The surgical treatment of unilateral vocal cord paralysis (UVCP): qualitative review analysis and meta-analysis study.

PURPOSE: The objectives of this meta-analysis were to summarize the key surgical procedures for UVCP and to evaluate which of these is associated with better results in terms of vocal improvement. METHODS: A systematic review of the literature was conducted in search of articles focused on the comparison of voice outcome between different techniques for the UVCP treatment. Then, a quantitative analysis was carried out for papers published from 2013 onwards, reporting only adult patients with unilateral paralysis for each study, and each surgical technique was evaluated for its capability of achieving good functional outcomes in terms of GRBAS-I scale and maximum phonation time in seconds (MPT). RESULTS: The search identified 1853 publications. A total of 159 articles were stratified and included according to our selection criteria. 21 out of 159 articles were selected for quantitative synthesis. For trans-oral techniques: the mean GRBAS-I scale were 2.33 before injection and 0.41 after injection. The mean MPT before injection were 4.78 and 12.50 after injection. For open techniques the mean GRBAS-I scale were 2.43 before surgery and 0.68 after surgery. For open technique, the mean MPT were 3.50 before surgery and 12.40 after surgery. CONCLUSIONS: The two types of techniques lead to an improvement in terms of vocal outcomes emphasizing that from the examined literature an indication emerges to perform an early injection because this could reduce the possible need for a more invasive intervention of permanent medialization in the future.

Adipocytes sustain pancreatic cancer progression through a non-canonical WNT paracrine network inducing ROR2 nuclear shuttling.

BACKGROUND: Solid epidemiological evidences connect obesity with incidence, stage and survival in pancreatic cancer. However, the underlying mechanistic basis linking adipocytes to pancreatic cancer progression remain largely elusive. We hypothesized that factors secreted by adipocytes could be responsible for epithelial-to-mesenchymal transition (EMT) induction and, in turn, a more aggressive phenotype in models of pancreatic preneoplastic lesions. METHODS: We studied the role of factors secreted by two adipogenic model systems from primary human bone marrow stromal cells (hBMSCs) in an in vitro experimental cell transformation model system of human pancreatic ductal epithelial (HPDE) cell stably expressing activated KRAS (HPDE/KRAS),Results:We measured a significant induction of EMT and aggressiveness in HPDE and HPDE/KRAS cell lines when cultured with medium conditioned by fully differentiated adipocytes (ADIPOCM) if compared with the same cells cultured with medium conditioned by hBMSC (hBMSCCM) from two different healthy donors. Several genes coding for soluble modulators of the non-canonical WNT signaling pathway, including FRZB, SFRP2, RSPO1, WNT5A and 5B were significantly overexpressed in fully differentiated adipocytes than in their respective in hBMSC. ADIPOCM induced the overexpression and the nuclear translocation of the Frizzled family member receptor tyrosine kinase-like orphan receptor (Ror) 2 in HPDE and HPDE/KRAS cells. Vantictumab, an anti-Frizzled monoclonal antibody, reduced ROR2 nuclear translocation and in turn the EMT and aggressiveness in HPDE and HPDE/KRAS cells. CONCLUSIONS: We demonstrated that adipocytes could induce EMT and aggressiveness in models of pancreatic preneoplastic lesions by orchestrating a complex paracrine signaling of soluble modulators of the non-canonical WNT signaling pathway that determine, in turn, the activation and nuclear translocation of ROR2. This signaling pathway could represent a novel target for pancreatic cancer chemoprevention. Most importantly, these factors could serve as novel biomarkers to select a risk population among obese subjects for screening and, thus, early diagnosis of pancreatic cancer.

Radiosurgery-assisted gingival displacement: a proof of concept technique to enhance the efficiency of intraoral digital impression.

Nowadays, an increasing number of dentists are using intraoral scanners (IOS) in their daily practice as an alternative to conventional impression taking. One of the main concerns is related to the capability of scanning the subgingival anatomy of the die, usually very challenging due to the limited operative field and the presence of oral fluids. The radiosurgery assisted gingival displacement technique (RAGD) may enhance the intraoral optical scanning of the finish line and neighbor tooth anatomy. The contour of the interim prosthesis is used to drive the tip of radiosurgery electrode along the tooth surface and open selectively the gingival crevice with a prosthetically-driven and minimally invasive approach. The clinical implication of this technique is related to increasing the efficiency and accuracy of the digital impression technique in the critical zone of the prosthetic shoulder.

