Nevin Manimala

Sci Rep. 2021 Jul 29;11(1):15431. doi: 10.1038/s41598-021-92176-1.

ABSTRACT

Currently, no approved vaccine is available against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes severe respiratory disease. The spike glycoprotein is typically considered a suitable target for MERS-CoV vaccine candidates. A computational strategy can be used to design an antigenic vaccine against a pathogen. Therefore, we used immunoinformatics and computational approaches to design a multi-epitope vaccine that targets the spike glycoprotein of MERS-CoV. After using numerous immunoinformatics tools and applying several immune filters, a poly-epitope vaccine was constructed comprising cytotoxic T-cell lymphocyte (CTL)-, helper T-cell lymphocyte (HTL)-, and interferon-gamma (IFN-γ)-inducing epitopes. In addition, various physicochemical, allergenic, and antigenic profiles were evaluated to confirm the immunogenicity and safety of the vaccine. Molecular interactions, binding affinities, and the thermodynamic stability of the vaccine were examined through molecular docking and dynamic simulation approaches, during which we identified a stable and strong interaction with Toll-like receptors (TLRs). In silico immune simulations were performed to assess the immune-response triggering capabilities of the vaccine. This computational analysis suggested that the proposed vaccine candidate would be structurally stable and capable of generating an effective immune response to combat viral infections; however, experimental evaluations remain necessary to verify the exact safety and immunogenicity profile of this vaccine.

PMID:34326355 | DOI:10.1038/s41598-021-92176-1

Pain. 2021 Jul 28. doi: 10.1097/j.pain.0000000000002415. Online ahead of print.

ABSTRACT

Efforts to reduce opioid-related harms have decreased opioid prescription but have provoked concerns about unintended consequences, particularly for long-term opioid therapy (LtOT) recipients. Research is needed to address the knowledge gap regarding how risk of substance-related morbidity changes across LtOT and its discontinuation. The present study used nationwide commercial insurance claims data and a within-individual design to examine associations of LtOT dose and discontinuation with substance-related morbidity. We identified 194 839 adolescents and adults who initiated opioid prescription in 2010-2018 and subsequently received LtOT. The cohort was followed for a median of 965 days (interquartile range, 525-1550), of which a median of 176 days (119-332) were covered by opioid prescription. During follow-up, there were 17 582 acute substance-related morbidity events, defined as claims for emergency visits, inpatient hospitalizations, and ambulance transportation with substance use disorder or overdose diagnoses. Relative to initial treatment, risk was greater within individual during subsequent periods of >60-120 (adjusted odds ratio [OR], 1.29; 95% CI, 1.12-1.49) and >120 (OR, 1.48; 95% CI, 1.24-1.76) daily morphine milligram equivalents. Risk was also greater during days 1-30 after discontinuations than during initial treatment (OR, 1.19; 95% CI, 1.05-1.35). However, it was no greater than during the 30 days before discontinuations, indicating that the risk may not be wholly attributable to discontinuation itself. Results were supported by a negative control pharmacotherapy analysis and additional sensitivity analyses. They suggest that LtOT recipients may experience increased substance-related morbidity risk during treatment subsequent to initial opioid prescription, particularly in periods involving higher doses.

PMID:34326295 | DOI:10.1097/j.pain.0000000000002415

Pain. 2021 Jul 28. doi: 10.1097/j.pain.0000000000002423. Online ahead of print.

ABSTRACT

In recent years, long-term prescribing and use of strong opioids for chronic non-cancer pain (CNCP) has increased in high-income countries. Yet existing uncertainties, controversies and differing recommendations make the rationale for prolonged opioid use in CNCP unclear. This systematic review and meta-analyses (MAs) compared the efficacy, safety and tolerability of strong opioids with placebo/non-opioid therapy in CNCP, with a special focus on chronic low back pain (CLBP). Systematic literature searches were performed in four electronic databases (Medline, Web of Science, Cochrane Library and CINAHL) in July 2019 and updated by regular alerts until December 2020. We included 16 placebo-controlled RCTs for CLBP and five studies (2 RCTs and 3 non-randomized studies) of opioids vs non-opioids for CNCP in the quantitative and qualitative synthesis. Random effects pairwise MAs were performed for efficacy, safety and tolerability outcomes and subgroup analyses for treatment duration, study design, and opioid experience status. Very low- to low-certainty findings suggest that 4-15 weeks (short-/intermediate term) opioid therapy in CLBP (compared to placebo) may cause clinically relevant reductions in pain but also more gastrointestinal and nervous system adverse events (AEs), with likely no effect on disability. In contrast, long-term opioid therapy (≥ 6 months) in CNCP may not be superior to non-opioids in improving pain or disability/pain-related function, but seems to be associated with more AEs, opioid abuse/dependence, and possibly an increase in all-cause mortality. Our findings also underline the importance and need for well-designed trials assessing long-term efficacy and safety of opioids for CNCP and CLBP.

