinx/Hispanic, 6% female and 89% men who have sex with men (MSM). Of the 537 named partners, 191 (35·6%) were linked to index cases in a cluster and of those 16% were either new diagnoses or viremic. There was no statistically significant difference in the probability of identifying partners with HIV transmission potential among index clients in a rapidly growing cluster versus those not in a cluster (adjusted Relative Risk 1·82, (0·81-4·06)).

CONCLUSION: Partner services that were initiated from index clients in a molecular cluster yielded similar new HIV case finding or identification of those with viremia as did interviews with index clients not in clusters. It remains unclear whether these findings are due to temporal disconnects between diagnoses and cluster identification, unobserved cluster members, or challenges with partner services implementation.

PMID:34873085 | DOI:10.1097/QAD.0000000000003140

Chin Med J (Engl). 2021 Dec 6. doi: 10.1097/CM9.0000000000001705. Online ahead of print.

ABSTRACT

BACKGROUND: As one of the most common endocrinal disorders for women at childbearing age, the diagnostic criteria of polycystic ovary syndrome (PCOS) have been defined differently among different international health organizations. Phenotypic heterogeneity of PCOS also brings about difficulties for its diagnosis and management assessment. Therefore, more efficient biomarkers representing the progression of PCOS are expected to be integrated into the monitoring of management process using metabolomic approaches.

METHODS: In this prospective randomized controlled trial, 117 PCOS patients were enrolled from December 2016 to September 2017. Classical diagnostic parameters, blood glucose, and metabolome were measured in these patients before and at 2 months and 3 months of different medical interventions. The receiver operating characteristic (ROC) curves were built based on multivariate statistical analysis using data at baseline and 3 months’ management, and combinational biomarkers with appreciable sensitivity and specificity were selected, which then validated with data collected at 2 months.

RESULTS: A set of metabolites including glutamic acid, aspartic acid, 1-methylnicotinamide, acetylcarnitine, glycerophosphocholine, and oleamide were filtered out with high performance in representing the improvement through 3-month management of PCOS with high sensitivity and specificity in ROC analysis and validation with other two groups showed an appreciable area under the curve over 0.96.

CONCLUSIONS: The six metabolites were representative of the remission of PCOS through medical intervention, making them a set of potential biomarkers for assessing the outcome of PCOS management.

TRIAL REGISTRATION: ClinicalTrials.gov, NCT03264638.

PMID:34873082 | DOI:10.1097/CM9.0000000000001705

J Physiol Pharmacol. 2021 Jun;72(3). doi: 10.26402/jpp.2021.3.13. Epub 2021 Dec 3.

ABSTRACT

This study aimed to investigate the mechanism of propofol (PR) pretreatment inducing high heme oxygenase-1 (HO-1) expression to protect alveolar type II epithelial cells (AEC-II) in rats with acute lung injury (ALI) induced by oleic acid (OA). In this study, 32 male Sprague-Dawley rats (250 – 300 g) were randomly divided into four groups (n = 8 in each group) as follows: group C (the normal control group), the OA group (the oleic acid injury control group), the OA + PR group (the PR pretreatment group), and the OA + IX group (the zinc porphyrin IX pretreatment group). Arterial blood gases, bronchoalveolar lavage fluid (BALF), and serum pulmonary surfactant-associated protein A (SP-A) were measured in each group. The changes in the AEC-II ultrastructure were observed under an electron microscope. The HO-1 protein expression was detected by immunohistochemistry, and HO-1 messenger ribonucleic acid (mRNA) was detected by polymerase chain reaction. The results of this study showed that there were significant differences in PO₂, pCO₂, and PaO₂/FiO₂ among the different groups (p < 0.05). The difference between BALF and SP-A in each group was statistically significant (p < 0.01). There were also significant differences in the integrated optical density of the HO-1 protein expression and HO-1 mRNA in the pulmonary tissue of the different groups (p < 0.05 or p < 0.01). The results of the electron microscopy showed that AEC-II were relatively irregular in the OA group. The cells degenerated and even disintegrated, the microvilli on the cell surface decreased, the lamellar bodies in the cytoplasm were evacuated, and some were discharged into the alveolar cavity. The above-mentioned changes in the OA + PR group were lower than in the OA group, while the changes were greater in the OA + IX group, compared with those in the OA group. We conclude that PR can significantly increase the expression of HO-1 in pulmonary tissues and reduce pulmonary injury, and, therefore, protect the AEC-II.