Colonization of Legionella spp. In dental unit waterlines.

Legionella spp. are ubiquitous in aquatic habitats and water distribution systems, including dental unit waterlines. Surveys have shown that the percentage of samples taken at different dental sites that were positive for Legionella spp. were highly variable and ranged from 0% to 100%. Cultivation is the principal approach to evaluating bacterial contamination employed in the past, but applying this approach to testing for Legionella spp. may result in false-negative data or underestimated bacterial counts. PCR and direct fluorescent counts can detect viable non-cultivable bacteria, which are not counted by plating procedures. Legionella spp., commonly form such viable non-culturable cells and it is likely that they contribute to the difference between plate count results and those of PCR and fluorescent-antibody detection. However, studies have shown that Legionella is present in the municipal water source in spite of the current filtration and chlorination procedures. Once Legionella reaches the building water system, it settles down into a biofilm layer of stagnant water. By means of this layer, Legionella can protect itself from antimicrobial agents and then multiply. Dental unit waterlines may be contaminated with opportunistic bacteria. The water quality in the dental units should be controlled to eliminate opportunistic pathogens and to provide water for dental treatment that meets public health standards for potable water.

Focus on periodontal disease and development of endocarditis.

Infective endocarditis is a devastating disease with high morbidity and mortality. The link to oral bacteria has been known for many decades and has caused ongoing concern for dentists, patients and cardiologists. The microbiota of the mouth is extremely diverse and more than 700 bacterial species have been detected. Half of them are uncultivable so far. Oral microbiota is not uniform, specific sites exist in the mouth such as tongue, palate, cheek, teeth and periodontal pockets that have their own microbiota. Factors involved in the development of a bacterial endocarditis are difficult to define but a vulnerable surface (i.e. a damaged endocardium) and a high bacterial load in the blood seems to be decisive. The cause of microorganisms, in 90% of cases, are staphylococcus, streptococcus and enterococcus. Oral streptococci belong to viridans group (streptococcus mutans and streptococcus sanguis). As they are part of dental plaque, they could enter the bloodstream causing bacteraemia through daily habits like chewing or tooth brushing. Effective treatment of periodontal infections is important to reduce local inflammation and bacteraemia. In addition, poor periodontal health appears to increase the risk of cardiovascular disease, pulmonary disease, and preterm and low birth weight. CONCLUSIONS: Long-standing oral disease prevention protocols reduce the risk of developing periodontal disease. Data suggests that methods used to prevent cases of IE that originate from oral bacteria should focus on improving oral hygiene and reducing or eliminating gingivitis, which should reduce the incidence of bacteraemia after tooth-brushing and the need to extract teeth owing to periodontal disease and caries.

Streamlined bioreactor-based production of human cartilage tissues.

Engineered tissue grafts have been manufactured using methods based predominantly on traditional labour-intensive manual benchtop techniques. These methods impart significant regulatory and economic challenges, hindering the successful translation of engineered tissue products to the clinic. Alternatively, bioreactor-based production systems have the potential to overcome such limitations. In this work, we present an innovative manufacturing approach to engineer cartilage tissue within a single bioreactor system, starting from freshly isolated human primary chondrocytes, through the generation of cartilaginous tissue grafts. The limited number of primary chondrocytes that can be isolated from a small clinically-sized cartilage biopsy could be seeded and extensively expanded directly within a 3D scaffold in our perfusion bioreactor (5.4 ± 0.9 doublings in 2 weeks), bypassing conventional 2D expansion in flasks. Chondrocytes expanded in 3D scaffolds better maintained a chondrogenic phenotype than chondrocytes expanded on plastic flasks (collagen type II mRNA, 18-fold; Sox-9, 11-fold). After this "3D expansion" phase, bioreactor culture conditions were changed to subsequently support chondrogenic differentiation for two weeks. Engineered tissues based on 3D-expanded chondrocytes were more cartilaginous than tissues generated from chondrocytes previously expanded in flasks. We then demonstrated that this streamlined bioreactor-based process could be adapted to effectively generate up-scaled cartilage grafts in a size with clinical relevance (50 mm diameter). Streamlined and robust tissue engineering processes, as the one described here, may be key for the future manufacturing of grafts for clinical applications, as they facilitate the establishment of compact and closed bioreactor-based production systems, with minimal automation requirements, lower operating costs, and increased compliance to regulatory guidelines.

