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Nevin Manimala Statistics

Identifying host-specific amino acid signatures for influenza A viruses using an adjusted entropy measure

BMC Bioinformatics. 2022 Aug 12;23(1):333. doi: 10.1186/s12859-022-04885-7.

ABSTRACT

BACKGROUND: Influenza A viruses (IAV) exhibit vast genetic mutability and have great zoonotic potential to infect avian and mammalian hosts and are known to be responsible for a number of pandemics. A key computational issue in influenza prevention and control is the identification of molecular signatures with cross-species transmission potential. We propose an adjusted entropy-based host-specific signature identification method that uses a similarity coefficient to incorporate the amino acid substitution information and improve the identification performance. Mutations in the polymerase genes (e.g., PB2) are known to play a major role in avian influenza virus adaptation to mammalian hosts. We thus focus on the analysis of PB2 protein sequences and identify host specific PB2 amino acid signatures.

RESULTS: Validation with a set of H5N1 PB2 sequences from 1996 to 2006 results in adjusted entropy having a 40% false negative discovery rate compared to a 60% false negative rate using unadjusted entropy. Simulations across different levels of sequence divergence show a false negative rate of no higher than 10% while unadjusted entropy ranged from 9 to 100%. In addition, under all levels of divergence adjusted entropy never had a false positive rate higher than 9%. Adjusted entropy also identifies important mutations in H1N1pdm PB2 previously identified in the literature that explain changes in divergence between 2008 and 2009 which unadjusted entropy could not identify.

CONCLUSIONS: Based on these results, adjusted entropy provides a reliable and widely applicable host signature identification approach useful for IAV monitoring and vaccine development.

PMID:35962315 | DOI:10.1186/s12859-022-04885-7

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Differential Gene Expression in Sporadic and Genetic Forms of Alzheimer’s Disease and Frontotemporal Dementia in Brain Tissue and Lymphoblastoid Cell Lines

Mol Neurobiol. 2022 Aug 12. doi: 10.1007/s12035-022-02969-2. Online ahead of print.

ABSTRACT

Sporadic early-onset Alzheimer’s disease (EOAD) and autosomal dominant Alzheimer’s disease (ADAD) provide the opportunity to investigate the physiopathological mechanisms in the absence of aging, present in late-onset forms. Frontotemporal dementia (FTD) causes early-onset dementia associated to tau or TDP43 protein deposits. A 15% of FTD cases are caused by mutations in C9orf72, GRN, or MAPT genes. Lymphoblastoid cell lines (LCLs) have been proposed as an alternative to brain tissue for studying earlier phases of neurodegenerative diseases. The aim of this study is to investigate the expression profile in EOAD, ADAD, and sporadic and genetic FTD (sFTD and gFTD, respectively), using brain tissue and LCLs. Sixty subjects of the following groups were included: EOAD, ADAD, sFTD, gFTD, and controls. Gene expression was analyzed with Clariom D microarray (Affymetrix). Brain tissue pairwise comparisons revealed six common differentially expressed genes (DEG) for all the patients’ groups compared with controls: RGS20, WIF1, HSPB1, EMP3, S100A11 and GFAP. Common up-regulated biological pathways were identified both in brain and LCLs (including inflammation and glial cell differentiation), while down-regulated pathways were detected mainly in brain tissue (including synaptic signaling, metabolism and mitochondrial dysfunction). CD163, ADAMTS9 and LIN7A gene expression disruption was validated by qPCR in brain tissue and NrCAM in LCLs in their respective group comparisons. In conclusion, our study highlights neuroinflammation, metabolism and synaptic signaling disturbances as common altered pathways in different AD and FTD forms. The use of LCLs might be appropriate for studying early immune system and inflammation, and some neural features in neurodegenerative dementias.

