Are omicron infections more frequently associated with bacterial co-infections?

Introduction: Clinical observations suggest that Omicron infections may present with different radiographic findings and be more frequently associated with bacterial co-infections, but there is a paucity of published data. This study aimed to compare the clinical and radiographic findings of patients hospitalized with Omicron versus alpha-delta infections. Materials and Methods: Between January 1, 2021 and June 30, 2021 (alpha and delta period) and between January 1, 2022 and July 31, 2022 (Omicron period), respectively 149 and 163 COVID-19 PCR-positive patients who were followed up in the COVID-19 ward and intensive care unit of a tertiary care center were included in the study. Clinical (presence of fever and purulent sputum), laboratory and radiologic findings of the two groups were compared. Sputum culture results and antibiotic use were also evaluated. Result: In the alpha/delta group, ground glass opacities were seen in 75.2% (112) of the patients, consolidation in 2.7% (4), and both findings together in 6.0% (9). In the Omicron group, ground glass was seen in 40.5% (66), consolidation in 5.5% (9), and both ground glass and consolidation together in 8.7% (13) (p< 0.001). Procalcitonin levels were 0.25 µg/L or higher in 29.6% and 43.9% of the patients in the alpha/delta and Omicron groups, respectively. Mean PCT values were 0.36 µg/L and 1.93 µg/L, respectively (p> 0.05). CRP levels were similar in both groups. Mean LDH level in the Omicron group was 278 U/L and was significantly lower than the alpha/delta group (381 U/L) (p< 0.001). The proportion of patients requiring intensive care during hospitalization was higher in the alpha/delta group (36.2% vs 26.4%) (p= 0.06). Conclusions: Lower LDH levels, less need for intensive care and less frequent development of ARDS indicate that Omicron causes milder disease, while a higher rate of consolidation and higher procalcitonin levels suggest a higher frequency of bacterial co-infections.

Sudarshan Kriya Yoga Breathing and a Meditation Program for Burnout Among Physicians: A Randomized Clinical Trial.

Importance: Physicians are exposed to high stress and strain that results in burnout, which affects them, their families, their patients, and the entire health care system; thus, there is an urgent need to develop methods to increase the resiliency of physicians. Sudarshan Kriya Yoga (SKY) is a comprehensive yoga breathing and meditation-based program that is a potential approach to mitigate physician burnout. Objective: To determine whether SKY can reduce psychological distress and improve wellness in physicians. Design, Setting, and Participants: This randomized clinical trial assessed the potential efficacy of SKY compared with a stress management education (SME) training as control. This study was conducted online from November 11, 2021, to March 14, 2022, and included physicians from Turkey, Germany, and Dubai. Both the SKY and the SME control groups received 1.5 hours of training for 3 consecutive days via a group video conference call. Participants were physicians willing to do some form of relaxation exercise everyday for 2 months. Exclusion criteria included presence of major illness and maintaining a regular mind-body program practice. Statistical analysis took place from March to November 2023. Interventions: Participants were randomly assigned 1:1 into 2 groups-the SKY group or the SME (control) group-using a computer algorithm. After the 3-day instruction period, the participants in the SKY group practiced for approximately 30 minutes per day on their own and participated in a weekly 1-hour, group-based online follow-up practice. After the 3-day instruction period, participants in the SME group reviewed and applied the notes from stress management education training at their initiative and had a weekly 1-hour group-based online follow-up session. Main Outcomes and Measures: The primary outcomes were stress and depression (measured by the 42-item Depression, Anxiety, and Stress Scale [DASS-42]) and insomnia measured by the Regensburg Insomnia Scale (RIS) with primary end point at 8 weeks. Secondary outcomes included anxiety (DASS-42); optimism (Life Orientation Test-Revised [LOT-R]); professional fulfillment, work exhaustion, interpersonal disengagement, and overall burnout (Professional Fulfillment Index [PFI]); and self-reported professional errors (Self-Reported Professional Error Questionnaire). Results: This study included 129 participants (SME, 63 participants [48.9%]; SKY, 66 participants [51.1%]; 115 females [89.2%]; 14 males [10.8%]; mean [SD] age, 46.2 [9.0] years). Compared with the SME control group, participants in the SKY group had significantly decreased stress on the DASS-42 at posttraining (difference, -6.8 points; 95% CI, -9.6 to -4.1 points; P = .006) and at postintervention (difference, -6.0 points; 95% CI, -8.8 to -3.3 points; P = .03), significantly decreased depression at posttraining (difference, -5.7 points; 95% CI, -8.6 to -2.8 points; P < .001) and postintervention (difference, -5.4 points; 95% CI, -8.3 to -2.5 points; P < .001), and significantly decreased anxiety at postintervention. In addition, there was a significant decrease in insomnia from baseline to postintervention in the SKY group (difference, -0.3 points; 95% CI, -2.3 to 1.7 points; P = .01). The SKY group also showed significantly increased professional fulfillment as well as significant decreases in work exhaustion, interpersonal disengagement, and burnout. There was no effect on self-reported medical errors. Conclusions and Relevance: In this randomized clinical trial, physicians who regularly practiced SKY throughout a 2-month period experienced improvements in wellness and decreased burnout. These data suggest that SKY may be an effective, practical, and safe strategy to increase wellness and mitigate burnout in physicians. Trial Registration: ClinicalTrials.gov Identifier: NCT05956470.

