HBcrAg values may predict virological and immunological responses to pegIFN-α in NUC-suppressed HBeAg-negative chronic hepatitis B.

OBJECTIVE: Selected populations of patients with chronic hepatitis B (CHB) may benefit from a combined use of pegylated interferon-alpha (pegIFN-α) and nucleos(t)ides (NUCs). The aim of our study was to assess the immunomodulatory effect of pegIFN-α on T and natural killer (NK) cell responses in NUC-suppressed patients to identify cellular and/or serological parameters to predict better T cell-restoring effect and better control of infection in response to pegIFN-α for a tailored application of IFN-α add-on. DESIGN: 53 HBeAg-negative NUC-treated patients with CHB were randomised at a 1:1 ratio to receive pegIFN-α-2a for 48 weeks, or to continue NUC therapy and then followed up for at least 6 months maintaining NUCs. Serum hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels as well as peripheral blood NK cell phenotype and function and HBV-specific T cell responses upon in vitro stimulation with overlapping HBV peptides were measured longitudinally before, during and after pegIFN-α therapy. RESULTS: Two cohorts of pegIFN-α treated patients were identified according to HBsAg decline greater or less than 0.5 log at week 24 post-treatment. PegIFN-α add-on did not significantly improve HBV-specific T cell responses during therapy but elicited a significant multispecific and polyfunctional T cell improvement at week 24 post-pegIFN-α treatment compared with baseline. This improvement was maximal in patients who had a higher drop in serum HBsAg levels and a lower basal HBcrAg values. CONCLUSIONS: PegIFN-α treatment can induce greater functional T cell improvement and HBsAg decline in patients with lower baseline HBcrAg levels. Thus, HBcrAg may represent an easily and reliably applicable parameter to select patients who are more likely to achieve better response to pegIFN-α add-on to virally suppressed patients.

How can sleep disorders affect our reaction towards external stressors: a lesson from the COVID-19 outbreak.

BACKGROUND: The COVID-19 outbreak produced extensive psychological consequences, especially among vulnerable populations. Sleep was identified as one of the most common "indirect targets" of the pandemia, with up to 74.8% of patients surviving from COVID-19 complaining of new-onset sleep disorders. However, so far, the clinic-psychological impact of the outbreak in patients affected by pre-existing sleep disorders has not been examined in details. MATERIALS AND METHODS: In the present study, we aim to assess the effect of the COVID-19 outbreak in a cohort of 190 adult patients affected by sleep disorders, compared to 265 age and sex-matched healthy sleepers. The assessment was implemented throughout the use of ad hoc anamnestic questions, exploration of dream content, and validated questionnaires, aiming to capture the broad range of the neuropsychological nuances of the COVID-19 impact. RESULTS: Subjects with pre-existent sleep disorders faced a more severe impact in terms of sleep quality and amount compared to healthy sleepers, presenting longer sleep latency, reduced sleep efficacy, and greater use of hypnotics and medications. On the other hand, healthy sleepers experienced deeper variation in sleeping habits, sleep duration, and greater impact on dream activity in terms of content, emotionality, and presence of recurrent dreams. Finally, in our sample, being female represents an important aggravating factor in the pandemic experience, both in terms of sleep deterioration and with respect to physical and mental health. For instance, females indeed presented the highest scores of Pittsburgh Sleep Quality Index (PSQI) both in cases and control groups (respectively 10 ± 3.8 vs 7.3 ± 3.9 in cases and 6.6 ± 3.6 vs 6.0 ± 3.4 in controls, p-value < 0.001). CONCLUSION: Pre-existent sleep disorders and the female sex might represent risk factors increasing the clinic-psychological burden in dramatic scenarios, such as the COVID-19 pandemia, requiring dedicated attention from clinicians.

Histopathological lesions of the gastrointestinal tract associated with the use of polystyrene sulfonate and sevelamer: a meta-analysis.