PMID:34873068 | DOI:10.26402/jpp.2021.3.13

Proc Natl Acad Sci U S A. 2021 Dec 7;118(49):e2108395118. doi: 10.1073/pnas.2108395118.

ABSTRACT

We hypothesized that cross-protection from seasonal epidemics of human coronaviruses (HCoVs) could have affected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, including generating reduced susceptibility in children. To determine what the prepandemic distribution of immunity to HCoVs was, we fitted a mathematical model to 6 y of seasonal coronavirus surveillance data from England and Wales. We estimated a duration of immunity to seasonal HCoVs of 7.8 y (95% CI 6.3 to 8.1) and show that, while cross-protection between HCoV and SARS-CoV-2 may contribute to the age distribution, it is insufficient to explain the age pattern of SARS-CoV-2 infections in the first wave of the pandemic in England and Wales. Projections from our model illustrate how different strengths of cross-protection between circulating coronaviruses could determine the frequency and magnitude of SARS-CoV-2 epidemics over the coming decade, as well as the potential impact of cross-protection on future seasonal coronavirus transmission.

PMID:34873059 | DOI:10.1073/pnas.2108395118

Proc Natl Acad Sci U S A. 2021 Dec 7;118(49):e2105859118. doi: 10.1073/pnas.2105859118.

ABSTRACT

RNA velocity is a promising technique for quantifying cellular transitions from single-cell transcriptome experiments and revealing transient cellular dynamics among a heterogeneous cell population. However, the cell transitions estimated from high-dimensional RNA velocity are often unstable or inaccurate, partly due to the high technical noise and less informative projection. Here, we present Velocity Autoencoder (VeloAE), a tailored representation learning method, to learn a low-dimensional representation of RNA velocity on which cellular transitions can be robustly estimated. On various experimental datasets, we show that VeloAE can both accurately identify stimulation dynamics in time-series designs and effectively capture expected cellular differentiation in different biological systems. VeloAE, therefore, enhances the usefulness of RNA velocity for studying a wide range of biological processes.

PMID:34873054 | DOI:10.1073/pnas.2105859118

Proc Natl Acad Sci U S A. 2021 Dec 7;118(49):e2026092118. doi: 10.1073/pnas.2026092118.

ABSTRACT

Despite the complexity of human memory, paradigms like free recall have revealed robust qualitative and quantitative characteristics, such as power laws governing recall capacity. Although abstract random matrix models could explain such laws, the possibility of their implementation in large networks of interacting neurons has so far remained underexplored. We study an attractor network model of long-term memory endowed with firing rate adaptation and global inhibition. Under appropriate conditions, the transitioning behavior of the network from memory to memory is constrained by limit cycles that prevent the network from recalling all memories, with scaling similar to what has been found in experiments. When the model is supplemented with a heteroassociative learning rule, complementing the standard autoassociative learning rule, as well as short-term synaptic facilitation, our model reproduces other key findings in the free recall literature, namely, serial position effects, contiguity and forward asymmetry effects, and the semantic effects found to guide memory recall. The model is consistent with a broad series of manipulations aimed at gaining a better understanding of the variables that affect recall, such as the role of rehearsal, presentation rates, and continuous and/or end-of-list distractor conditions. We predict that recall capacity may be increased with the addition of small amounts of noise, for example, in the form of weak random stimuli during recall. Finally, we predict that, although the statistics of the encoded memories has a strong effect on the recall capacity, the power laws governing recall capacity may still be expected to hold.

PMID:34873052 | DOI:10.1073/pnas.2026092118

Open Heart. 2021 Dec;8(2):e001709. doi: 10.1136/openhrt-2021-001709.