An in silico approach to the identification of diagnostic and prognostic markers in low-grade gliomas.

Low-grade gliomas (LGG) are central nervous system Grade I tumors, and as they progress they are becoming one of the deadliest brain tumors. There is still great need for timely and accurate diagnosis and prognosis of LGG. Herein, we aimed to identify diagnostic and prognostic biomarkers associated with LGG, by employing diverse computational approaches. For this purpose, differential gene expression analysis on high-throughput transcriptomics data of LGG versus corresponding healthy brain tissue, derived from TCGA and GTEx, respectively, was performed. Weighted gene co-expression network analysis of the detected differentially expressed genes was carried out in order to identify modules of co-expressed genes significantly correlated with LGG clinical traits. The genes comprising these modules were further used to construct gene co-expression and protein-protein interaction networks. Based on the network analyses, we derived a consensus of eighteen hub genes, namely, CD74, CD86, CDC25A, CYBB, HLA-DMA, ITGB2, KIF11, KIFC1, LAPTM5, LMNB1, MKI67, NCKAP1L, NUSAP1, SLC7A7, TBXAS1, TOP2A, TYROBP, and WDFY4. All detected hub genes were up-regulated in LGG, and were also associated with unfavorable prognosis in LGG patients. The findings of this study could be applicable in the clinical setting for diagnosing and monitoring LGG.

Outcomes of high-risk breast lesions diagnosed using image-guided core needle biopsy: results from a multicenter retrospective study.

PURPOSE: The clinical management of high-risk lesions using image-guided biopsy is challenging. This study aimed to evaluate the rates at which such lesions were upgraded to malignancy and identify possible predictive factors for upgrading high-risk lesions. METHODS: This retrospective multicenter analysis included 1.343 patients diagnosed with high-risk lesions using an image-guided core needle or vacuum-assisted biopsy (VAB). Only patients managed using an excisional biopsy or with at least one year of documented radiological follow-up were included. For each, the Breast Imaging Reporting and Data System (BI-RADS) category, number of samples, needle thickness, and lesion size were correlated with malignancy upgrade rates in different histologic subtypes. Pearson's chi-squared test, the Fisher-Freeman-Halton test, and Fisher's exact test were used for the statistical analyses. RESULTS: The overall upgrade rate was 20.6%, with the highest rates in the subtypes of intraductal papilloma (IP) with atypia (44.7%; 55/123), followed by atypical ductal hyperplasia (ADH) (38.4%; 144/375), lobular neoplasia (LN) (12.7%; 7/55), papilloma without atypia (9.4%; 58/611), flat epithelial atypia (FEA) (8.7%; 10/114), and radial scars (RSs) (4.6%; 3/65). There was a significant relationship between the upgrade rate and BI-RADS category, number of samples, and lesion size Lesion size was the most predictive factor for an upgrade in all subtypes. CONCLUSION: ADH and atypical IP showed considerable upgrade rates to malignancy, requiring surgical excision. The LN, IP without atypia, pure FEA, and RS subtypes showed lower malignancy rates when the BI-RADS category was lower and in smaller lesions that had been adequately sampled using VAB. After being discussed in a multidisciplinary meeting, these cases could be managed with follow-up instead of excision.

The expression of HDAC9 and P300 in papillary thyroid carcinoma cell line.