Background: Gastrointestinal severe adverse events such as ulceration and perforation have been reported for sodium or calcium polystyrene sulfonate and sevelamer. Howewer, their role in the pathogenesis is unclear. Chronic kidney disease is a well known risk factor, while the role of hypertension and/or diabetes is uncertain. Methods: A meta-analysis of the published literature was conducted to review the clinical features, risk factors and histopathological findings of patients who experienced gastrointestinal adverse events after administration of polystyrene sulfonate or sevelamer. Results: The meta-analysis indicated that patients were more likely to show necrosis and/or perforation when the resin used was polystyrene sulfonate compared to sevelamer (p < 0.001). Death was more likely in patients taking polystyrene sulfonate compared to sevelamer (p < 0.001). Discussion: The results show that sevelamer is more likely to lead to inflammation or ulceration in the gastrointestinal tract than polystyrene sulfonate, which is more likely to be associated with severe gastrointestinal adverse events such as necrosis and/or perforation. Polystyrene sulfonate is significantly associated with death compared to sevelamer.

Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro.

OBJECTIVE: Exhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function. DESIGN: HBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients. RESULTS: Severely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2. CONCLUSIONS: The possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability.

Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B.

BACKGROUND & AIMS: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies. METHODS: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed. RESULTS: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function. CONCLUSIONS: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection. IMPACT AND IMPLICATIONS: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models.

Carotid endarterectomy in asymptomatic octogenarians: Outcomes at 30 days and 5 years.

BACKGROUND: The following study investigated the 30-day and 5-year relative survival rate and freedom from neurological events in asymptomatic carotid stenosis (ACS) octogenarians who had undergone elective carotid endarterectomy (CEA). METHODS: Between January 2008 and June 2014, a retrospective review was conducted on ACS patients who had undergone elective CEA. The patients' sample was divided into two groups: Group A (GA) included octogenarians and Group B (GB) included younger patients. The GA patients were subjected to a risk-scoring system and follow-up. The two groups were compared analysing the following primary endpoints: 30-day mortality, stroke, stroke/death and acute myocardial infarction (AMI); GA patients' survival rate and freedom from neurological events at 5 years. The 30-day secondary endpoints included carotid shunting, redo surgical, need for general anaesthesia with preserved consciousness (GAPC) conversion and length of hospital stay. RESULTS: We identified 620 patients with ACS, of them 144 (23.2%) belonged to the GA and 476 (76.8%) belonged to the GB. No statistical difference between the two groups was found regarding the primary and secondary endpoints. One hundred nineteen of 144 GA patients (82.6%) underwent the follow-up; the median follow-up was 78.3 months. The GA patients' 5-year survival rate was 62%, while freedom from cerebral events was 94.9%. Analysis regarding GA patients' 5-year survival rate revealed a significantly lower percentage among the patients with a severe risk score compared with those with a moderate risk score (respectively, 29.5% vs 67.7%; p = .005). The multivariate analysis showed that chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD) were independently associated with lower survival. CONCLUSIONS: The 30-day outcomes of CEA in octogenarians are comparable to those in younger patients. Comprehensive life expectancy and preoperative score, rather than age alone, should be taken into account before performing CEA on octogenarian patients, considering the short- and long-term efficacy in stroke prevention.

Clinical characteristics of a large cohort of patients with narcolepsy candidate for pitolisant: a cross-sectional study from the Italian PASS Wakix® Cohort.

INTRODUCTION: Narcolepsy is a chronic and rare hypersomnia of central origin characterized by excessive daytime sleepiness and a complex array of symptoms as well as by several medical comorbidities. With growing pharmacological options, polytherapy may increase the possibility of a patient-centered management of narcolepsy symptoms. The aims of our study are to describe a large cohort of Italian patients with narcolepsy who were candidates for pitolisant treatment and to compare patients' subgroups based on current drug prescription (drug-naïve patients in whom pitolisant was the first-choice treatment, switching to pitolisant from other monotherapy treatments, and adding on in polytherapy). METHODS: We conducted a cross-sectional survey based on Italian data from the inclusion visits of the Post Authorization Safety Study of pitolisant, a 5-year observational, multicenter, international study. RESULTS: One hundred ninety-one patients were enrolled (76.4% with narcolepsy type 1 and 23.6% with narcolepsy type 2). Most patients (63.4%) presented at least one comorbidity, mainly cardiovascular and psychiatric. Pitolisant was prescribed as an add-on treatment in 120/191 patients (62.8%), as switch from other therapies in 42/191 (22.0%), and as a first-line treatment in 29/191 (15.2%). Drug-naive patients presented more severe sleepiness, lower functional status, and a higher incidence of depressive symptoms. CONCLUSION: Our study presents the picture of a large cohort of Italian patients with narcolepsy who were prescribed with pitolisant, suggesting that polytherapy is highly frequent to tailor a patient-centered approach.