TAK1-regulated expression of BIRC3 predicts resistance to preoperative chemoradiotherapy in oesophageal adenocarcinoma patients.

BACKGROUND: About 20% of resectable oesophageal carcinoma is resistant to preoperative chemoradiotherapy. Here we hypothesised that the expression of the antiapoptotic gene Baculoviral inhibitor of apoptosis repeat containing (BIRC)3 induced by the transforming growth factor ß activated kinase 1 (TAK1) might be responsible for the resistance to the proapoptotic effect of chemoradiotherapy in oesophageal carcinoma. METHODS: TAK1 kinase activity was inhibited in FLO-1 and KYAE-1 oesophageal adenocarcinoma cells using (5Z)-7-oxozeaenol. The BIRC3 mRNA expression was measured by qRT-PCR in 65 pretreatment frozen biopsies from patients receiving preoperatively docetaxel, cisplatin, 5-fluorouracil, and concurrent radiotherapy. Receiver operator characteristic (ROC) analyses were performed to determine the performance of BIRC3 expression levels in distinguishing patients with sensitive or resistant carcinoma. RESULTS: In vitro, (5Z)-7-oxozeaenol significantly reduced BIRC3 expression in FLO-1 and KYAE-1 cells. Exposure to chemotherapeutic agents or radiotherapy plus (5Z)-7-oxozeaenol resulted in a strong synergistic antiapoptotic effect. In patients, median expression of BIRC3 was significantly (P<0.0001) higher in adenocarcinoma than in the more sensitive squamous cell carcinoma subtype. The BIRC3 expression significantly discriminated patients with sensitive or resistant adenocarcinoma (AUC-ROC=0.7773 and 0.8074 by size-based pathological response or Mandard's tumour regression grade classifications, respectively). CONCLUSIONS: The BIRC3 expression might be a valid biomarker for predicting patients with oesophageal adenocarcinoma that could most likely benefit from preoperative chemoradiotherapy.

Potential use of acupuncture in the treatment of first bite syndrome.

OBJECTIVES: First bite syndrome (FBS) is an early postoperative pain syndrome characterized by the sudden onset of pain in the parotid region at the first bite of each meal. The etiology is not certain, hence a standardized therapy does not exist. METHODS: A 50-year old woman referred to us complaining of a swelling in the right parotid region. Fine-needle aspiration biopsy (FNAB) was diagnostic for pleomorphus adenoma of the deep lobe of the parotid gland. A 50-year old man presented with a mass in the right side of the neck, FNAB was diagnostic for parapharyngeal space neurinoma. The first patient was submitted to total parotidectomy with facial nerve preservation, the second to extracapsular dissection of the tumor. A week after surgery both patients developed FBS. A qualitative/quantitative description of pain was obtained by means of a self-coded questionnaire. The score ranges from 8 to 44, corresponding to the lowest and the highest discomfort possible, respectively. Acupuncture was used to treat these 2 patients. The treatment protocol comprised 6 sessions, one per week, lasting 30 minutes each. RESULTS: Our questionnaire was administered before and after treatment and the score dropped from 33 to 25 in the female, from 30 to 15 in the male patient. CONCLUSION: FBS is a complication of upper cervical surgery with a high morbidity rate. We describe the first two cases of FBS that were successfully treated with acupuncture in our ENT department. We believe that this procedure may represent a valid therapeutic alternative in the future.

Subtotal gastrectomy for gastric cancer: long term outcomes of Billroth I reconstruction at a single European institute.