PURPOSE: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer and accounts for 85-90% of all thyroid cancers. Metastatic differentiated thyroid cancer, radioiodine-refractory thyroid cancer, and anaplastic thyroid cancer still lack effective therapeutic options. Here, we aimed to assess HDAC9 and P300 expression in the papillary thyroid carcinoma cell line and compare them with normal thyroid cells. METHODS: Nthy-ori-3-1, a normal thyroid cell line, and BCPAP, a PTC cell line, were cultured for 24 and 48 h and immunofluorescence staining was used to determine the levels of HDAC9 and P300 protein expression. HDAC9 paracrine release was assessed using an ELISA assay. RESULTS: HDAC9 protein expression was higher in both cell groups at the 48th hour than at the 24th hour; however, P300 protein expression was lower in BCPAP cells at the 48th hour than at the 24th hour. In comparison to Nthy-ori-3-1, BCPAP expressed more HDAC9 and P300 proteins. HDAC9 secretion slightly increased in Nthy-ori-3-1 cells from 24 to 48 h. Furthermore, HDAC9 secretion in BCPAP cells dramatically decreased from 24 to 48 h. CONCLUSION: Our findings revealed that the expression of HDAC9 and P300 was higher in the PTC cell line than in normal thyroid cells. This indicates that the acetylation mechanism in thyroid cancer cells is not the same as it is in healthy cells. Epigenetic studies may reveal the mechanisms underlying PTC with further analysis.

A prospective cohort study: can advanced ultrasonography replace magnetic resonance imaging in the diagnosis of placental adhesion disorders?

OBJECTIVES: To define and compare the diagnostic accuracy of ultrasonography (USG) and magnetic resonance imaging (MRI) for the placental adhesive disorder (PAD). METHODS: A prospective study was conducted between January 2019 and February 2020 in a tertiary referral university hospital. A total of 115 placenta previa cases were included in the study during the third trimester of gestation. USG examination was performed, and the placenta was scanned in a systematic manner using gray-scale ultrasound, color Doppler flow mapping, and 3-D imaging for each participant. Thereafter, all participants underwent an MRI examination. USG and MRI findings were compared with histopathological findings. RESULTS: Loss of the retroplacental sonolucent zone (71% [95% CI 47-88]) and an irregular retroplacental sonolucent zone (71% [95% CI 47-88]) were the most sensitive USG parameters. For MRI, the uterine bulging parameter was the most sensitive (60% [95% CI 36-80]) and specific (91% [95% CI 83-96]) findings, and it had the highest accuracy rate (85% [95% CI 77-91]). Overall, the USG sensitivity, specificity, and accuracy rates were 77% (95% CI 54-92), 87% (95% CI 79-93), and 85% (95% CI 77-91), respectively. The MRI sensitivity, specificity, and accuracy rates for all participants were 81% (95% CI 59-94), 85% (95% CI 76-92), and 84% (95% CI 76-90), respectively. CONCLUSIONS: In the diagnosis of PAD, the specificity and accuracy of USG are higher than that of MRI, whereas the sensitivity of MRI is better than that of USG.

Evaluation of IL-10, MCP-1, IFN gamma, and protectin D1 levels in patients with Hashimoto's thyroiditis.

PURPOSE: Hashimoto's thyroiditis (HT) is one of the most prevalent autoimmune endocrine diseases and caused by the loss of immune tolerance for the thyroid gland. Many pathophysiological mechanisms were speculated about the development of HT. In our study, we aimed to reveal the relationship between HT and IL-10, MCP-1, IFNɤ, and PD1 levels and compare them with control subjects. METHODS: We collected 37 patients with HT and 25 controls referred to our outpatient clinic. The diagnosis of HT was based on the detection of circulating antibodies to thyroid antigens and decreasing echogenicity on thyroid USG in patients with appropriate clinical characteristics. Serum IL-10, MCP-1, IFNɤ, and PD1 levels were detected using an ELISA KIT (96 T) method according to the manufacturer's instructions. RESULTS: All subjects were euthyroid (median TSH level was 1.68 mU/L in HT vs 1.83 mU/L in the controls, p = 0.672). Twenty-three of 37 patients with HT were taking L-thyroxin replacement. Levels of serum IL-10, IFNɤ, and PD1 in patients with HT were higher than the controls, but the differences were not statistically significant (p = 0.393, p = 0.495, and p = 0.052 respectively). The serum levels of MCP-1 in HT patients were statistically different and higher than the controls (p = 0.018). Correlation analysis displayed significant associations between IL-10, MCP-1, IFNɤ, and PD1 levels. CONCLUSION: Our study demonstrated that serum MCP-1 levels in HT patients were significantly increased; on the other hand, significant difference was not found between HT patients and the controls in terms of serum IL-10, IFNɤ, and PD1 levels.