The risk of lymph node metastasis in T1 colorectal cancer: new parameters to assess the degree of submucosal invasion.

PURPOSE: In T1 colorectal cancer, the depth is the main factor assessing the degree of submucosal invasion (DSI) to predict the risk of lymph node metastasis (LNM). The width (WSI) and the area of submucosal invasion (ASI) have been suggested as additional parameters to assess the risk of LNM. A review of the literature was undertaken on the correlation between WSI and ASI parameters and the incidence of LNM. METHODS: A Medline, PubMed, and Cochrane Library search was performed to retrieve all studies reporting correlation between WSI/ASI and risk of LNM in T1 colorectal cancer. RESULTS: Eight studies including 1727 patients were identified. All considered the degree of WSI and its influence on LNM: seven assessed different width cut-off of submucosal invasion, and one study the mean width of submucosal invasion in patients having or not involved lymph nodes. The WSI was significantly a prognostic factor for LNM (p < 0.05) in four studies. Both 2 and 3 mm seem to be the most discriminatory cut-off values of submucosal width invasion in defining the risk difference of LNM above and below the cut-off (2 mm, OR = infinite; 3 mm, OR = 6.9). Patients having a cut-off ≤ 5 mm of WSI showed a low risk (5.6%) of LNM rendering radical surgery unnecessary. Four studies assessed the risk of LNM according to the involved submucosal area (width × depth). In two of these, the ASI was a significant prognostic factor for LNM (p < 0.05). CONCLUSION: The WSI and ASI seem to be reliable prognostic factors for LNM in T1 colorectal cancer. There is no agreement on ideal cut-off value.

Sorafenib and hepatocellular carcinoma: is alpha-fetoprotein a biomarker predictive of tumor biology and primary resistance?

Background: Alpha-fetoprotein (AFP) is the only biomarker with proven prognostic value in advanced hepatocellular carcinoma. Preliminary data indicate crosstalk between AFP and VEGF signaling. Methods: The authors looked at 69 patients with advanced hepatocellular carcinoma who were previously tested for VEGFR2 expression, had available baseline AFP serum concentrations and were treated with sorafenib within clinical trials. Results: Shorter progression-free survival and overall survival were associated with increased AFP level and elevated VEGFR2 staining. At multivariate analysis of AFP level was the only independent prognostic factor for progression-free survival and overall survival. Conclusion: The authors' study confirms the adverse prognostic role of elevated baseline AFP and also suggests a possible role of AFP in primary resistance to sorafenib therapy.

Lay abstract Alpha-fetoprotein (AFP) is a plasma protein commonly used as a tumor marker for hepatocellular carcinoma. Sorafenib is a targeted therapy used to block the growth of cancer cells in several ways. It affects various proteins on the surface of cancer cells as well as targets inside the cell. Some of these targets are involved in tumor angiogenesis (growth of new blood vessels). In the present analysis, elevated AFP plasma levels before starting sorafenib therapy were correlated with inferior survival compared with patients with low AFP levels, thus suggesting a possible role of AFP in resistance to sorafenib therapy. Using a specific antibody, the authors also studied the expression on cancer cells of VEGFR2, which is a protein involved in angiogenesis and one of the targets of sorafenib. No correlation was found between AFP level and VEGFR2 expression. The underlying mechanisms involved in resistance to sorafenib therapy still need to be clarified and deserve further studies.

Efficacy and tolerability of short contact therapy with tretinoin, clindamycin, and glycolic acid gel in acne: A randomized, controlled, assessor-blinded two-center trial: The MASCOTTE study.