ABSTRACT

OBJECTIVE: Advancement in healthcare provision has led to increasing octogenarian ST elevation myocardial infarction (STEMI) presentation to hospital for early revascularisation therapies. Limited literature to date exists to suggest octogenarian STEMI population; with majority of trials excluding these age group patients. Due to an ageing population, we expect increasing rates of STEMI in the octogenarian and nonagenarian population in the future. This study seeks to identify the outcomes of patients over the age of 80 presenting with STEMI and determine the factors associated with better or worse outcome.

PATIENTS AND METHODS: This study is a single-centre retrospective observational study involving patients’ age 80 or older presenting with STEMI between January 2014 and December 2019. Patient data were collected by chart review and analysis of the local STEMI database. Standard Bayesian statistics were employed for analysis.

RESULTS: 1301 patients presented with STEMI during this period. 159/1301 (12.2%) were 80 years or older that fulfilled STEMI criteria, 35/159 (22.1%) were medically managed. 107/124 (86.29%) had angiographic evidence of acute total or partial thrombotic occlusion, and 97/107 were treated with primary percutaneous coronary intervention (PPCI). The activation ECG most commonly exhibited an anterior STEMI, while inferior STEMI ECGs had the strongest positive predictive value. PPCI group had a 30-day mortality rate of 20% (p=0.07) and 1-year mortality was 22.4%. Highest mortality was observed with cardiogenic shock, low ejection fraction, higher high sensitivity cardiac troponin T and creatinine at presentation. Conservatively managed patients had significant higher mortality rate (48% vs 22.4%, p=0.005) at 1 year.

CONCLUSION: Patients over the age of 80 who present with STEMI and undergo PPCI have a significantly lower mortality rate at 1 year. These patients have a 77.6% survival at 1 year, with 92.4% likelihood of discharge to home (without need for long-term nursing home care). Cardiogenic shock in this group was associated with a 1-year mortality of 87.5%. Despite the advanced age, we suggest favourable outcomes described in the absence of patients presenting with cardiogenic shock.

PMID:34873049 | DOI:10.1136/openhrt-2021-001709

Proc Natl Acad Sci U S A. 2021 Dec 14;118(50):e2114743118. doi: 10.1073/pnas.2114743118.

ABSTRACT

The H3.3 histone variant and its chaperone HIRA are involved in active transcription, but their detailed roles in regulating somatic hypermutation (SHM) of immunoglobulin variable regions in human B cells are not yet fully understood. In this study, we show that the knockout (KO) of HIRA significantly decreased SHM and changed the mutation pattern of the variable region of the immunoglobulin heavy chain (IgH) in the human Ramos B cell line without changing the levels of activation-induced deaminase and other major proteins known to be involved in SHM. Except for H3K79me2/3 and Spt5, many factors related to active transcription, including H3.3, were substantively decreased in HIRA KO cells, and this was accompanied by decreased nascent transcription in the IgH locus. The abundance of ZMYND11 that specifically binds to H3.3K36me3 on the IgH locus was also reduced in the HIRA KO. Somewhat surprisingly, HIRA loss increased the chromatin accessibility of the IgH V region locus. Furthermore, stable expression of ectopic H3.3G34V and H3.3G34R mutants that inhibit both the trimethylation of H3.3K36 and the recruitment of ZMYND11 significantly reduced SHM in Ramos cells, while the H3.3K79M did not. Consistent with the HIRA KO, the H3.3G34V mutant also decreased the occupancy of various elongation factors and of ZMYND11 on the IgH variable and downstream switching regions. Our results reveal an unrecognized role of HIRA and the H3.3K36me3 modification in SHM and extend our knowledge of how transcription-associated chromatin structure and accessibility contribute to SHM in human B cells.

PMID:34873043 | DOI:10.1073/pnas.2114743118

BMJ Open. 2021 Dec 6;11(12):e054222. doi: 10.1136/bmjopen-2021-054222.