BACKGROUND/AIMS: The role of Billroth I (BI) subtotal gastrectomy (SG) for gastric cancer (GC) remains controversial in Western countries. The aim of the study is to critically analyze the long term outcomes of this procedure in a large single-institution experience. METHODOLOGY: Between 1990 and 2004, 158 patients underwent BI SG for GC at the Regina Elena Cancer Institute of Rome. Evaluation focused on cancer recurrence of the gastric stump, functional outcome and endoscopic findings. RESULTS: Actuarial survival rate 10 years after resection in stage I-II was 70.7 per cent. After curative resection, primary cancer of the gastric stump occurred in one patient seven years after resection (0.7 per cent), whereas two patients had early recurrence (1.4 per cent) one and three years postoperatively. There were no oesophageal cancers. In survivors, Visick grades I and II achieved 95 per cent, and postoperative endoscopy showed no evidence of mucosal changes in 85 per cent of the patients. Twelve per cent of the patients took acid blocker regularly, however, the incidence of functional failure was 5 per cent. CONCLUSIONS: In selected patients, Billroth I subtotal gastrectomy is a safe and effective procedure that provides long-term survival and very good functional outcome.

Salvage surgery after unsuccessful radiotherapy in early glottic cancer.

Surgery is the main therapeutic option to control recurrent laryngeal cancer after radiotherapy (RT) relapse. Most RT-recurred cancer is treated aggressively; although, conservative laryngeal surgery was attempted in selected cases. Here, we report our experiences with salvage laryngeal surgery for early glottic cancers that did not respond to RT. We analyzed files from 1980 to 2006 and selected 173 patients surgically treated for a RT-failed early glottic carcinoma (stage I-II according to 2010 TNM: 114 T1N0, 59 T2N0). Among them, 47 patients (27%) underwent a salvage partial laryngectomy (SPL) and 126 (73%) had a salvage total laryngectomy (STL). When compared with initial T staging, we found 61% of lesions were up-staged, 31% had the same staged lesion, and only 8% were down-staged (according to rTNM). No statistically significant differences were found in terms of disease-free survival and overall survival when SPL and STL patients were compared. Univariate analysis showed that T, rT, and rTNM were prognostic factors for overall survival (p = 0.045, p = 0.028, and p = 0.037, respectively); yet, these significances were lost in multivariate analysis. Our results suggest that salvage surgery is feasible in most cases of RT-recurred early glottic cancer; although, a conservative approach achieves good oncological and functional results only in select RT-recurred patients.

Prognostic role of internal jugular vein preservation in neck dissection for head and neck cancer.

BACKGROUND AND OBJECTIVES: Sparing internal jugular vein (IJV) in neck dissection for head and neck cancer is controversial. We aimed at evaluating the prognostic impact of IJV preservation. METHODS: We examined 206 files of head and neck cancer patients who underwent radical or modified radical neck dissection at the Otolaryngology University of Florence. The site of primary tumor was larynx and hypopharynx in 44.66%, oropharynx in 25.24%, oral cavity in 23.3%, unknown in 4.85%, salivary glands and rhinopharynx in 0.97%. In 60.19% the IJV was resected, in 39.81% preserved. Prognostic impact of IJV preservation was assessed by Kaplan-Meier and multivariate analysis. RESULTS: Neck recurrence occurred in 25.2%: the IJV was resected in 42.31%, in 57.69% preserved (P = 0.02). At multivariate analysis, neck recurrence resulted significantly associated to extracapsular spread (ECS) (P = 0.009), IJV preservation (P = 0.01), positive margins (P = 0.02). In ECS positive patients, a higher risk of neck recurrence was documented for IJV preservation (P = 0.012). A worse prognosis was observed for patients with IJV spared (P = 0.06). CONCLUSIONS: IJV preservation is associated with an increased risk of neck failure and a worse outcome, mainly in patients with ECS of nodes.

Intracranial haemorrhage in the Italian population of haemophilia patients with and without inhibitors.

Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided.

Deregulation of PERK in the autoimmune disease pemphigus vulgaris occurs via IgG-independent mechanisms.