Retinoids and antibiotics topical treatments are commonly used as first line therapy in mild to moderate acne. However, irritant contact dermatitis is a common side effect of topical retinoids. A strategy to increase local tolerability is the "short contact therapy" (SCT) approach, consisting in the application of the product with the complete removal after 30 to 60 minutes using a non-aggressive cleanser. A gel containing tretinoin 0.02%, clindamycin 0.8%, and glycolic acid 4% in polyvinyl alcohol (MP-gel) has shown to be effective as monotherapy in mild to moderate acne with a tolerability profile similar to other topical retinoids. So far, no trials have been performed with this gel comparing the tolerability profile of SCT with standard application therapy (SAT). We conducted a 2-center randomized parallel groups, controlled, assessor-blinded study, comparing MP-gel applied as SCT in comparison with MP-gel used as SAT (The "MASCOTTE" trial). Forty-six subjects (nine men and 37 women, mean age 23 ± 4 years, range 18-31 years) with mild-to-moderate acne were enrolled, after their written informed consent in a randomized, parallel groups controlled, assessor-blinded 8-week trial. Twenty-three were assigned to MP-gel once daily (evening application) using the SCT approach (ie, complete removal of product after 1 hour using a gentle cleanser), and 23 were randomized to the SAT approach with the same gel. The primary endpoint was the evolution of the tolerability score (TS) assessed evaluating four items: erythema, dryness, stinging, and burning, using a 4-point score scale (from 0: no symptom to 3: severe symptom). Secondary endpoints were the evolution of global acne grading system (GAGS) score (range: from 0 to >39) and the investigator global assessment (IGA of acne severity) score (range from 0 to 4). TS was evaluated at 2, 4, and 8 weeks. GAGS and IGA scores were evaluated at baseline and at week eight. At week eight, an efficacy global score (EGS) (from 1: no efficacy to 4: very good efficacy) and a tolerability global score (TGS) (from 1: very low tolerability to 3: very good tolerability) evaluation were also done. All the evaluations were performed by an investigator unaware of treatment groups allocation (SCT or SAT). Thirty-eight subjects (83%) completed the 8-week treatment period. Eight subjects (two in the SCT group and six in the SAT group) dropped out prematurely due to low skin tolerability. In the SCT the TS at week two was 1.3 ± 1.7, in the SAT group TS was significantly higher (3.1 ± 1.7) (P = .028). TS was significantly lower in SCT group vs SAT also at weeks four and eight (P = .01; ANOVA test). The GAGS score at baseline was 19 ± 7 in the SCT group and 23 ± 4 in the SAT group (NS). At week 8 the GAGS score in SCT was significantly reduced to 8.5 ± 2.8 (-55%) (P = .001 vs baseline) and was also significantly lower in comparison with SAT group (8.5 vs 15; P = .0054). The IGA scores at baseline were 1.9 ± 0.6 in SCT and 2.4 ± 0.7 in SAT group. At week eight, in comparison with baseline values IGA score was reduced significantly by 48% in SCT and by 30% in SAT. EGS and TGS were significantly higher (better clinical efficacy and better tolerability) in SCT in comparison with SAT (3.6 ± 0.5 and 2.9 ± 0.3 vs 2.7 ± 0.6 and 1.5 ± 0.7; respectively). This tretinoin, clindamycin, glycolic acid gel, applied as SCT, has shown a better skin tolerability and at least a comparable clinical efficacy in comparison with the standard application modality in the treatment of mild-to-moderate acne. The SCT therefore could be an effective treatment strategy which could improve subjects' compliance and adherence.

Evaluation of masticatory function in patients with cleft lip and/or palate.

The aim of this study was to evaluate the masticatory pattern in children with cleft lip and/or palate (CL/P) through investigation of the prevalence of reverse sequencing chewing cycles. The study group included 18 patients with CL/P (mean age: 7.4 yr, SD: 1.4 yr), 15 of whom had dental crossbite. The controls included a group of 18 non-CL/P children with the same types of crossbite as the study group (mean age: 7.2 yr, SD: 1.5 yr) and a group of 18 non-CL/P subjects with normal occlusion (mean age: 9.8 yr, SD: 1.9 yr). Mandibular movements during chewing of soft and hard bolus were recorded with a kinesiograph. Kinematic signals were analysed using a custom-made software. A statistical analysis was performed to compare the degree of reverse-sequencing chewing cycles between patients and controls (Kruskal-Wallis test with Dwass-Steel-Critchlow-Fligner pairwise comparisons post hoc test). A significant difference between patients with CL/P and non-CL/P subjects with normal occlusion was highlighted on the left side of mastication, which was the side with the higher prevalence of crossbite with both types of bolus. No statistical differences were found between CL/P patients and healthy controls with crossbite. Cleft-affected patients with posterior crossbite exhibited an anomalous masticatory pattern with increased reverse chewing cycles on the crossbite side.