PMID:35962298 | DOI:10.1007/s12035-022-02969-2

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Economic Burden and Health-Related Quality of Life of Respiratory Syncytial Virus and Influenza Infection in European Community-Dwelling Older Adults

J Infect Dis. 2022 Aug 12;226(Supplement_1):S87-S94. doi: 10.1093/infdis/jiac069.

ABSTRACT

BACKGROUND: Respiratory syncytial virus (RSV) and influenza virus infections result in a considerable mortality and morbidity among the aging population globally. Influenza vaccination for older adults before the seasonal influenza epidemic has been evaluated to be cost-effective in many countries. Interventions against RSV in older adults are in the pipeline, and evaluating their cost-effectiveness is crucial for decision making. To inform such evaluations, our aim was to estimate average costs and health-related quality of life (HRQoL) in older adults with RSV and influenza infection.

METHODS: The European RESCEU observational cohort study followed 1040 relatively healthy community-dwelling older adults aged 60 years and older during 2 consecutive winter seasons. Health care resource use and HRQoL were collected and analyzed during RSV episodes, and also during influenza episodes. Country-specific unit cost data were mainly obtained from national databases. Direct costs were estimated from a patient, health care provider, and health care payers’ perspective, whereas indirect costs were estimated from a societal perspective. Due to small sample size, no formal statistical comparisons were made.

RESULTS: Thirty-six RSV and 60 influenza episodes were reported, including 1 hospitalization. Means (median; first-third quartile) of €26.4 (€5.5; 0-47.3) direct and €4.4 (€0; 0-0) indirect costs were reported per nonhospitalized RSV episode, and €42.5 (€36; 3.3-66.7) direct and €32.1 (€0; 0-0) indirect costs per nonhospitalized influenza episode. For RSV episodes, the utility value decreased from 0.896 (0.928; 0.854-0.953) to 0.801 (0.854; 0.712-0.937) from preseason to 1 week after symptom onset; for influenza, the change was from 0.872 (0.895; 0.828-0.953) to 0.664 (0.686; 0.574-0.797).

CONCLUSIONS: The average costs and HRQoL estimates of older adults treated outside the hospital can be used to inform the design of future studies and the decision making regarding interventions to prevent RSV infection in older adults. Larger studies are needed to provide better country-specific and complementary cost estimates and to allow for formal statistical comparison of costs between RSV and influenza.

CLINICAL TRIALS REGISTRATION: NCT03621930.

PMID:35961055 | DOI:10.1093/infdis/jiac069

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Characteristics and Treatment of Patients Diagnosed With Paradoxical Adipose Hyperplasia After Cryolipolysis: A Case Series and Scoping Review

Aesthet Surg J. 2022 Aug 12:sjac219. doi: 10.1093/asj/sjac219. Online ahead of print.

ABSTRACT

BACKGROUND: Paradoxical adipose hyperplasia (PAH), a rare side effect of CoolSculpting (cryolipolysis), is characterized by fatty enlargement of the treatment area occurring months after the procedure.

OBJECTIVES: The purpose of this study is to report a retrospective case series of patients diagnosed with PAH at our institution, increase the collective understanding of this complication and subsequent management, and raise the question of who should ethically perform cryolipolysis.

METHODS: All participants diagnosed with PAH by a plastic surgeon at a large academic medical center were identified. Demographic information, medical history, procedure details, time to PAH diagnosis, and corrective surgical intervention details were collected. Mean duration of time from cryolipolysis treatment to diagnosis of PAH was calculated, along with other descriptive statistics. A scoping review of all PAH literature published in PubMed, Embase, and Web of Science was also conducted.

RESULTS: Four patients diagnosed with PAH after cryolipolysis were identified for inclusion in this study. The calculated incidence of PAH at our center was 0.67%. All patients requested therapy for PAH and subsequently underwent either liposuction, abdominoplasty, or both. The mean duration of in-person follow-up time after final surgical treatment of PAH was 13.8 ± 19.8 months (range: 2.8-43.5). Fortunately, no patients showed signs of PAH recurrence, and three out of four patients did not show signs of residual deformity.