BACKGROUND: Serum and IgG isolated from patients with the autoimmune blistering disease pemphigus vulgaris (PV) trigger complex intracellular pathways in keratinocytes, including alterations of the cell cycle and metabolism, which ultimately lead to cell-cell detachment (acantholysis). We have shown previously that one of the earliest pathogenic events in PV is the activation of protein kinases, including the PKR-like endoplasmic reticulum (ER) kinase PERK. OBJECTIVES: In the present study we investigated in more detail the role of PERK in the pathogenesis of PV. METHODS: PERK levels were assessed by Western blotting and in-cell enzyme-linked immunosorbent assay, and PERK expression was silenced by siRNA technology. The effects of PV sera/IgG on keratinocyte cultures were investigated by flow cytometry, MTT and adhesion assays. RESULTS: We show that PERK is activated in keratinocytes exposed to PV serum, as demonstrated by an increase in phosphorylated PERK levels and phosphorylation of eIF2α. Decreased expression of PERK by siRNA reduced the effects of PV serum on the cell cycle and keratinocyte viability, two key events in PV pathophysiology. As impairment of metabolic activity in PV is partially due to non-IgG serum factors, we then investigated the activation of PERK in keratinocytes incubated with whole PV serum, purified PV IgG and IgG-depleted PV serum. The data demonstrated that PV sera depleted of IgG, but not PV IgG, triggered PERK phosphorylation and this correlated with a marked reduction of metabolic activity in keratinocytes exposed to IgG-free serum. Knockdown of PERK by siRNA abrogated the changes in the cell cycle and apoptosis induced by IgG-depleted PV serum. Finally, the reduction of metabolic activity observed in keratinocytes exposed to IgG-depleted PV serum was almost absent in PERK-deficient cells. CONCLUSIONS: Taken together, the results demonstrate that activation of PERK participates in the reduction of metabolic activity and cell viability seen in PV and that this phenomenon depends on non-IgG factors. PERK activation may represent a novel signalling mechanism linking ER stress and acantholysis in PV.

Real-time measurements of human chondrocyte heat production during in vitro proliferation.

Isothermal microcalorimeters (IMC) are highly sensitive instruments that allow the measurement of heat flow in the microwatt range. Due to their detection of minute thermal heat, IMC techniques have been used in numerous biological applications, including the study of fermentation processes, pharmaceutical development, and cell metabolism. In this work, with the ultimate goal of establishing a rapid and real-time method to predict the proliferative capacity of human articular chondrocytes (HAC), we explored to use of IMC to characterize one of the crucial steps within the process of cartilage tissue engineering, namely the in vitro expansion of HAC. We first established an IMC-based model for the real-time monitoring of heat flow generated by HAC during proliferation. Profiles of the heat and heat flow curves obtained were consistent with those previously shown for other cell types. The average heat flow per HAC was determined to be 22.0 ± 5.3 pW. We next demonstrated that HAC proliferation within the IMC-based model was similar to proliferation under standard culture conditions, verifying its relevance for simulating the typical cell culture application. HAC growth and HAC heat over time appeared correlated for cells derived from particular donors. However, based on the results from 12 independent donors, no predictive correlation could be established between the growth rate and the heat increase rate of HAC. This was likely due to variability in the biological function of HAC derived from different donors, combined with the complexity of tightly couple metabolic processes beyond proliferation. In conclusion, IMC appears to be a promising technique to characterize cell proliferation. However, studies with more reproducible cell sources (e.g., cell lines) could be used before adding the complexity associated with primary human cells.

Prevalence of retained/transmigrated permanent and persistence of primary teeth associated with odontomas in young children.