Pneumothorax and pulmonary hemorrhage after CT-guided lung biopsy: incidence, clinical significance and correlation.

OBJECTIVES: To evaluate the incidence and clinical significance of pneumothorax (PTX) and pulmonary hemorrhage (PH) after CT-guided lung biopsy (CT-LB). To test correlations of PTX and chest tube insertion (CTI) with PH and other imaging and procedural parameters. METHODS: Pre-procedural CT and CT-LB scans of 904 patients were examined. Incidence of PTX and PH and PH location (type-1 along needle track; type-2 perilesional) and severity according to its thickness (low grade < 6 mm; high grade > 6 mm) were recorded. PTX was considered clinically significant if treated with CTI, PH if treated with endoscopic/endovascular procedure. Binary logistic regression analyses were used to determine the effects of different imaging and procedural parameters on the likelihood to develop PTX, CTI and PH and to define their correlation. RESULTS: PTX occurred in 306/904 cases (33.8%); CTI was required in 18/306 (5.9%). PH occurred in 296/904 cases (32.7%), and no case required treatment. Nodule-to-pleura distance (ORPTX = 1.052; ORCTI = 1.046; ORPH 1.077), emphysema (ORPTX = 1.287; ORPH = 0.573), procedure time (ORPTX = 1.019; ORCTI = 1.039; ORPH = 1.019), target size (ORPTX = 0.982; ORPH = 0.968) and needle gauge (ORPTX = 0.487; ORCTI = 4.311; ORPH = 2.070) showed statistically significant correlation to PTX, CTI and PH. Type-1 PH showed a protective effect against PTX and CTI (ORPTX = 0.503; ORCTI = 0.416). CONCLUSION: PTX and PH have similar incidence after CT-guided lung biopsy. PH along needle track may represent a protective factor against development of PTX and against PTX requiring CTI.

Combined GS-4774 and Tenofovir Therapy Can Improve HBV-Specific T-Cell Responses in Patients With Chronic Hepatitis.

BACKGROUND & AIMS: One strategy to treat chronic hepatitis B virus (HBV) infection could be to increase the functions of virus-specific T cells. We performed a multicenter phase 2 study to evaluate the safety and efficacy of GS-4774, a yeast-based therapeutic vaccine engineered to express HBV antigens, given with tenofovir disoproxil fumarate (TDF) to untreated patients with chronic HBV infection. METHODS: We performed an open-label study at 34 sites in Canada, Italy, New Zealand, Romania, South Korea, and United States from July 2014 to August 2016. Adults who were positive for HB surface antigen (HBsAg) > 6 months and levels of HBV DNA ≥2000 IU/mL who had not received antiviral treatment for HBV within 3 months of screening were randomly assigned (1:2:2:2) to groups given oral TDF 300 mg daily alone (n = 27; controls) or with 2, 10, or 40 yeast units GS-4774 (n = 168), administered subcutaneously every 4 weeks until week 20 for a total of 6 doses. Blood samples were collected and analyzed and patients received regular physical examinations. Efficacy was measured by decrease in HBsAg from baseline to week 24. Specific responses to HBV (production of interferon gamma [IFNG], tumor necrosis factor [TNF], interleukin 2 [IL2], and degranulation) were measured in T cells derived from 12 HBeAg-negative patients with genotype D infections, after overnight or 10 days of stimulation of peripheral blood mononuclear cells with peptides from the entire HBV proteome. T-regulatory cells were analyzed for frequency and phenotype. Data from studies of immune cells were compared with data on reductions in HBsAg, HBV DNA, and alanine aminotransferase in blood samples from patients. RESULTS: GS-4774 was safe and well tolerated but did not produce significant decreases in levels of HBsAg. Production of IFNG, TNF, and IL2 increased significantly at weeks 24 and 48, compared with baseline, in HBV-specific CD8+ T cells from patients given GS-4774 but not from controls. GS-4774 had greater effects on CD8+ than CD4+ T cells, which were not affected at all or very weakly by TDF with or without GS-4774. GS-4774 did not affect responses of T cells to other viruses tested. HBV core peptides induced the greatest production of IFNG by T cells following overnight stimulation, whereas HBV envelope antigens did not induce a response. Following 10 days of stimulation, production of IFNG and TNF increased with time of exposure to GS-4774; the greatest levels of responses were to HBV envelope antigens followed by core and polymerase peptides. We observed a correlation in patients given GS-4774 between increased T-cell functions and reductions in numbers of T-regulatory cells. CONCLUSIONS: In a phase 2 study of patients with chronic HBV infection given TDF with or without GS-4774, we found that vaccination can increase production of IFNG, TNF, and IL2 by CD8+ T cells exposed to antigenic peptides, with little effect on CD4+ T cells. Although GS-4774 did not reduce levels of HBsAg in patients, its strong immune stimulatory effect on CD8+ T cells might be used in combination with other antiviral agents to boost the antivirus immune response. Clinicaltrials.gov no: NCT02174276.