CONCLUSIONS: Findings from this patient cohort and scoping review provide evidence that although revisions may be required, conventional body contouring methods, not in the armamentarium of non-plastic surgeon practitioners, effectively alleviated PAH.

PMID:35961054 | DOI:10.1093/asj/sjac219

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Nevin Manimala Statistics

The reproductive numbers of SARS-CoV-2 vary depending on the compartmental model used during epidemiological modeling

J Travel Med. 2022 Aug 12:taac096. doi: 10.1093/jtm/taac096. Online ahead of print.

NO ABSTRACT

PMID:35961008 | DOI:10.1093/jtm/taac096

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Total Knee Arthroplasty After Genicular Nerve Radiofrequency Ablation: Reduction in Prolonged Opioid Use Without Increased Postsurgical Complications

J Am Acad Orthop Surg Glob Res Rev. 2022 Aug 12;6(8). doi: 10.5435/JAAOSGlobal-D-22-00125. eCollection 2022 Aug 1.

ABSTRACT

INTRODUCTION: Genicular nerve radiofrequency ablation (GNRFA) is an increasingly used nonsurgical treatment modality for patients with advanced knee osteoarthritis. Previous studies have demonstrated this to be an effective and safe method to decrease pain and increase functionality in this patient population. The purpose of this study was to compare 2-year postoperative complication rates and rates of prolonged postoperative opioid usage between patients undergoing total knee arthroplasty (TKA) after previous GNRFA and those undergoing TKA alone.

METHODS: Patients who underwent primary TKA after prior GNRFA (GNRFA-TKA) of the ipsilateral knee were identified in a national all-payer claims database from 2010 to 2019. Univariate and multivariable analyses were conducted comparing those with prior GNRFA and those without. Outcomes of interest included prolonged postoperative opioid usage, 2-year revision rates, and 90-day medical complications. Statistical analysis was conducted using R software provided by the PearlDiver Database.

RESULTS: In total, 675 patients in the GNRFA-TKA cohort were compared with a control cohort of 255,351 patients. Genicular nerve radiofrequency ablation-total knee arthroplasty patientshad lower odds of prolonged opioid use postoperatively (OR: 0.478; 95%: 0.409 to 0.559; P < 0.001). No notable difference was observed in the 2-year surgical outcomes between cohorts. Patients in the GNRFA-TKA cohort had lower odds of requiring a blood transfusion and having postoperative anemia, all arrhythmias, and urinary infections compared with primary TKA control patients.

CONCLUSION: Preoperative GNRFA leads to a lower rate of prolonged postoperative opioid use in patients undergoing TKA, without an increased risk of complications. Future prospective studies are needed to validate the findings of this database study.

PMID:35960987 | DOI:10.5435/JAAOSGlobal-D-22-00125

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Prioritizing Mental Health in Residency

Cutis. 2022 Jun;109(6):E36-E38. doi: 10.12788/cutis.0551.

ABSTRACT

Residency is both physically and mentally taxing. Although some tout these struggles as a rite of passage to practice medicine, rates of physician burnout and suicide unfortunately remain higher than the general population. Limitations on work hours, mandatory reporting of work hour violations, and resident wellness programs have aimed to improve these statistics, but the time constraints and physical demands of residency offer little room for trainees to focus on their mental health. In 2020, the COVID-19 pandemic tested an already strained health care system, bringing to light the prevalence of depression and anxiety among residents. This article explores this prevalence and highlights several modalities available to residents who are seeking to prioritize their mental health.

PMID:35960972 | DOI:10.12788/cutis.0551

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Safety and immunogenicity of the first Kazakh inactivated vaccine for COVID-19

Hum Vaccin Immunother. 2022 Aug 12:2087412. doi: 10.1080/21645515.2022.2087412. Online ahead of print.