AIM: Odontomas are odontogenic tumours of the jaws; they are generally asymptomatic with an unknown aetiology. This study was conducted on non-syndromic children aged 9 to 14 years to explore the side effects deriving from the presence of these benign tumours, as retention, transmigration, ectopic eruption of permanent teeth and the permanence of primary teeth in the affected area. METHODS: Two hundred panoramic (OPT) and 92 Cone Beam Computed Tomography radiographs (CBCT) of patients (130 males and 70 females) were analysed from February 2018 to December 2019. Two hundred odontomas (145 compound and 55 complex type) and 800 teeth (160 primary and 640 permanent) were included. RESULTS: The prevalence of these tumours in both male and female subjects was 65% and 35%, respectively; the prevalence of compound odontomas in maxillary and mandibular bones was respectively 27.58% and 72.41%. The prevalence of complex odontomas in maxillary bones in female and male subjects was 37.5% and 62.5% respectively. It was observed the presence of a primary tooth in 81% of cases, the presence of retained teeth in 16.5% and a dental transmigration in the remaining 2.5% of cases in the compound type. Gender (p?=0.158) has no significant correlation. CONCLUSIONS: An early diagnosis and removal of odontomas in primary dentition is crucial in order to prevent later dental complications. Since the detection of odontomas is mainly an accidental radiological finding, the need for routine radiographic analysis should be highlighted.

Will a tumor pandemic come after the COVID-19 pandemic? Head and Neck cancer perspective.

The COVID-19 pandemic demands a reassessment of head and neck oncology treatment paradigms by posing several challenges for oncology services, with unprecedented pressure on the regional health care system. Since February 2020 this has severely disrupted health-care services, leading to accumulating clinic caseload and substantial delays for operations. The head and neck cancer services have been faced with the difficult task of managing the balance between infection risk to health-care providers and the risk of disease progression from prolonged waiting times. Herein, we share our experience in Firenze (Italy) and propose our action plan on the management of head and neck cancer services via multi-institution collaboration.

How to avoid life-threatening complications following head and neck space infections: an algorithm-based approach to apply during times of emergency. When and why to hospitalise a neck infection patient.

BACKGROUND: Head and neck space infections present with a potential mortality rate of 40-50 per cent. This paper proposes an algorithm-based management of head and neck space infection to prevent life-threatening events. METHODS: A total of 225 patients with head and neck space infection were prospectively analysed at our institution. An experimental scoring system determined the level of clinical risk for the development of major complications. Accordingly, patients were classified into three risk groups: low-, intermediate- and high-risk. RESULTS: Only intermediate- and high-risk patients were hospitalised. Intermediate-risk patients received intravenous medical therapy with daily re-evaluation; 18 of them required delayed surgery. Of the high-risk patients, three required immediate surgical treatment and five received delayed surgery, while in five cases medical therapy was the only treatment received. Low-risk patients were treated in an out-patient setting. CONCLUSION: The algorithm-based management of head and neck space infection was successful in enabling the avoidance of lethal complications onset.

A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B.

BACKGROUND: Host genetic modifiers of the natural history of chronic hepatitis B (CHB) remain poorly understood. Recently, a genome-wide association study (GWAS)-identified polymorphism in the STAT4 gene that contributes to the risk for hepatocellular carcinoma (HCC) was shown to be associated with the full spectrum of hepatitis B virus (HBV) outcomes in Asian patients. However, the functional mechanisms for this effect are unknown and the role of the variant in modulating HBV disease in Caucasians has not been investigated. AIMS: To determine whether STAT4 genetic variation is associated with liver injury in Caucasian patients with CHB and to investigate potential mechanisms mediating this effect. METHODS: STAT4 rs7574865 was genotyped in 1085 subjects (830 with CHB and 255 healthy controls). STAT4 expression in liver, PBMCs and NK cells, STAT4 phosphorylation and secretion of interferon-gamma (IFN-γ) according to STAT4 genetic variation was examined. RESULTS: STAT4 rs7574865 genotype was independently associated with hepatic inflammation (OR: 1.42, 95% CI: 1.07-2.06, P = 0.02) and advanced fibrosis (OR: 1.83, 95% CI: 1.19-2.83, P = 0.006). The minor allele frequency of rs7574865 was significantly lower than that in healthy controls. rs7574865 GG risk carriers expressed lower levels of STAT4 in liver, PBMCs and in NK cells, while NK cells from patients with the risk genotype had impaired STAT4 phosphorylation following stimulation with IL-12/IL-18 and a reduction in secretion of IFN-γ. CONCLUSION: Genetic susceptibility to HBV persistence, hepatic inflammation and fibrosis in Caucasians associates with STAT4 rs7574865 variant. Downstream effects on NK cell function through STAT4 phosphorylation-dependent IFN-γ production likely contribute to these effects.