Do acne treatments affect insulin-like growth factor-1 serum levels? A clinical and laboratory study on patients with acne vulgaris.

Acne is a chronic inflammatory disease affecting sebaceous gland follicles. Lately, acne has considered an insulin-like growth factor-1 (IGF-1) mediated disease. Recent research demonstrated that IGF-1 levels decrease after 3 months of isotretinoin. The purpose of our study is evaluating the influence of acne treatments on IGF-1 serum levels. Forty-six subjects with acne vulgaris aged 14 to 30 years were subdivided into three groups according to their severity of acne and treated following the European Dermatology Forum guidelines. IGF-1 was measured in patients before and after the treatment and then compared to the IGF-1 of a healthy population of the same age. IGF-1 resulted higher in patients than in controls but there was not a statistically significant variation after treatment. To the best of our knowledge, this is the first study evaluating the influence of topical and systemic acne treatment on IGF-1 serum levels. In contrast with the literature, our results suggest that common therapies for acne are not able to significantly modify IGF-1 serum levels.

Histopathological determinants of autofluorescence patterns in oral carcinoma.

Biological tissues (including oral mucosa) can absorb and re-emit specific light wavelengths, detectable through spectrophotometric devices. Such a phenomenon is known as "autofluorescence" (AF). Several devices evaluating tissue AF have been developed and commercialized in the last two decades. Among these, the VELscope® system has been proposed as a visual diagnostic aid for potentially malignant disorders and malignant lesions of the oral mucosa. In the present pilot study, we investigated which are the main histopathological features possibly related to variations in AF patterns in a set of 20 oral squamous cell verrucous carcinoma. Among all the histological features investigated, only the mean width of keratin was significantly different between hypofluorescent and hyperfluorescent carcinomas. The results of the present study demonstrate that AF features of oral malignant lesions are significantly associated with the width of their keratin layer.

Incidence of Epilepsy after Neonatal Seizures: A Population-Based Study.

BACKGROUND: The incidence of childhood and adolescence epilepsy varies in different areas and over time. Published reports in the Italian pediatric population are few and there is no information on the incidence of epilepsy using the new clinical definition of the disease signed by the International League Against Epilepsy. An increased risk of epilepsy is reported in subjects who presented with neonatal seizures (NS), but few population-based studies are available that compare incidence and age at onset of epilepsy in children with and without NS. OBJECTIVES: Ascertain the incidence of epilepsy in children in the province of Parma by applying the new practical clinical definition of epilepsy, and compare incidence and age of epilepsy onset in children with and without previous NS. METHODS: The study was carried out in the province of Parma, Emilia-Romagna Region, Northern Italy, using different data sources (clinical records and administrative data), and considered all the children born in the province of Parma between January 2002 and December 2014 and developing epilepsy by December 2016. We calculated the incidence of epilepsy in patients up to 14 years of age, incidence of epilepsy after NS and cumulative incidence of epilepsy at 1, 5, and 10 years' follow-up. To evaluate age at onset of epilepsy, we divided patients into 3 groups (epilepsy onset within 1 month, between 1 and 12 months, and after 1 year of life) and we compared age at onset of epilepsy between patients who had had previous NS and those who had not. RESULTS: The incidence of epilepsy was 78.6/100,000 persons-years (boys 88.1/100,000, girls 68.6/100,000). The incidence of epilepsy after NS was 15.2% (8.2% for male, 23.5% for female; 16.3% in born at term, 14.3% in pre-term). The incidence of epilepsy at 1, 5, and 10 years' follow-up was higher in patients with previous NS than in others. The age at onset of epilepsy was significantly different in the 2 groups, and was younger in those with history of NS: mean age at onset was 10.5 months in those with NS and of 61.8 months in the others. CONCLUSIONS: The incidence rate of epilepsy in the Parma district was higher than that reported in other Italian areas studied, probably due to the different methodology used and the application of the most recent definition of epilepsy. Children with NS were at higher risk of epilepsy and develop the disease at a younger age.