High chitotriosidase and AGE levels in acromegaly: a case-control study.

PURPOSE: Acromegaly is associated with oxidative stress and inflammation parameters. Chitotriosidase (CHITO) is a marker of macrophage activation and plays a pivotal role in the activation of inflammatory and immunological responses. Our study aimed to determine CHITO,YKL-40, advanced glycation end product (AGE), and high-sensitivity C-reactive protein (hsCRP) levels to investigate malondialdehyde (MDA), catalase, superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities and to evaluate any association of these parameters with carotid intima media thickness (cIMT) in patients with controlled acromegaly. METHODS: Thirty controlled acromegaly patients and 41 age- and sex-matched control cases were studied. We obtained demographic data, hormonal and metabolic parameters, and cIMT. CHITO activity was measured with the fluorometric method of Chamoles et al. YKL-40 and hsCRP levels were measured using ELISA. AGEs were measured based on spectrofluorimetric detection. GSH-Px activity was determined by a colorimetric assay. MDA, SOD, and catalase activities were determined in hemolysis. RESULTS: Higher CHITO, AGE, and hsCRP concentrations were observed in patients with acromegaly compared to controls. SOD levels were non-significantly higher in the acromegaly group, while catalase activities were lower in patients with acromegaly. Correlation analyses of CHITO, AGEs, YKL-40, hsCRP, MDA, catalase, GSH-Px, and SOD with metabolic, anthropometric, and laboratory parameters did not demonstrate any significant correlation (p > 0.05). There was no significant difference between groups with regard to cIMT levels. CONCLUSION: This is the first study investigating CHITO and AGE levels in patients with acromegaly. Serum CHITO, AGE, and hsCRP levels in acromegalic patients were significantly increased. It may be important to evaluate CHITO, AGE, and hsCRP levels in acromegalic patients who are already under cardiometabolic surveillance due to risk of developing cardiovascular disease.

A 10-year retrospective analysis of intimate partner violence patients in the emergency department.

BACKGROUND: Intimate partner violence (IPV) is an important human rights problem faced by one in three women worldwide. The aim of this study is to evaluate the demographic, trauma, and radiological characteristics of patients admitted to a tertiary emer-gency department due to IPV. METHODS: Sociodemographic characteristics (age, gender, education level, and marital status), trauma characteristics (severity, type, and location), radiological imaging findings (radiography, computed tomography, and magnetic resonance imaging) of patients diagnosed with IPV were evaluated. RESULTS: In the study, 1225 patients were evaluated, and 98.7% of them were women (mean age 35 [IQR: 17] years). Of the pa-tients, 63.1% were high school and university graduates. The rate of married women was 74.6%. No relationship was found between gender, age, educational status, and marital status (p>0.05). Most of the traumas were minor (85.4%) and blunt (81.9%) trauma, and the most common types of trauma were kicking (49.9%) and punching (47.3%). It was found that the most frequently affected areas of the patients were the head and neck (76.7%), and the frequency of pelvic trauma was high in male patients (p<0.05). The most com-mon bone fracture was nasal (40.5%) followed by ulna fractures (14.5%). The left-sided diaphyseal fractures were the most common in patients exposed to IPV. In our study, the frequency of mortality was 12.9%, and it was found to be significantly higher in males (p<0.05). CONCLUSION: Female patients are more frequently exposed to IPV. Specific injury characteristics can be detected in patients diagnosed with IPV and old fractures detected in these patients should alert the clinician about IPV.

Effect of stimulation time on the expression of human macrophage polarization markers.