PMID:34326292 | DOI:10.1097/j.pain.0000000000002423

Qual Manag Health Care. 2021 Jul 28. doi: 10.1097/QMH.0000000000000314. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Patient experience in outpatient hemodialysis has been shown to be significantly correlated with health outcomes. The current gold standard for assessing patient experience in outpatient hemodialysis is the In-Center Hemodialysis Consumer Assessment of Healthcare Providers and Systems (ICH-CAHPS). Online reviews of outpatient hemodialysis centers could potentially serve as an additional source of information regarding patient experience, but they have not been well validated. This study aims to determine whether overall scores and subscores from patient-authored online reviews of outpatient dialysis centers are correlated with current gold standard survey-based measures of patient experience in outpatient hemodialysis.

METHODS: All reviews of hemodialysis centers posted to the online review site CiteHealth.com between March 2008 and October 2019 were collected (1081 reviews of 762 centers). Publicly-available ICH-CAHPS survey summary data and End Stage Renal Disease Quality Incentive Program (ESRD QIP) summary data from May 2016 to October 2019 were obtained from the Dialysis Facility Compare website. Spearman correlation coefficients were calculated between facilities’ mean online review overall scores and subscores within a given year and their ICH-CAHPS ratings from the same year. Statistical significance was assessed with a 2-tailed permutation test. A Bonferroni correction for multiple hypothesis testing was applied.

RESULTS: The mean “Overall” score from CiteHealth.com had a significant positive correlation with the “Center Care Quality,” “Staff,” and “Facility” scores from ICH-CAHPS surveys. No significant correlation could be found between the mean “Overall” CiteHealth.com score and any other ICH-CAHPS patient satisfaction metric. There was a significant positive correlation between the mean CiteHealth.com “Center” score and the ICH-CAHPS “Center Care Quality” score, the mean CiteHealth.com “Facility” score and the ICH-CAHPS “Facility” score, and the mean CiteHealth.com “Staff” score and the ICH-CAHPS “Staff” score. No significant correlation was found between the mean CiteHealth.com “Nephrologist” score and the ICH-CAHPS “Nephrologist” score. No significant correlation was found between online review scores and ESRD QIP health outcome measures.

CONCLUSION: Certain components of online reviews are significantly correlated with ICH-CAHPS measures of patient experience. Additionally, online reviews come with narrative comments that can offer specific insights into positive and negative aspects of patient care that cannot always be elucidated by numeric survey questions. Online reviews may have utility as an adjunctive source of information to patient experience surveys such as the ICH-CAHPS.

PMID:34326289 | DOI:10.1097/QMH.0000000000000314

Adv Anat Pathol. 2021 Jul 29. doi: 10.1097/PAP.0000000000000314. Online ahead of print.

ABSTRACT

Among all sarcoma types, liposarcoma is the most common sarcoma that develops “dedifferentiation.” Since its initial description by Dr Harry Evans, the spectrum of what is now acceptably included under the rubric of “dedifferentiated liposarcoma” (DL) has expanded, sometimes supported by cytogenetic and molecular advances. Similarly, the range of morphologic appearances considered to represent the precursor of DL, atypical lipomatous tumor (ALT)/well-differentiated liposarcoma, also has broadened, not uncommonly creating variants with significant, almost indistinguishable, morphologic overlap with occasional forms of DL, especially problematic in small biopsy specimens. More specifically, the precise criteria separating cellular forms of ALT from what some consider “low-grade” variants of DL remains controversial and inconsistently applied, even among individual pathologists within institutions. For this separation, the only objective and reproducible criteria historically shown to accurately predict a statistically significant difference in prognosis and survival is mitotic rate, alone or incorporated into a histologic grade [eg, Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)], consistently identifying a higher grade neoplasm capable of metastases. While DL may have a better prognosis than other nonmyoid adult pleomorphic soft tissue sarcomas, definitive conclusions are difficult to establish due to nonuniform criteria for staging and establishing tumor size/volume of the high-grade component, compounded by variable definitions and thresholds for rendering the diagnosis of DL. If appropriate therapeutic approaches are to be applied to DL, there needs to uniform agreement regarding the histologic definition, grading, and staging of DL. Herein, is a comprehensive historical perspective on DL and ALT/well-differentiated liposarcoma, seeking to provide insights, updates, and a proposal for uniform, evidence-based guidelines.

PMID:34326285 | DOI:10.1097/PAP.0000000000000314

Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2022518118. doi: 10.1073/pnas.2022518118.