Maternal cardiac parameters can help in differentiating the clinical profile of preeclampsia and in predicting progression from mild to severe forms.

BACKGROUND: A primary role of maternal heart dysfunction in the pathophysiology of preeclampsia had been previously advocated although if contradictory results have been reported. OBJECTIVES: The objectives of the study were to describe maternal hemodynamic parameters according to 2 main preeclampsia phenotypes and to investigate whether cardiac findings may be helpful in characterizing the severity and the progression of the disease. STUDY DESIGN: This was a prospective cohort study. We used an ultrasonic cardiac output monitor system to compare the hemodynamic parameters of women with preeclampsia with a group of healthy normotensive women enrolled as controls with a ratio of 1:2. Cardiac output, systemic vascular resistance, and stroke volume were compared among controls and preeclamptic women who were grouped in accordance to the following characteristics: early preeclampsia (<34 weeks' gestation) vs late preeclampsia onset (≥34 weeks' gestation); preeclampsia associated with appropriate for gestational age or small-for-gestational-age newborns. Hemodynamic characteristics were also compared between preeclamptic women with a mild form vs those who progressed toward a severe form. RESULTS: A total of 38 preeclamptic women and 61 normotensive women were included in the study. Both cases of preeclampsia associated with small-for-gestational-age neonates as those with normal-sized ones showed higher systemic vascular resistance compared with the control group (respectively, 1580.6 ± 483.2 vs 1479.1 ± 433.3 vs 1105.3 ± 293.1; P < .0001), while a lower cardiac output was reported only for preeclamptic women with small-for-gestational-age neonates compared with controls (5.7 ± 1.5 vs 6.5 ± 1.3; P = .02). Maternal cardiac parameters were comparable between these 2 groups of preeclamptic women (small-for-gestational-age vs appropriate-for-gestational-age preeclampsia) with the exception of a lower stroke volume in the former one (64.8 ± 24.4 vs 75.2 ± 17.8; P = .04). Similarly, women with both early and late preeclampsia showed higher systemic vascular resistance compared with controls (1559.5 ± 528.3 vs 1488.5 ± 292.9 vs 1105.3 ± 293.1, respectively; P < .001), while a lower cardiac output was noted only in the early-onset group compared with controls (5.5 ± 1.2 P = .02). Maternal cardiac findings were similar between women with early vs late-onset preeclampsia. Hemodynamic parameters are significantly different between those women with mild preeclampsia who remained stable compared with those who progressed toward a severe disease. Cardiac output Z-score, systemic vascular resistance Z-score, and uterine arteries' pulsatility index Z-score showed similar sensitivity (80% vs 75% vs 80%, respectively) and specificity (73% vs. 73% vs 74%, respectively), while the association of systemic vascular resistance Z-score and uterine arteries pulsatility index Z-score showed a sensitivity of 95% and a specificity of 80% (area under the curve, 0.90) in predicting evolution toward severe forms. CONCLUSION: Evaluation of maternal cardiovascular system could help clinician in defining a subset of preeclamptic patients with more profound placental impairment and might predict the likelihood of progression toward a severe condition in cases with a mild preeclampsia at clinical onset.

The cellular effects of Pulsed Electromagnetic Fields on osteoblasts: A review.