Macrophages are highly plastic cells that can polarize into functionally distinct subsets in vivo and in vitro in response to environmental signals. The development of protocols to model macrophage polarization in vitro greatly contributes to our understanding of macrophage biology. Macrophages are divided into two main groups: Pro-inflammatory M1 macrophages (classically activated) and anti-inflammatory M2 macrophages (alternatively activated), based on several key surface markers and the production of inflammatory mediators. However, the expression of these common macrophage polarization markers is greatly affected by the stimulation time used. Unfortunately, there is no consensus yet regarding the optimal stimulation times for particular macrophage polarization markers in in vitro experiments. This situation is problematic, (i) as analysing a particular marker at a suboptimal time point can lead to false-negative results, and (ii) as it clearly impedes the comparison of different studies. Using human monocyte-derived macrophages (MDMs) in vitro, we analysed how the expression of the main polarization markers for M1 (CD64, CD86, CXCL9, CXCL10, HLA-DR, IDO1, IL1ß, IL12, TNF), M2a (CD200R, CD206, CCL17, CCL22, IL-10, TGM2), and M2c (CD163, IL-10, TGFß) macrophages changes over time at mRNA and protein levels. Our data establish the most appropriate stimulation time for the analysis of the expression of human macrophage polarization markers in vitro. Providing such a reference guide will likely facilitate the investigation of macrophage polarization and its reproducibility.

The Relation of End-Tidal CO 2 Values With Infarct Volume and Early Prognosis in Patients With Acute Ischemic Stroke.

BACKGROUND: The aim of this study is to reveal the relationship between end-tidal CO 2 (EtCO 2 ) values with infarct volume and early prognosis in patients diagnosed with acute ischemic stroke in the emergency department. MATERIALS AND METHODS: This prospective cross-sectional study was conducted in a tertiary hospital. The demographics, characteristics, EtCO 2 , volume of the stroke area on diffusion-weighted magnetic resonance imaging and the modified Rankin Scale (mRS) of the patients were recorded. The values calculated at admission and at discharge were labeled as "mRS-1" and "mRS-2," respectively, and the mRS-2 measurement was used as a prognostic indicator. The "good" and the "poor" functional outcomes were defined as mRS ≤2 and mRS >2, respectively. Correlations between levels of EtCO 2 and infarct volume, mRS were calculated. RESULTS: In total, 44 patients were included in the study. The median age of the patients was 69 years (interquartile range; 16; min-max: 35 to 88 y) and 68.2% of them were male. In the univariate logistic regression models of the mRS-2 [0 to 2 (0) and 3 to 6 (1)], all variables were not statistically significant to predict mRS-2 group. There were statistically significant differences in EtCO 2 values between mRS-1 ( P =0.03) and mRS-2 ( P =0.04). A negative moderate correlation was found between EtCO 2 and mRS-2 ( r =-0.410; P =0.006). The correlation between EtCO 2 and infarct volume was not statistically significant ( r =-0.256; P =0.093). CONCLUSIONS: This study highlights the importance of capnography follow-up of patients with acute ischemic stroke. In patients with acute ischemic stroke, the EtCO 2 value measured at the time of admission is lower in the group with high mRS at both admission and discharge.

Tuberculosis despite latent infection screening and treatment in patients receiving TNF inhibitor therapy.

INTRODUCTION: Although latent tuberculosis infection (LTBI) treatment is given before anti-tumor necrosis factor (TNF) treatment, tuberculosis (TB) still develops in these patients and the risk factors are not well known. Besides, there is little data on the safety of isoniazid (INH) treatment in this group of patients. This study aimed to determine the risk factors for the development of tuberculosis and the safety of LTBI in such patients. METHODS: All patients (n=665) given anti-TNF in a single center were included in this study. Complete data were obtained from the records of 389 patients. RESULTS: Seven patients (1.1%) were diagnosed with TB. There was no significant difference in age, gender, smoking rate, comorbidities, leukocyte counts, hemoglobin, creatinine, AST, ALT, protein levels, and tuberculin reaction between patients with and without TB. Of 389 patients, 289 (76%) had received INH prophylaxis, including 43 tuberculin-negative patients. Thirty patients had anti-TNF use prior to INH prophylaxis. None of these patients had TB in the follow-up period. Seven patients who developed TB had completed LTBI treatment, including one patient who was tuberculin-negative. The time from the completion of INH treatment to the diagnosis of TB was 6-61 months. None had any history of contact with TB during this period. INH treatment was associated with hepatotoxicity in 49 patients (17%); all resolved without any need to stop INH. CONCLUSION: Patients on anti-TNF treatment had a high rate of TB despite INH prophylaxis, but no risk factor for TB development was identified. Mild hepatotoxicity frequently developed during LTBI treatment. Key Points • Tuberculosis still develops in patients treated with tumor necrosis factor (TNF)-inhibitors despite prior screening and treatment for latent tuberculosis infection (LTBI). • In this cohort, all patients in whom tuberculosis developed had been treated for LTBI and all but one were initially tuberculin-positive. No risk factors have been identified. • The current policy of treating tuberculin-positive patients with a 9-month INH regimen does not seem to be fully effective in preventing tuberculosis.