ABSTRACT

The observational absence of giant convection cells near the Sun’s outer surface is a long-standing conundrum for solar modelers. We herein propose an explanation. Rotation strongly influences the internal dynamics, leading to suppressed convective velocities, enhanced thermal-transport efficiency, and (most significantly) relatively smaller dominant length scales. We specifically predict a characteristic convection length scale of roughly 30-Mm throughout much of the convection zone, implying weak flow amplitudes at 100- to 200-Mm giant cells scales, representative of the total envelope depth. Our reasoning is such that Coriolis forces primarily balance pressure gradients (geostrophy). Background vortex stretching balances baroclinic torques. Both together balance nonlinear advection. Turbulent fluxes convey the excess part of the solar luminosity that radiative diffusion cannot. We show that these four relations determine estimates for the dominant length scales and dynamical amplitudes strictly in terms of known physical quantities. We predict that the dynamical Rossby number for convection is less than unity below the near-surface shear layer, indicating rotational constraint.

PMID:34326248 | DOI:10.1073/pnas.2022518118

Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2020402118. doi: 10.1073/pnas.2020402118.

ABSTRACT

To mimic the mechanical response of passive biological cilia in complex fluids, we study the bending dynamics of an anchored elastic fiber submitted to a dilute granular suspension under shear. We show that the bending fluctuations of the fiber accurately encode minute variations of the granular suspension concentration. Indeed, besides the stationary bending induced by the continuous phase flow, the passage of each single particle induces an additional deflection. We demonstrate that the dominant particle/fiber interaction arises from contacts of the particles with the fiber, and we propose a simple elastohydrodynamics model to predict their amplitude. Our results provide a mechanistic and statistical framework to describe particle detection by biological ciliated systems.

PMID:34326246 | DOI:10.1073/pnas.2020402118

RMD Open. 2021 Jul;7(2):e001710. doi: 10.1136/rmdopen-2021-001710.

ABSTRACT

OBJECTIVE: Non-pharmacological interventions support patients with connective tissue diseases to better cope with and self-manage their diseases. This study aimed to map existing evidence on non-pharmacological interventions in patients with systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and mixed connective tissue diseases regarding content, feasibility and potential suitability in an e-health setting.

METHODS: A literature search was performed in eight different databases in July 2020. The intervention’s content was extracted using the ‘Better reporting of interventions: template for intervention description and replication (TIDieR) checklist and guide’. A Sankey diagram and descriptive statistics were used to analyse the data and illustrate the relationships between the interventions.

RESULTS: Of 8198 identified records, 119 papers were eligible. One hundred and four of them (87.4%) were conducted between 2000 and 2020, mainly in the USA (SLE n=24 (21.2%), SSc n=16 (14.2%)), Brazil (SLE n=8 (7.1%), SSc n=5 (4.4%)) and Italy (SLE n=0 (0%), SSc n=12 (10.6%)). Fifty-two studies (SLE n=24 (21.2%), SSc n=28 (24.8%)) used multicomponent interventions. The single interventions were physical exercises (SLE n=16 (14.2%), SSc n=17 (15.0%)), coaching/counselling (SLE n=11 (18.0%), SSc n=0 (0%)) and education (SLE n=2 (1.8%), SSc n=3 (2.7%)). Primary outcomes focused on physical function (SLE n=1 (0.9%), SSc n=15 (13.3%)), mouth opening in SSc (n=4 (5.9%)) and physical capacity (SLE n=2 (1.8%), SSc n=1 (0.9%)). No interventions for mixed connective tissue disease were found.

CONCLUSION: There was a great variety in the intervention’s content due to differences in body structure, activity limitations and participation restrictions in SLE and SSc. These results highlight the need for personalised, multicomponent, non-pharmacological interventions, which could be delivered as e-health interventions.

PMID:34326205 | DOI:10.1136/rmdopen-2021-001710

Eur Respir J. 2021 Jul 29:2003969. doi: 10.1183/13993003.03969-2020. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).

OBJECTIVE: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.

METHODS: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (pediatric cases/controls: 134/35; adult cases/controls: 149/31). Exacerbation of allergic airway disease in mice was induced by sensitising to OVA, challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor, Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (CF, n=14) and CF with allergic broncho-pulmonary aspergillosis (ABPA, n=9) as well as severe allergic, uncontrolled asthmatics (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed by the Asthma Control Test.

RESULTS: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in CF plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic odds ratio 31.5).

CONCLUSION: C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.

PMID:34326188 | DOI:10.1183/13993003.03969-2020

J Immunother Cancer. 2021 Jul;9(7):e002851. doi: 10.1136/jitc-2021-002851.

ABSTRACT

BACKGROUND: The modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.

METHODS: We retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis.

RESULTS: 156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533).

CONCLUSION: The mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.

PMID:34326170 | DOI:10.1136/jitc-2021-002851