Electromagnetic fields (EMFs) have long been known to interact with living organisms and their cells and to bear the potential for therapeutic use. Among the most extensively investigated applications, the use of Pulsed EMFs (PEMFs) has proven effective to ameliorate bone healing in several studies, although the evidence is still inconclusive. This is due in part to our still-poor understanding of the mechanisms by which PEMFs act on cells and affect their functions and to an ongoing lack of consensus on the most effective parameters for specific clinical applications. The present review has compared in vitro studies on PEMFs on different osteoblast models, which elucidate potential mechanisms of action for PEMFs, up to the most recent insights into the role of primary cilia, and highlight the critical issues underlying at least some of the inconsistent results in the available literature. Bioelectromagnetics. 2019;9999:XX-XX. © 2019 Bioelectromagnetics Society.

Postoperative hypocalcemia: analysis of factors influencing early hypocalcemia development following thyroid surgery.

BACKGROUND: Early Hypocalcemia is the most frequent complication after thyroid surgery. Several studies have tried to identify factors (patient caracteristics or surgical technique variations) affecting hypocalcemia following thyroid surgery. This studiy evaluates the role of several factors in postoperative hypocalcemia development. METHODS: A retrospective study conducted on 2108 patients that underwent thyroid surgery in a single center (1669 women and 439 men). Postoperative early hypocalcemia was defined as serum calcium levels lower than 8,0 mg/dl measured 24 h after surgery. Following factors were evaluated in the study: sex, age, glandular hyperfunction, preoperative diagnosis, preoperative serum calcium levels, preoperative serum PTH levels, type of surgery performed (total thyroidectomy vs. lobectomy); minimally invasive video assisted thyroidectomy (MIVAT); number of parathyroid preserved in situ, postoperative serum calcium levels, changes in perioperative calcium levels (difference between preoperative values ​​and postoperative calcium levels), presence of carcinoma in the surgical specimen, presence of thyroiditis based on histopatology reports. RESULTS: Among evaluated factors only gender and surgical procedure revealed to be significantly correlated to early hypocalcemia development. In fact female patients experienced postoperative hypocalcemia in 42% (701/1669) of cases, which was signicantly higher than the 21.4% (94/439) identified in men. We also noticed a greater hypocalcemia incidence in patient undergoing total thyroidectomy (38.8%) than in patient undergoing lobectomy group (13.8%). Early hypocalcemia development didn't appear to be related to preoperative serum calcium levels but it showed a statistically significant correlation with perioperative serum calcium level drop. CONCLUSION: This findings suggest that sex (female gender is a strong risk factor),surgical procedure and perioperative changes in serum calcium are the only factors (among all variables examined) that influence early hypocalcemia development.

The Effect of Chorionicity on Maternal Cardiac Adaptation to Uncomplicated Twin Pregnancy: A Prospective Longitudinal Study.

OBJECTIVE: The objective of this study was to longitudinally evaluate maternal echocardiographic findings in uncomplicated twin gestations according to chorionicity. METHODS: Healthy women with twin pregnancy were assessed with transthoracic echocardiography across the first, second, and third trimesters. Cardiac findings were compared within each group and between monochorionic (MC) and dicho-rionic (DC) pregnancies. RESULTS: Overall, 19 MC and 48 DC uncomplicated twin pregnancies were included. In the MC group, no significant maternal haemodynamic changes were documented across gestation, with the exception of a decrease in ejection fraction. Compared to DC pregnancies, in the MC set lower cardiac output (second and third trimester, p = 0.001 and p = 0.006, respectively) and higher total vascular resistance (first trimester, p = 0.032) were observed. Regarding the diastolic function in MC twins, significantly higher values were observed for mitral E/A ratio (third trimester, p = 0.014), septal mitral E1/A1 ratio (third trimester, p = 0.030), lateral mitral E1 (second and third trimester, p = 0.014 and p = 0.029, respectively), and E1/A1 ratio (third trimester, p = 0.006). CONCLUSIONS: Maternal cardiac adaptation in twin pregnancy seems to differ significantly according to chorionicity. In particular, in MC pregnancies the impairment of diastolic function is less pronounced, presumably due to the lower circulating volume.