Different selection dynamics of S and RdRp between SARS-CoV-2 genomes with and without the dominant mutations.

SARS-CoV-2 is a betacoronavirus responsible for the COVID-19 pandemic that has affected millions of people worldwide. Pharmaceutical research against COVID-19 and the most frequently used tests for SARS-CoV-2 both depend on the genomic and peptide sequences of the virus for their robustness. Therefore, understanding the mutation rates and content of the virus is critical. Two key proteins for SARS-CoV-2 infection and replication are the S protein, responsible for viral entry into the cells, and RdRp, the RNA polymerase responsible for replicating the viral genome. Due to their roles in the viral cycle, these proteins are crucial for the fitness and infectiousness of the virus. Our previous findings had shown that the two most frequently observed mutations in the SARS-CoV-2 genome, 14408C>T in the RdRp coding region, and 23403A>G in the S gene, are correlated with higher mutation density over time. In this study, we further detail the selection dynamics and the mutation rates of SARS-CoV-2 genes, comparing them between isolates carrying both mutations, and isolates carrying neither. We find that the S gene and the RdRp coding region show the highest variance between the genotypes, and their selection dynamics contrast each other over time. The S gene displays higher tolerance for positive selection in mutant isolates early during the appearance of the double mutant genotype, and undergoes increasing negative selection over time, whereas the RdRp region in the mutant isolates shows strong negative selection throughout the pandemic.

TAp73ß Can Promote Hepatocellular Carcinoma Dedifferentiation.

Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73ß (TAp73ß) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73ß-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73ß caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73ß had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73ß upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73ß may promote malignant dedifferentiation of HCC cells.

Differential expression of full-length and NH2 terminally truncated FAM134B isoforms in normal physiology and cancer.

Selective autophagy of the endoplasmic reticulum (ER), namely ER-phagy, is mediated by ER-localized receptors, which are recognized and sequestered by GABARAP/LC3B-decorated phagophores and transferred to lysosomes for degradation. Being one such receptor, FAM134B plays critical roles in cellular processes such as protein quality control and neuronal survival. FAM134B has also been associated with different cancers, although its exact role remains elusive. We report here that the FAM134B gene encodes not one but at least two different protein isoforms: the full-length and the NH2 terminally truncated forms. Their relative expression shows extreme variation, both within normal tissues and among cancer types. Expression of full-length FAM134B is restricted to the brain, testis, spleen, and prostate. In contrast, NH2 terminally truncated FAM134B is dominant in the heart, skeletal muscle, kidney, pancreas, and liver. We compared wild-type and knockout mice to study the role of the Fam134b gene in starvation. NH2 terminally truncated FAM134B-2 was induced in the liver, skeletal muscle, and heart but not in the pancreas and stomach following starvation. Upon starvation, Fam134b-/- mice differed from wild-type mice by less weight loss and less hyperaminoacidemic and hypocalcemic response but increased levels of serum albumin, total serum proteins, and α-amylase. Interestingly, either NH2 terminally truncated FAM134B or both isoforms were downregulated in liver, lung, and colon cancers. In contrast, upregulation was observed in stomach and chromophobe kidney cancers.NEW & NOTEWORTHY We reported tissues expressing FAM134B-2 such as the kidney, muscle, heart, and pancreas, some of which exhibit stimulated expression upon nutrient starvation. We also demonstrated the effect of Fam134b deletion during ad libitum and starvation conditions. Resistance to weight loss and hypocalcemia, accompanied by an increase in serum albumin and α-amylase levels, indicate critical roles of Fam134b in physiology. Furthermore, the differential expression of FAM134B isoforms was shown to be significantly dysregulated in human cancers.

Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load.