ABSTRACT

This article describes the results of a preclinical safety and immunogenicity study of QazCovid-in®, the first COVID-19 vaccine developed in Kazakhstan, on BALB/c mice, rats, ferrets, Syrian hamsters and rhesus macaques (Macaca mulatta). The study’s safety data suggests that this immunobiological preparation can be technically considered a Class 5 nontoxic vaccine. The series of injections that were made did not produce any adverse effect or any change in the general condition of the model animals’ health, while macroscopy and histology studies identified no changes in the internal organs of the BALB/c mice and rats. This study has demonstrated that a double immunization enhances the growth of antibody titers as assessed by the microneutralization assay (MNA) and the enzyme-linked immunosorbent assay (ELISA) in a pre-clinical immunogenicity test on animal models. The best GMT results were assessed in MNA and ELISA 7 days after re-vaccination; however, we noted that GMT antibody results in ELISA were lower than in MNA. A comparative GMT assessment after the first immunization and the re-immunization identified significant differences between model animal groups and a growth of GMT antibodies in all of them; also, differences between the gender groups were statistically significant. Moreover, the most marked MNA immune response to the QazCovid-in® vaccine was seen in the Syrian hamsters, while their SARS-CoV-2-specific antibody activity as assessed with ELISA was the lowest.

PMID:35960911 | DOI:10.1080/21645515.2022.2087412

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Elotuzumab Plus Pomalidomide and Dexamethasone for Relapsed/Refractory Multiple Myeloma: Final Overall Survival Analysis From the Randomized Phase II ELOQUENT-3 Trial

J Clin Oncol. 2022 Aug 12:JCO2102815. doi: 10.1200/JCO.21.02815. Online ahead of print.

ABSTRACT

PURPOSE: In the phase II ELOQUENT-3 trial (ClinicalTrials.gov identifier: NCT02654132), elotuzumab combined with pomalidomide/dexamethasone (EPd) significantly improved progression-free survival (PFS) versus pomalidomide/dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM) previously treated with lenalidomide and a proteasome inhibitor (PI). Here, we present the final overall survival (OS) results.

METHODS: Patients with RRMM who had received ≥ 2 prior lines of therapy, with disease refractory to last therapy and either refractory or relapsed and refractory to lenalidomide and a PI were randomly assigned (1:1) to receive EPd or Pd. The primary end point was PFS per investigator assessment. ORR and OS were secondary end points planned to be tested hierarchically.

RESULTS: A total of 117 patients were randomly assigned to EPd (n = 60) and Pd (n = 57). Among treated patients (EPd 60, Pd 55), there were 37 (61.7%) deaths in the EPd group and 41 (74.5%) in the Pd group, most commonly because of disease progression (EPd 41.7%, Pd 49.1%). Median (95% CI) OS was significantly improved with EPd (29.8 [22.9 to 45.7] months) versus Pd (17.4 [13.8 to 27.7] months), with a hazard ratio of 0.59 (95% CI, 0.37 to 0.93; P = .0217). OS benefit with EPd was observed in most patient subgroups. The safety profile of EPd was consistent with prior reports with no new safety signals detected.

CONCLUSION: EPd demonstrated a statistically significant improvement in OS versus Pd in patients with RRMM previously treated with lenalidomide and a PI who had disease refractory to last therapy. In this setting, ELOQUENT-3 is the first randomized study of a triplet regimen incorporating a monoclonal antibody and Pd to improve both PFS and OS significantly.

PMID:35960908 | DOI:10.1200/JCO.21.02815

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A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma

J Clin Oncol. 2022 Aug 12:JCO2200405. doi: 10.1200/JCO.22.00405. Online ahead of print.

ABSTRACT

PURPOSE: A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker-positive mUC.

METHODS: DRD biomarker-positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model.

RESULTS: Out of 248 patients, 74 (29.8%) were DRD biomarker-positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib.

CONCLUSION: Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

PMID:35960902 | DOI:10.1200/JCO.22.00405