ABSTRACT

OBJECTIVES: Patients undergoing surgery for severe aortic stenosis (SAS) can be treated with either transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (SAVR). The choice of procedure depends on several factors, including the clinical judgement of the heart team and patient preferences, which are captured by actively informing and involving patients in a process of shared decision making (SDM). We synthesised the most up-to-date and accessible evidence on the benefits and risks that may be associated with TAVI versus SAVR to support SDM in this highly personalised decision-making process.

DESIGN: Systematic review and meta-analysis.

DATA SOURCES: MEDLINE (Ovid), Embase (Ovid) and the Cochrane Central Register of Controlled Trials (CENTRAL; Wiley) were searched from January 2000 to August 2020 with no language restrictions. Reference lists of included studies were searched to identify additional studies.

ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) that compared TAVI versus SAVR in patients with SAS and reported on all-cause or cardiovascular mortality, length of stay in intensive care unit or hospital, valve durability, rehospitalisation/reintervention, stroke (any stroke or major/disabling stroke), myocardial infarction, major vascular complications, major bleeding, permanent pacemaker (PPM) implantation, new-onset or worsening atrial fibrillation (NOW-AF), endocarditis, acute kidney injury (AKI), recovery time or pain were included.

DATA EXTRACTION AND SYNTHESIS: Two independent reviewers were involved in data extraction and risk of bias (ROB) assessment using the Cochrane tool (one reviewer extracted/assessed the data, and the second reviewer checked it). Dichotomous data were pooled using the Mantel-Haenszel method with random-effects to generate a risk ratio (RR) with 95% CI. Continuous data were pooled using the inverse-variance method with random-effects and expressed as a mean difference (MD) with 95% CI. Heterogeneity was assessed using the I² statistic.

RESULTS: 8969 records were retrieved and nine RCTs (61 records) were ultimately included (n=8818 participants). Two RCTs recruited high-risk patients, two RCTs recruited intermediate-risk patients, two RCTs recruited low-risk patients, one RCT recruited high-risk (≥70 years) or any-risk (≥80 years) patients; and two RCTs recruited all-risk or ‘operable’ patients. While there was no overall change in the risk of dying from any cause (30 day: RR 0.89, 95% CI 0.65 to 1.22; ≤1 year: RR 0.90, 95% CI 0.79 to 1.03; 5 years: RR 1.09, 95% CI 0.98 to 1.22), cardiovascular mortality (30 day: RR 1.03, 95% CI 0.77 to 1.39; ≤1 year: RR 0.90, 95% CI 0.76 to 1.06; 2 years: RR 0.96, 95% CI 0.83 to 1.12), or any type of stroke (30 day: RR 0.83, 95% CI 0.61 to 1.14;≤1 year: RR 0.94, 95% CI 0.72 to 1.23; 5 years: RR 1.07, 95% CI 0.88 to 1.30), the risk of several clinical outcomes was significantly decreased (major bleeding, AKI, NOW-AF) or significantly increased (major vascular complications, PPM implantation) for TAVI vs SAVR. TAVI was associated with a significantly shorter hospital stay vs SAVR (MD -3.08 days, 95% CI -4.86 to -1.29; 4 RCTs, n=2758 participants). Subgroup analysis generally favoured TAVI patients receiving implantation via the transfemoral (TF) route (vs non-TF); receiving a balloon-expandable (vs self-expanding) valve; and those at low-intermediate risk (vs high risk). All RCTs were rated at high ROB, predominantly due to lack of blinding and selective reporting.

CONCLUSIONS: No overall change in the risk of death from any cause or cardiovascular mortality was identified but 95% CIs were often wide, indicating uncertainty. TAVI may reduce the risk of certain side effects while SAVR may reduce the risk of others. Most long-term (5-year) results are limited to older patients at high surgical risk (ie, early trials), therefore more data are required for low risk populations. Ultimately, neither surgical technique was considered dominant, and these results suggest that every patient with SAS should be individually engaged in SDM to make evidence-based, personalised decisions around their care based on the various benefits and risks associated with each treatment.

PROSPERO REGISTRATION NUMBER: CRD42019138171.

PMID:34873012 | DOI:10.1136/bmjopen-2021-054222