SARS-CoV-2 is a betacoronavirus responsible for COVID-19, a pandemic with global impact that first emerged in late 2019. Since then, the viral genome has shown considerable variance as the disease spread across the world, in part due to the zoonotic origins of the virus and the human host adaptation process. As a virus with an RNA genome that codes for its own genomic replication proteins, mutations in these proteins can significantly impact the variance rate of the genome, affecting both the survival and infection rate of the virus, and attempts at combating the disease. In this study, we analyzed the mutation densities of viral isolates carrying frequently observed mutations for four proteins in the RNA synthesis complex over time in comparison to wildtype isolates. Our observations suggest mutations in nsp14, an error-correcting exonuclease protein, have the strongest association with increased mutation load without selective pressure and across the genome, compared to nsp7, nsp8 and nsp12, which form the core polymerase complex. We propose nsp14 as a priority research target for understanding genomic variance rate in SARS-CoV-2 isolates and nsp14 mutations as potential predictors for high mutability strains.

Platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios predict tumor size and survival in HCC patients: Retrospective study.

BACKGROUND: Inflammation is a recognized concomitant of hepatocellular carcinoma (HCC) and its indices are prognostically useful. AIMS: To evaluate two commonly used inflammatory indices, neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR), to examine their relationship to maximum tumor diameter (MTD) and to survival. METHODS: A database of 1024 prospectively-accrued HCC patients was examined, who had full baseline tumor parameter data, including CT scan information on HCC size and whose survival was known. Analyses of NLR and PLR were correlated to MDT and to survival. NLR and PLR cutoffs were calculated from receiver operator characteristic curves. RESULTS: Every MTD pair had significantly different PLR values, for MTD groups of groups <2/≥2, <3/≥3, <4/≥4, <5/≥5 cm. However there were few significant differences in NLR values. Logistic regression models of different MTD groups likewise showed significance for PLR. Patients with both low NLR and low PLR had the longest overall survival compared to all the other 3 combinations of NLR and PLR. In a Cox regression analysis, univariate models on NLR (≤3.02/>3.02) and PLR (≤6.82/>6.82) groups, showed significance for PLR, p = 0.034 and approaching significance for NLR, p = 0.057. CONCLUSIONS: MTD pairs down to <2/≥2 cm showed significance for PLR, survival showed significance for PLR and almost for NLR.

Mutation density changes in SARS-CoV-2 are related to the pandemic stage but to a lesser extent in the dominant strain with mutations in spike and RdRp.

Since its emergence in Wuhan, China in late 2019, the origin and evolution of SARS-CoV-2 have been among the most debated issues related to COVID-19. Throughout its spread around the world, the viral genome continued acquiring new mutations and some of them became widespread. Among them, 14408 C>T and 23403 A>G mutations in RdRp and S, respectively, became dominant in Europe and the US, which led to debates regarding their effects on the mutability and transmissibility of the virus. In this study, we aimed to investigate possible differences between time-dependent variation of mutation densities (MDe) of viral strains that carry these two mutations and those that do not. Our analyses at the genome and gene level led to two important findings: First, time-dependent changes in the average MDe of circulating SARS-CoV-2 genomes showed different characteristics before and after the beginning of April, when daily new case numbers started levelling off. Second, this pattern was much delayed or even non-existent for the "mutant" (MT) strain that harbored both 14408 C>T and 23403 A>G mutations. Although these differences were not limited to a few hotspots, it is intriguing that the MDe increase is most evident in two critical genes, S and Orf1ab, which are also the genes that harbor the defining mutations of the MT genotype. The nature of these unexpected relationships warrants further research.

RdRp mutations are associated with SARS-CoV-2 genome evolution.

COVID-19, caused by the novel SARS-CoV-2 virus, started in China in late 2019, and soon became a global pandemic. With the help of thousands of viral genome sequences that have been accumulating, it has become possible to track the evolution of the viral genome over time as it spread across the world. An important question that still needs to be answered is whether any of the common mutations affect the viral properties, and therefore the disease characteristics. Therefore, we sought to understand the effects of mutations in RNA-dependent RNA polymerase (RdRp), particularly the common 14408C>T mutation, on mutation rate and viral spread. By focusing on mutations in the slowly evolving M or E genes, we aimed to minimize the effects of selective pressure. Our results indicate that 14408C>T mutation increases the mutation rate, while the third-most common RdRp mutation, 15324C>T, has the opposite effect. It is possible that 14408C>T mutation may have contributed to the dominance of its co-mutations in Europe and elsewhere.